| <!DOCTYPE html> |
| <html lang="en-US"> |
| <head> |
| <meta charset="UTF-8"> |
| <title>891075d1-b60e-43c2-9ebf-b03e781c2ea4</title> |
| <meta name="viewport" content="width=device-width, initial-scale=1"> |
| <link rel="stylesheet" href="https://cdn.mathpix.com/fonts/cmu.css"/> |
| <style>html,body { |
| width: 100%; |
| height: 100%; |
| } |
| *, *::before,*::after { |
| box-sizing: border-box; |
| } |
| body { |
| margin: 0; |
| color: #1E2029; |
| font-size: 14px; |
| line-height: normal; |
| } |
| hr { |
| box-sizing: content-box; |
| height: 0; |
| overflow: visible; |
| } |
| h1, h2, h3, h4, h5, h6 { |
| margin-top: 0; |
| margin-bottom: 0.5em; |
| color: rgba(0, 0, 0, 0.85); |
| font-weight: 500; |
| } |
| p { |
| margin-top: 0; |
| margin-bottom: 1em; |
| } |
| ol, ul, dl { |
| margin-top: 0; |
| margin-bottom: 1em; |
| } |
| ol ol, ul ul, ol ul, ul ol { |
| margin-bottom: 0; |
| } |
| dt { |
| font-weight: 500; |
| } |
| dd { |
| margin-bottom: 0.5em; |
| margin-left: 0; |
| } |
| blockquote { |
| margin: 0 0 1em; |
| } |
| dfn { |
| font-style: italic; |
| } |
| b, strong { |
| font-weight: bolder; |
| } |
| small { |
| font-size: 80%; |
| } |
| sub, sup { |
| position: relative; |
| font-size: 75%; |
| line-height: 0; |
| vertical-align: baseline; |
| } |
| sub { |
| bottom: -0.25em; |
| } |
| sup { |
| top: -0.5em; |
| } |
| a { |
| color: #0B93ff; |
| text-decoration: none; |
| background-color: transparent; |
| outline: none; |
| cursor: pointer; |
| transition: color 0.3s; |
| } |
| a:hover { |
| color: #33aaff; |
| } |
| a:active { |
| color: #0070d9; |
| } |
| a:active, a:hover { |
| text-decoration: none; |
| outline: 0; |
| } |
| a[disabled] { |
| color: rgba(0, 0, 0, 0.25); |
| cursor: not-allowed; |
| pointer-events: none; |
| } |
| pre, code, kbd, samp { |
| font-size: 1em; |
| } |
| pre { |
| margin-top: 0; |
| margin-bottom: 1em; |
| overflow: auto; |
| } |
| figure { |
| margin: 0 0 1em; |
| } |
| img { |
| vertical-align: middle; |
| border-style: none; |
| } |
| svg:not(:root) { |
| overflow: hidden; |
| } |
| table { |
| border-collapse: collapse; |
| } |
| caption { |
| padding-top: 0.75em; |
| padding-bottom: 0.3em; |
| color: rgba(0, 0, 0, 0.45); |
| text-align: left; |
| caption-side: bottom; |
| } |
| th { |
| text-align: inherit; |
| } |
| mjx-container[jax="SVG"] { |
| direction: ltr; |
| } |
| |
| mjx-container[jax="SVG"] > svg { |
| overflow: visible; |
| min-height: 1px; |
| min-width: 1px; |
| } |
| |
| mjx-container[jax="SVG"] > svg a { |
| fill: blue; |
| stroke: blue; |
| } |
| |
| mjx-container[jax="SVG"][display="true"] { |
| display: block; |
| text-align: center; |
| margin: 1em 0; |
| } |
| |
| mjx-container[jax="SVG"][display="true"][width="full"] { |
| display: flex; |
| } |
| |
| mjx-container[jax="SVG"][justify="left"] { |
| text-align: left; |
| } |
| |
| mjx-container[jax="SVG"][justify="right"] { |
| text-align: right; |
| } |
| |
| g[data-mml-node="merror"] > g { |
| fill: red; |
| stroke: red; |
| } |
| |
| g[data-mml-node="merror"] > rect[data-background] { |
| fill: yellow; |
| stroke: none; |
| } |
| |
| g[data-mml-node="mtable"] > line[data-line], svg[data-table] > g > line[data-line] { |
| stroke-width: 70px; |
| fill: none; |
| } |
| |
| g[data-mml-node="mtable"] > rect[data-frame], svg[data-table] > g > rect[data-frame] { |
| stroke-width: 70px; |
| fill: none; |
| } |
| |
| g[data-mml-node="mtable"] > .mjx-dashed, svg[data-table] > g > .mjx-dashed { |
| stroke-dasharray: 140; |
| } |
| |
| g[data-mml-node="mtable"] > .mjx-dotted, svg[data-table] > g > .mjx-dotted { |
| stroke-linecap: round; |
| stroke-dasharray: 0,140; |
| } |
| |
| g[data-mml-node="mtable"] > g > svg { |
| overflow: visible; |
| } |
| |
| [jax="SVG"] mjx-tool { |
| display: inline-block; |
| position: relative; |
| width: 0; |
| height: 0; |
| } |
| |
| [jax="SVG"] mjx-tool > mjx-tip { |
| position: absolute; |
| top: 0; |
| left: 0; |
| } |
| |
| mjx-tool > mjx-tip { |
| display: inline-block; |
| padding: .2em; |
| border: 1px solid #888; |
| font-size: 70%; |
| background-color: #F8F8F8; |
| color: black; |
| box-shadow: 2px 2px 5px #AAAAAA; |
| } |
| |
| g[data-mml-node="maction"][data-toggle] { |
| cursor: pointer; |
| } |
| |
| mjx-status { |
| display: block; |
| position: fixed; |
| left: 1em; |
| bottom: 1em; |
| min-width: 25%; |
| padding: .2em .4em; |
| border: 1px solid #888; |
| font-size: 90%; |
| background-color: #F8F8F8; |
| color: black; |
| } |
| |
| foreignObject[data-mjx-xml] { |
| font-family: initial; |
| line-height: normal; |
| overflow: visible; |
| } |
| |
| mjx-container[jax="SVG"] path[data-c], mjx-container[jax="SVG"] use[data-c] { |
| stroke-width: 3; |
| } |
| #setText > div { |
| justify-content: inherit; |
| margin-top: 0; |
| margin-bottom: 1em; |
| |
| |
| } |
| #setText div:last-child { |
| margin-bottom: 0 !important; |
| } |
| #setText > br, #preview-content br { |
| line-height: 1.2; |
| } |
| #preview-content > div { |
| margin-top: 0; |
| margin-bottom: 1em; |
| |
| } |
| .proof > div, |
| #preview-content .proof > div, #setText .proof > div, |
| .theorem > div, |
| #preview-content .theorem > div, #setText .theorem > div { |
| margin-top: 1rem; |
| } |
| mjx-container { |
| text-indent: 0; |
| overflow-y: hidden; |
| overflow-x: auto; |
| padding-top: 1px; |
| padding-bottom: 1px; |
| |
| } |
| .math-inline mjx-container { |
| display: inline-block !important; |
| page-break-inside: avoid; |
| max-width: 100%; |
| padding: 0; |
| line-height: 0; |
| } |
| .math-inline[data-overflow="visible"] mjx-container { |
| overflow: visible; |
| } |
| .math-inline mjx-container mjx-assistive-mml { |
| max-width: 100%; |
| } |
| .math-block { |
| align-items: center; |
| page-break-after: auto; |
| page-break-inside: avoid; |
| margin: 0; |
| display: block; |
| } |
| .math-inline { |
| display: inline-flex; |
| max-width: 100%; |
| } |
| .math-block[data-width="full"] { |
| overflow-x: auto; |
| display: flex; |
| } |
| .math-block[data-width="full"] mjx-container[jax=SVG][display=true] { |
| display: flex; |
| flex: 1 1; |
| justify-content: center; |
| } |
| svg .math-inline { |
| display: initial; |
| max-width: initial; |
| } |
| svg .math-inline mjx-container { |
| max-width: initial; |
| } |
| svg mjx-container { |
| overflow: visible; |
| padding: 0; |
| } |
| svg .math-block[data-width="full"] { |
| overflow: visible; |
| } |
| .math-block, .math-inline { |
| --mmd-highlight-color: rgba(0, 147, 255, 0.25); |
| --mmd-highlight-text-color: #1e2029; |
| } |
| .math-block[data-highlight-color] mjx-container[jax="SVG"] > svg { |
| background-color: var(--mmd-highlight-color); |
| } |
| .math-block[data-highlight-text-color] mjx-container[jax="SVG"] > svg { |
| color: var(--mmd-highlight-text-color); |
| } |
| .math-inline[data-highlight-color] mjx-container[jax="SVG"] { |
| background-color: var(--mmd-highlight-color); |
| } |
| .math-inline[data-highlight-text-color] mjx-container[jax="SVG"] { |
| color: var(--mmd-highlight-text-color); |
| } |
| .math-block p { |
| flex-shrink: 1; |
| } |
| .math-block mjx-container { |
| margin: 0 !important; |
| } |
| .math-error { |
| background-color: yellow; |
| color: red; |
| } |
| #preview-content img, #setText img { |
| max-width: 100%; |
| } |
| #preview-content blockquote, #setText blockquote { |
| page-break-inside: avoid; |
| color: #666; |
| margin: 0 0 1em 0; |
| padding-left: 3em; |
| border-left: .5em solid #eee; |
| } |
| #preview-content pre, #setText pre { |
| border: none; |
| padding: 0; |
| overflow: auto; |
| font-size: 85%; |
| line-height: 1.45; |
| border-radius: 6px; |
| box-sizing: border-box; |
| background: #f8f8fa; |
| } |
| #preview-content pre code, #setText pre code { |
| padding: 1rem; |
| display: block; |
| overflow-x: auto; |
| line-height: 24px; |
| } |
| #preview-content table, #setText table { |
| display: table; |
| overflow: auto; |
| max-width: 100%; |
| border-collapse: collapse; |
| page-break-inside: avoid; |
| margin-bottom: 1em; |
| } |
| #preview-content table th, #setText table th { |
| text-align: center; |
| font-weight: bold; |
| } |
| #preview-content table td, #setText table td, |
| #preview-content table th, #setText table th { |
| border: 1px solid #dfe2e5; |
| padding: 6px 13px; |
| } |
| #preview-content table tr, #setText table tr { |
| background-color: #fff; |
| border-top: 1px solid #c6cbd1; |
| } |
| #preview-content table tr:nth-child(2n), #setText table tr:nth-child(2n) { |
| background-color: #f6f8fa; |
| } |
| .main-title, |
| #preview-content .main-title, #setText .main-title { |
| text-align: center; |
| line-height: 1.2; |
| margin: 0 auto 1em auto; |
| } |
| .author, |
| #preview-content .author, #setText .author { |
| text-align: center; |
| margin: 0 auto; |
| display: flex; |
| justify-content: center; |
| flex-wrap: wrap; |
| } |
| .author p, |
| #preview-content .author p, #setText .author p { |
| min-width: 30%; |
| max-width: 50%; |
| padding: 0 7px; |
| } |
| .author > p > span, |
| #preview-content .author > p > span, #setText .author > p > span { |
| display: block; |
| text-align: center; |
| } |
| .section-title, |
| #preview-content .section-title, #setText .section-title { |
| margin-top: 1.5em; |
| } |
| .abstract, |
| #preview-content .abstract, #setText .abstract { |
| text-align: justify; |
| margin-bottom: 1em; |
| } |
| .abstract p, |
| #preview-content .abstract p, #setText .abstract p { |
| margin-bottom: 0; |
| } |
| #preview-content sup, #setText sup { |
| top: -.5em; |
| position: relative; |
| font-size: 75%; |
| line-height: 0; |
| vertical-align: baseline; |
| } |
| .text-url, |
| #preview-content .text-url, #setText .text-url { |
| color: #0B93ff; |
| cursor: text; |
| pointer-events: none; |
| } |
| .text-url a:hover, |
| #preview-content .text-url a:hover, #setText .text-url a:hover { |
| color: #0B93ff; |
| } |
| mark, |
| #preview-content mark, #setText mark { |
| background-color: #feffe6; |
| } |
| span[data-underline-type] mark, |
| #preview-content span[data-underline-type] mark, |
| #setText span[data-underline-type] mark { |
| background: inherit; |
| background-color: #feffe6; |
| padding-top: 0; |
| padding-bottom: 0; |
| } |
| *[data-has-dotfill] { |
| position: relative; |
| overflow: hidden; |
| } |
| *[data-has-dotfill] .dotfill::after { |
| position: absolute; |
| padding-left: .25ch; |
| content: " . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . " |
| ". . . . . . . . . . . . . . . . . . . . . . . "; |
| text-align: right; |
| } |
| .smiles, |
| #preview-content .smiles, #setText .smiles { |
| text-align: center; |
| } |
| div.svg-container, |
| #preview-content > div.svg-container, |
| #setText > div.svg-container { |
| display: flex; |
| justify-content: center; |
| } |
| @media print { |
| #preview { |
| font-size: 10pt !important; |
| } |
| .math-block svg, .math-inline svg { |
| shape-rendering: crispEdges; |
| margin-top: 1px; |
| } |
| #preview-content img, #setText img { |
| display: block; |
| } |
| #preview-content .figure_img img, #setText .figure_img img { |
| display: inline; |
| } |
| #preview-content h1, #preview-content h2, #preview-content h3, |
| #preview-content h4, #preview-content h5, #preview-content h6, |
| #setText h1, #setText h2, #setText h3, |
| #setText h4, #setText h5, #setText h6 { |
| page-break-inside: avoid; |
| position: relative; |
| border: 2px solid transparent; |
| } |
| #preview-content h1::after, #preview-content h2::after, #preview-content h3::after, |
| #preview-content h4::after, #preview-content h5::after, #preview-content h6::after, |
| #setText h1::after, #setText h2::after, #setText h3::after, |
| #setText h4::after, #setText h5::after, #setText h6::after { |
| content: ""; |
| display: block; |
| height: 100px; |
| margin-bottom: -100px; |
| position: relative; |
| } |
| } |
| #preview-content code, #setText code { |
| font-family: Inconsolata; |
| font-size: inherit; |
| display: initial; |
| background: #f8f8fa; |
| } |
| #preview-content .mmd-highlight code, #setText .mmd-highlight code, |
| #preview-content pre.mmd-highlight code, #setText pre.mmd-highlight code { |
| background-color: transparent; |
| } |
| #preview-content pre code, #setText pre code { |
| font-family: 'DM Mono', Inconsolata, monospace; |
| color: #333; |
| font-size: 15px; |
| } |
| .hljs-comment, .hljs-quote, |
| #preview-content .hljs-comment, #setText .hljs-comment, |
| #preview-content .hljs-quote, #setText .hljs-quote { |
| color: #998; |
| font-style: italic; |
| } |
| .hljs-command, |
| #preview-content .hljs-command, #setText .hljs-command { |
| color: #005cc5; |
| } |
| .hljs-keyword, .hljs-selector-tag, .hljs-subst, |
| #preview-content .hljs-keyword, #setText .hljs-keyword, |
| #preview-content .hljs-selector-tag, #setText .hljs-selector-tag, |
| #preview-content .hljs-subst, #setText .hljs-subst { |
| color: #d73a49; |
| font-weight: bold; |
| } |
| .hljs-number, .hljs-literal, .hljs-variable, |
| .hljs-template-variable, .hljs-tag .hljs-attr, |
| #preview-content .hljs-number, #setText .hljs-number, |
| #preview-content .hljs-literal, #setText .hljs-literal, |
| #preview-content .hljs-variable, #setText .hljs-variable, |
| #preview-content .hljs-template-variable, #setText .hljs-template-variable, |
| #preview-content .hljs-tag .hljs-attr, #setText .hljs-tag .hljs-attr { |
| color: #005cc5; |
| } |
| .hljs-string, .hljs-doctag, |
| #preview-content .hljs-string, #setText .hljs-string, |
| #preview-content .hljs-doctag, #setText .hljs-doctag { |
| color: #24292e; |
| } |
| .hljs-title, .hljs-section, .hljs-selector-id, |
| #preview-content .hljs-title, #setText .hljs-title, |
| #preview-content .hljs-section, #setText .hljs-section, |
| #preview-content .hljs-selector-id, #setText .hljs-selector-id { |
| color: #6f42c1; |
| font-weight: bold; |
| } |
| .hljs-subst, |
| #preview-content .hljs-subst, #setText .hljs-subst { |
| font-weight: normal; |
| } |
| .hljs-type, .hljs-class .hljs-title, |
| #preview-content .hljs-type, #setText .hljs-type, |
| #preview-content .hljs-class .hljs-title, #setText .hljs-class .hljs-title { |
| color: #458; |
| font-weight: bold; |
| } |
| .hljs-tag, .hljs-name, .hljs-attribute, |
| #preview-content .hljs-tag, #setText .hljs-tag, |
| #preview-content .hljs-name, #setText .hljs-name, |
| #preview-content .hljs-attribute, #setText .hljs-attribute { |
| color: #000080; |
| font-weight: normal; |
| } |
| .hljs-regexp, .hljs-link, |
| #preview-content .hljs-regexp, #setText .hljs-regexp, |
| #preview-content .hljs-link, #setText .hljs-link { |
| color: #009926; |
| } |
| .hljs-symbol, .hljs-bullet, |
| #preview-content .hljs-symbol, #setText .hljs-symbol, |
| #preview-content .hljs-bullet, #setText .hljs-bullet { |
| color: #990073; |
| } |
| .hljs-built_in, .hljs-builtin-name, |
| #preview-content .hljs-built_in, #setText .hljs-built_in, |
| #preview-content .hljs-builtin-name, #setText .hljs-builtin-name { |
| color: #24292e; |
| } |
| .hljs-meta, |
| #preview-content .hljs-meta, #setText .hljs-meta { |
| color: #999; |
| font-weight: bold; |
| } |
| .hljs-meta-keyword, |
| #preview-content .hljs-meta-keyword, #setText .hljs-meta-keyword { |
| color: #d73a49; |
| } |
| .hljs-meta-string, |
| #preview-content .hljs-meta-string, #setText .hljs-meta-string { |
| color: #032f62; |
| } |
| .hljs-deletion, |
| #preview-content .hljs-deletion, #setText .hljs-deletion { |
| background: #fdd; |
| } |
| .hljs-addition, |
| #preview-content .hljs-addition, #setText .hljs-addition { |
| background: #dfd; |
| } |
| .hljs-emphasis, |
| #preview-content .hljs-emphasis, #setText .hljs-emphasis { |
| font-style: italic; |
| } |
| .hljs-strong, |
| #preview-content .hljs-strong, #setText .hljs-strong { |
| font-weight: bold; |
| } |
| .table_tabular, |
| #preview-content .table_tabular, #setText .table_tabular { |
| overflow-x: auto; |
| padding: 0 2px 0.5em 2px; |
| } |
| .tabular, |
| #preview-content .tabular, #setText .tabular { |
| display: inline-table !important; |
| width: auto; |
| table-layout: auto; |
| border-collapse: collapse; |
| border-spacing: 0; |
| margin: 0 0 1em; |
| font-size: inherit; |
| height: fit-content; |
| } |
| .tabular th, |
| #preview-content .tabular th, #setText .tabular th { |
| border: none !important; |
| padding: 6px 13px; |
| background-color: transparent; |
| font-weight: bold; |
| } |
| .tabular tr, |
| #preview-content .tabular tr, #setText .tabular tr { |
| border-top: none !important; |
| border-bottom: none !important; |
| background-color: transparent; |
| } |
| .tabular td, |
| #preview-content .tabular td, #setText .tabular td { |
| border-style: none !important; |
| background-color: #fff; |
| border-color: #000 !important; |
| word-break: keep-all; |
| padding: 0.1em 0.5em !important; |
| } |
| .tabular td > p, |
| #preview-content .tabular td > p, #setText .tabular td > p { |
| margin-bottom: 0; |
| margin-top: 0; |
| } |
| .tabular td._empty, |
| #preview-content .tabular td._empty, #setText .tabular td._empty { |
| height: 1.3em; |
| } |
| .tabular td .f, |
| #preview-content .tabular td .f, #setText .tabular td .f { |
| opacity: 0; |
| } |
| #preview-content .sub-table table, #setText .sub-table table { |
| margin-bottom: 0; |
| } |
| html[data-theme="dark"] .tabular tr, |
| html[data-theme="dark"] #preview-content .tabular tr, html[data-theme="dark"] #setText .tabular tr, |
| html[data-theme="dark"] .tabular td, |
| html[data-theme="dark"] #preview-content .tabular td, html[data-theme="dark"] #setText .tabular td { |
| background-color: #202226; |
| border-color: #fff !important; |
| } |
| .figure_img, |
| #preview-content .figure_img, #setText .figure_img { |
| margin-bottom: 0.5em; |
| overflow-x: auto; |
| } |
| div.figure_img img, |
| #preview-content div.figure_img img, #setText div.figure_img img { |
| display: inline; |
| margin: 0; |
| } |
| ol.enumerate, ul.itemize, |
| #preview-content ol.enumerate, #setText ol.enumerate, |
| #preview-content ul.itemize, #setText ul.itemize { |
| padding-inline-start: 40px; |
| margin: 0 0 1em 0; |
| } |
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| </head> |
| <body> |
| <div id="preview" class="preview scrollEditor"> |
| <div id="container-ruller" /> |
| <div id="preview-content"> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="statistical-analysis-plan"> |
| Statistical Analysis Plan</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="inorganic-nitrite-delivery-to-improve-exercise-capacity-in-hfpef"> |
| Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="indie-hfpef"> |
| INDIE-HFpEF</h2> |
| <div>A randomized, double-blind, placebo-controlled crossover study to assess the effect of inorganic nitrite <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="6.483ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 2865.6 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mrow"><g data-mml-node="mo"><path data-c="28" d="M94 250Q94 319 104 381T127 488T164 576T202 643T244 695T277 729T302 750H315H319Q333 750 333 741Q333 738 316 720T275 667T226 581T184 443T167 250T184 58T225 -81T274 -167T316 -220T333 -241Q333 -250 318 -250H315H302L274 -226Q180 -141 137 -14T94 250Z"></path></g><g data-mml-node="mi" transform="translate(389,0)"><path data-c="1D441" d="M234 637Q231 637 226 637Q201 637 196 638T191 649Q191 676 202 682Q204 683 299 683Q376 683 387 683T401 677Q612 181 616 168L670 381Q723 592 723 606Q723 633 659 637Q635 637 635 648Q635 650 637 660Q641 676 643 679T653 683Q656 683 684 682T767 680Q817 680 843 681T873 682Q888 682 888 672Q888 650 880 642Q878 637 858 637Q787 633 769 597L620 7Q618 0 599 0Q585 0 582 2Q579 5 453 305L326 604L261 344Q196 88 196 79Q201 46 268 46H278Q284 41 284 38T282 19Q278 6 272 0H259Q228 2 151 2Q123 2 100 2T63 2T46 1Q31 1 31 10Q31 14 34 26T39 40Q41 46 62 46Q130 49 150 85Q154 91 221 362L289 634Q287 635 234 637Z"></path></g><g data-mml-node="msub" transform="translate(1277,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g><g data-mml-node="mo" transform="translate(2476.6,0)"><path data-c="29" d="M60 749L64 750Q69 750 74 750H86L114 726Q208 641 251 514T294 250Q294 182 284 119T261 12T224 -76T186 -143T145 -194T113 -227T90 -246Q87 -249 86 -250H74Q66 -250 63 -250T58 -247T55 -238Q56 -237 66 -225Q221 -64 221 250T66 725Q56 737 55 738Q55 746 60 749Z"></path></g></g></g></g></svg></mjx-container></span> on aerobic capacity (peak <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="4.454ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 1968.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" transform="translate(769,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> ).</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="original-protocol-date"> |
| Original Protocol Date</h2> |
| <div>April 22, 2016</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="amendment-1-date"> |
| Amendment 1 Date</h2> |
| <div>November 10, 2016</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="sponsor"> |
| Sponsor</h2> |
| <div>National Heart, Lung and Blood Institute</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="protocol-principal-investigators"> |
| Protocol Principal Investigators</h2> |
| <div>Barry Borlaug, MD</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="table-of-contents"> |
| Table of Contents</h2> |
| <ol> |
| <li>Overview ..... 3<br> |
| 1.1 Synopsis ..... 3<br> |
| 1.2 Study Treatments ..... 3</li> |
| <li>Study Design ..... 3<br> |
| 2.1 Overview</li> |
| </ol> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 3<br> |
| 2.2 Randomization ..... 3<br> |
| 2.3 Data Sources ..... 3<br> |
| 3. Analysis Population and Missing Data ..... 3<br> |
| 4. General Methodology ..... 4<br> |
| 5. Primary Endpoint ..... 4<br> |
| 6. Secondary Endpoints ..... 4<br> |
| 7. Tertiary Endpoints ..... 5<br> |
| 8. Primary Endpoint Description ..... 5<br> |
| 8.1 Primary Endpoint ..... 5<br> |
| 9. Secondary Endpoint Descriptions ..... 6<br> |
| 9.1 Secondary Endpoint #1</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 6<br> |
| 9.2 Secondary Endpoint #2</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 7<br> |
| 9.3 Secondary Endpoint #3</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 7<br> |
| 9.4 Secondary Endpoint #4</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 8<br> |
| 9.5 Secondary Endpoint #5</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 8<br> |
| 9.6 Secondary Endpoint #6</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 8<br> |
| 9.7 Secondary Endpoint #7 - . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... 9<br> |
| 9.8 Secondary Endpoint #8</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 9<br> |
| 9.9 Secondary Endpoint #9</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 10<br> |
| 9.10 Secondary Endpoint #10</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 10<br> |
| 9.11 Secondary Endpoint #11</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 11<br> |
| 10. Tertiary Endpoint Descriptions</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 11<br> |
| 10.1 Tertiary Endpoint #1</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 11<br> |
| 10.2 Tertiary Endpoint #2</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 12<br> |
| 10.3 Tertiary Endpoint #3</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 12<br> |
| 11. Safety Analyses</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 12<br> |
| 11.1 Safety Endpoint #1</div> |
| <div><span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.14ex;" xmlns="http://www.w3.org/2000/svg" width="4.525ex" height="0.084ex" role="img" focusable="false" viewBox="0 25 2000 37"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1000,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g><g data-mml-node="mi" transform="translate(1500,0)"><path data-c="5F" d="M0 -62V-25H499V-62H0Z"></path></g></g></g></svg></mjx-container></span> ..... 12<br> |
| 12. Interim Analysis ..... 13</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="1.-overview"> |
| 1. Overview</h2> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="1.1-synopsis"> |
| 1.1 Synopsis</h3> |
| <div>The Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE-HFpEF) trial is a placebocontrolled 2*2 crossover trial to assess the effect of inorganic nitrite ( <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="4.723ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 2087.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D441" d="M234 637Q231 637 226 637Q201 637 196 638T191 649Q191 676 202 682Q204 683 299 683Q376 683 387 683T401 677Q612 181 616 168L670 381Q723 592 723 606Q723 633 659 637Q635 637 635 648Q635 650 637 660Q641 676 643 679T653 683Q656 683 684 682T767 680Q817 680 843 681T873 682Q888 682 888 672Q888 650 880 642Q878 637 858 637Q787 633 769 597L620 7Q618 0 599 0Q585 0 582 2Q579 5 453 305L326 604L261 344Q196 88 196 79Q201 46 268 46H278Q284 41 284 38T282 19Q278 6 272 0H259Q228 2 151 2Q123 2 100 2T63 2T46 1Q31 1 31 10Q31 14 34 26T39 40Q41 46 62 46Q130 49 150 85Q154 91 221 362L289 634Q287 635 234 637Z"></path></g><g data-mml-node="msub" transform="translate(888,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> ) with dose up-titration on exercise capacity as assessed by cardiopulmonary exercise test.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="1.2-study-treatments"> |
| 1.2 Study Treatments</h3> |
| <div>Given the crossover nature of the study, each patient will receive both inorganic nitrite and matching placebo, with the treatment order determined during the randomization process. Each study phase will consist of a 2 week washout period, 1 week at the 46 mg dose (TID), and 3 weeks at the 80 mg dose (TID). Study medication is administered three times per day, at least four hours apart in a blinded fashion during each study phase.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="2.-study-design"> |
| 2. Study Design</h2> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.1-overview"> |
| 2.1 Overview</h3> |
| <div>The INDIE-HFpEF study is a randomized, double-blind, placebo-controlled crossover study in heart failure patients with preserved ejection fraction. A total of 100 patients will be enrolled in the trial.</div> |
| <div>The treatments in this study are blinded. Each study phase will last for 6 weeks. The first 2 weeks of each study phase will be the washout period with study treatment received during the last 4 weeks.</div> |
| <div>The over-arching hypothesis is that, compared to placebo, treatment with inorganic nitrite will lead to improved exercise capacity as assessed by cardiopulmonary exercise testing.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.2-randomization"> |
| 2.2 Randomization</h3> |
| <div>Patients are randomized in a <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.148ex" height="1.507ex" role="img" focusable="false" viewBox="0 -666 1833.6 666"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mo" transform="translate(777.8,0)"><path data-c="3A" d="M78 370Q78 394 95 412T138 430Q162 430 180 414T199 371Q199 346 182 328T139 310T96 327T78 370ZM78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z"></path></g><g data-mml-node="mn" transform="translate(1333.6,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></svg></mjx-container></span> ratio to a specific treatment receipt order: inorganic nitrite in study phase 1 and Placebo in study phase 2 OR Placebo in study phase 1 and inorganic nitrite in study phase 2 . The randomization scheme consists of a permuted block design with stratification by clinical site.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="2.3-data-sources"> |
| 2.3 Data Sources</h3> |
| <div>A database of case report form and biomarker core lab data will be created in Inform, and the data then transferred to SAS for analysis. The randomized treatment assignment will be provided through data provided by the Webez system, an Almac Clinical Services web-based randomization system. The accelerometer data was provided by the Accelerometer Core Lab located at Mayo Clinic. The core lab provided both cleaned and raw data for download. The data is stored on Solaris server uxctstp01 in the folder /hf_net/INDIE/data.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="3.-analysis-population-and-missing-data"> |
| 3. Analysis Population and Missing Data</h2> |
| <div>All randomized patients will be included in the analysis population for assessing the primary, secondary and tertiary endpoints. Given the crossover design of the study, each patient will have endpoints measured at two times; the first at the conclusion of Phase 1 (Visit 2) treatment and the second at the conclusion of Phase 2 treatment (Visit 3). All endpoints will be analyzed on an intent-to-treat basis.</div> |
| <div>However, as described in subsequent sections of this document, some patients may be excluded from certain analyses if key data elements are missing. With the extensive efforts being made in collaboration with the clinical sites to ensure data quality and completeness, it is expected that exclusion of patients for any endpoint analysis will be minimal. The specific endpoint descriptions in Sections 8 through 10 describe the circumstances that would lead to a patient being excluded from a specific analysis.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="4.-general-methodology"> |
| 4. General Methodology</h2> |
| <div>Medians, <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="4.362ex" height="1.981ex" role="img" focusable="false" viewBox="0 -853.7 1928 875.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="msup" transform="translate(1000,0)"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mtext"><path data-c="74" d="M27 422Q80 426 109 478T141 600V615H181V431H316V385H181V241Q182 116 182 100T189 68Q203 29 238 29Q282 29 292 100Q293 108 293 146V181H333V146V134Q333 57 291 17Q264 -10 221 -10Q187 -10 162 2T124 33T105 68T98 100Q97 107 97 248V385H18V422H27Z"></path><path data-c="68" d="M41 46H55Q94 46 102 60V68Q102 77 102 91T102 124T102 167T103 217T103 272T103 329Q103 366 103 407T103 482T102 542T102 586T102 603Q99 622 88 628T43 637H25V660Q25 683 27 683L37 684Q47 685 66 686T103 688Q120 689 140 690T170 693T181 694H184V367Q244 442 328 442Q451 442 463 329Q464 322 464 190V104Q464 66 466 59T477 49Q498 46 526 46H542V0H534L510 1Q487 2 460 2T422 3Q319 3 310 0H302V46H318Q379 46 379 62Q380 64 380 200Q379 335 378 343Q372 371 358 385T334 402T308 404Q263 404 229 370Q202 343 195 315T187 232V168V108Q187 78 188 68T191 55T200 49Q221 46 249 46H265V0H257L234 1Q210 2 183 2T145 3Q42 3 33 0H25V46H41Z" transform="translate(389,0)"></path><path data-c="A0" d="" transform="translate(945,0)"></path></g></g></g></g></g></svg></mjx-container></span> and <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="4.362ex" height="1.981ex" role="img" focusable="false" viewBox="0 -853.7 1928 875.7"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="37" d="M55 458Q56 460 72 567L88 674Q88 676 108 676H128V672Q128 662 143 655T195 646T364 644H485V605L417 512Q408 500 387 472T360 435T339 403T319 367T305 330T292 284T284 230T278 162T275 80Q275 66 275 52T274 28V19Q270 2 255 -10T221 -22Q210 -22 200 -19T179 0T168 40Q168 198 265 368Q285 400 349 489L395 552H302Q128 552 119 546Q113 543 108 522T98 479L95 458V455H55V458Z"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(500,0)"></path></g><g data-mml-node="msup" transform="translate(1000,0)"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mtext"><path data-c="74" d="M27 422Q80 426 109 478T141 600V615H181V431H316V385H181V241Q182 116 182 100T189 68Q203 29 238 29Q282 29 292 100Q293 108 293 146V181H333V146V134Q333 57 291 17Q264 -10 221 -10Q187 -10 162 2T124 33T105 68T98 100Q97 107 97 248V385H18V422H27Z"></path><path data-c="68" d="M41 46H55Q94 46 102 60V68Q102 77 102 91T102 124T102 167T103 217T103 272T103 329Q103 366 103 407T103 482T102 542T102 586T102 603Q99 622 88 628T43 637H25V660Q25 683 27 683L37 684Q47 685 66 686T103 688Q120 689 140 690T170 693T181 694H184V367Q244 442 328 442Q451 442 463 329Q464 322 464 190V104Q464 66 466 59T477 49Q498 46 526 46H542V0H534L510 1Q487 2 460 2T422 3Q319 3 310 0H302V46H318Q379 46 379 62Q380 64 380 200Q379 335 378 343Q372 371 358 385T334 402T308 404Q263 404 229 370Q202 343 195 315T187 232V168V108Q187 78 188 68T191 55T200 49Q221 46 249 46H265V0H257L234 1Q210 2 183 2T145 3Q42 3 33 0H25V46H41Z" transform="translate(389,0)"></path><path data-c="A0" d="" transform="translate(945,0)"></path></g></g></g></g></g></svg></mjx-container></span> percentiles will be presented for continuous variables; the number and percentage of patients in each category will be presented for categorical variables. For all endpoints a p -value <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.312ex;" xmlns="http://www.w3.org/2000/svg" width="6.411ex" height="1.819ex" role="img" focusable="false" viewBox="0 -666 2833.8 804"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="2264" d="M674 636Q682 636 688 630T694 615T687 601Q686 600 417 472L151 346L399 228Q687 92 691 87Q694 81 694 76Q694 58 676 56H670L382 192Q92 329 90 331Q83 336 83 348Q84 359 96 365Q104 369 382 500T665 634Q669 636 674 636ZM84 -118Q84 -108 99 -98H678Q694 -104 694 -118Q694 -130 679 -138H98Q84 -131 84 -118Z"></path></g><g data-mml-node="mn" transform="translate(1055.8,0)"><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z"></path><path data-c="2E" d="M78 60Q78 84 95 102T138 120Q162 120 180 104T199 61Q199 36 182 18T139 0T96 17T78 60Z" transform="translate(500,0)"></path><path data-c="30" d="M96 585Q152 666 249 666Q297 666 345 640T423 548Q460 465 460 320Q460 165 417 83Q397 41 362 16T301 -15T250 -22Q224 -22 198 -16T137 16T82 83Q39 165 39 320Q39 494 96 585ZM321 597Q291 629 250 629Q208 629 178 597Q153 571 145 525T137 333Q137 175 145 125T181 46Q209 16 250 16Q290 16 318 46Q347 76 354 130T362 333Q362 478 354 524T321 597Z" transform="translate(778,0)"></path><path data-c="35" d="M164 157Q164 133 148 117T109 101H102Q148 22 224 22Q294 22 326 82Q345 115 345 210Q345 313 318 349Q292 382 260 382H254Q176 382 136 314Q132 307 129 306T114 304Q97 304 95 310Q93 314 93 485V614Q93 664 98 664Q100 666 102 666Q103 666 123 658T178 642T253 634Q324 634 389 662Q397 666 402 666Q410 666 410 648V635Q328 538 205 538Q174 538 149 544L139 546V374Q158 388 169 396T205 412T256 420Q337 420 393 355T449 201Q449 109 385 44T229 -22Q148 -22 99 32T50 154Q50 178 61 192T84 210T107 214Q132 214 148 197T164 157Z" transform="translate(1278,0)"></path></g></g></g></svg></mjx-container></span> will be considered statistically significant and all tests will be 2 -sided. Analyses will be performed using validated SAS software (SAS Institute, Inc., Cary, NC). Appropriate statistical models will be used to examine the effect of treatment on both the primary, secondary, and tertiary outcomes in the study.</div> |
| <div>The majority of the endpoints will be analyzed using a linear mixed model. Within the context of the mixed models, the period effect will be examined to determine whether both treatment effects are consistently higher or lower when comparing Phases 1 and 2 of the study (e.g., Peak <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="4.454ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 1968.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" transform="translate(769,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> is increased in Phase 2 for both treatments vs Phase 1). The sequence effect will be examined to determine if the treatment effect differs based on the treatment order (inorganic nitrite then Placebo or Placebo then inorganic nitrite). Alternative modeling may also be performed using paired t-tests or appropriately structured general linear models.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="5.-primary-endpoint"> |
| 5. Primary Endpoint</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="primary-endpoint"> |
| Primary Endpoint</h2> |
| <div>#1: Within patient comparison of exercise capacity as assessed by peak <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="17.519ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 7743.6 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" 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388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(6409.6,0)"><path data-c="1D456" d="M184 600Q184 624 203 642T247 661Q265 661 277 649T290 619Q290 596 270 577T226 557Q211 557 198 567T184 600ZM21 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| <div>See Section 8 for a detailed description of the primary endpoint, including rules that will be followed for handling incomplete data.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="6.-secondary-endpoints"> |
| 6. Secondary Endpoints</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="secondary-endpoints"> |
| Secondary Endpoints</h2> |
| <div>#1: Within patient comparison of arbitrary accelerometer units (AAU) during the maximally tolerated dose of inorganic nitrite vs placebo<br> |
| #2: Within patient comparison of Kansas City Cardiomyopathy Questionnaire (KCCQ) symptom scores both clinical and overall, comparing inorganic nitrite vs placebo<br> |
| #3: Within patient comparison of New York Heart Association (NYHA) functional class, comparing inorganic nitrite vs placebo<br> |
| #4: Patient preference for study phase (inorganic nitrite vs. placebo)<br> |
| #5: Within patient comparison of medial E/e' ratio as assessed on echocardiography, comparing inorganic nitrite vs placebo<br> |
| #6: Within patient comparison of left atrial volume index as assessed on echocardiography, comparing inorganic nitrite vs placebo<br> |
| #7: Within patient comparison of pulmonary artery systolic pressure (PASP) as assessed on echocardiography, comparing inorganic nitrite vs placebo<br> |
| #8: Within patient comparison of core lab NT Pro BNP, comparing inorganic nitrite vs placebo<br> |
| #9: Within patient comparison of <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="10.033ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4434.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msub"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="TeXAtom" transform="translate(616,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mi"><path data-c="1D438" d="M492 213Q472 213 472 226Q472 230 477 250T482 285Q482 316 461 323T364 330H312Q311 328 277 192T243 52Q243 48 254 48T334 46Q428 46 458 48T518 61Q567 77 599 117T670 248Q680 270 683 272Q690 274 698 274Q718 274 718 261Q613 7 608 2Q605 0 322 0H133Q31 0 31 11Q31 13 34 25Q38 41 42 43T65 46Q92 46 125 49Q139 52 144 61Q146 66 215 342T285 622Q285 629 281 629Q273 632 228 634H197Q191 640 191 642T193 659Q197 676 203 680H757Q764 676 764 669Q764 664 751 557T737 447Q735 440 717 440H705Q698 445 698 453L701 476Q704 500 704 528Q704 558 697 578T678 609T643 625T596 632T532 634H485Q397 633 392 631Q388 629 386 622Q385 619 355 499T324 377Q347 376 372 376H398Q464 376 489 391T534 472Q538 488 540 490T557 493Q562 493 565 493T570 492T572 491T574 487T577 483L544 351Q511 218 508 216Q505 213 492 213Z"></path></g></g></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(1206.2,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(1706.2,0)"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="mi" transform="translate(2475.2,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(3235.2,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> slope (ventilator efficiency) as assessed on cardiopulmonary exercise testing, comparing inorganic nitrite vs placebo<br> |
| #10: Within patient comparison of <span class="math-inline "> |
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| #11: Within patient comparison of exercise duration as assessed during cardiopulmonary exercise testing, comparing inorganic nitrite vs placebo</div> |
| <div>See Section 9 for a detailed description of each secondary endpoint, including rules that will be followed for handling incomplete data.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="7.-tertiary-endpoints"> |
| 7. Tertiary Endpoints</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="tertiary-endpoints"> |
| Tertiary Endpoints</h2> |
| <div>#1: Primary endpoint comparison within the following subgroups:<br> |
| a. Baseline core lab NT Pro BNP <span class="math-inline "> |
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| b. Baseline systolic blood pressure above and below the median<br> |
| c. Age above and below the median<br> |
| d. Male vs female<br> |
| e. Baseline estimated glomerular filtration rate (GFR) by MDRD above and below the median<br> |
| f. On vs off study drug at time of visit based on active study drug phase<br> |
| g. Atrial fibrillation/flutter vs not<br> |
| h. Diabetes vs no diabetes<br> |
| i. BMI above and below the median<br> |
| j. Baseline activity level above and below the median<br> |
| #2: Within patient comparison of core lab cystatin C, comparing inorganic nitrite vs placebo<br> |
| #3: Within patient comparison of core lab cyclic guanosine monophosphate (cGMP), comparing inorganic nitrite vs placebo</div> |
| <div>Note: The protocol states that we will also examine novel accelerometry endpoints, guided by NEAT-HFpEF ancillary paper analyses (in progress). As of yet, there are no novel endpoints under consideration for this study.</div> |
| <div>See Section 10 for a detailed description of each tertiary endpoint, including rules that will be followed for handling incomplete data.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="8.-endpoint-descriptions"> |
| 8. Endpoint Descriptions</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="8.1---primary-endpoint"> |
| 8.1 - Primary Endpoint</h2> |
| <div>Endpoint Description: Exercise capacity as assessed by peak <span class="math-inline "> |
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| <span class="math-inline "> |
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| <div>Additional Covariates: Baseline peak VO <span class="math-inline " data-overflow="visible"> |
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| <div>Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Sensitivity Analysis: Two sensitivity analyses will be performed.</div> |
| <ol> |
| <li>Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the cardiopulmonary exercise test was performed.</li> |
| <li>To address a potential question seen in some journal reviews, the original mixed model will be run again, adding a new covariate for random effect of enrolling site.</li> |
| </ol> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on peak <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="4.454ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 1968.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" transform="translate(769,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span>. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A higher peak VO2 indicates an improved exercise capacity in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.-secondary-endpoint-descriptions"> |
| 9. Secondary Endpoint Descriptions</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.1---secondary-endpoint-%5C%231"> |
| 9.1 - Secondary Endpoint #1</h2> |
| <div>Endpoint Description: Arbitrary accelerometry units (AAU) during maximally tolerated dose of inorganic nitrite vs placebo</div> |
| <div>Response Variable Definition: For each study phase, the average daily AAU will be calculated for the period of time that patient was taking 80 mg daily (or maximally tolerated dose if 80 mg not tolerated), approximate time periods are study weeks 4-6 and 10-12. Only complete days are used and there should be 21 days in the dosing period.</div> |
| <div>Additional Covariates: period effect, sequence effect, baseline daily average AAU, and random effect of patient</div> |
| <div>Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Sensitivity Analysis: For this sensitivity analysis, each average will be divided by the study phase 114 day baseline period average daily AAU (approximately study weeks <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.186ex;" xmlns="http://www.w3.org/2000/svg" width="5.028ex" height="1.692ex" role="img" focusable="false" viewBox="0 -666 2222.4 748"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mo" transform="translate(722.2,0)"><path data-c="2212" d="M84 237T84 250T98 270H679Q694 262 694 250T679 230H98Q84 237 84 250Z"></path></g><g data-mml-node="mn" transform="translate(1722.4,0)"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></svg></mjx-container></span> ) to create a ratio. Values greater than 1 indicate increased activity.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on daily activity level. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: Higher AAU indicates more activity in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.2---secondary-endpoint-%5C%232"> |
| 9.2 - Secondary Endpoint #2</h2> |
| <div>Endpoint Description: Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary Scores<br> |
| Response Variable Definition: Visit 2 and Visit 3 KCCQ scores, classified as to treatment received in prior treatment period. Each summary score will be an individual endpoint and have its own model.</div> |
| <div>Additional Covariates: Baseline KCCQ score (as appropriate), period effect, sequence effect, and random effect of patient</div> |
| <div>Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Sensitivity Analysis: Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the KCCQ questionnaire was completed.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on each KCCQ summary score. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A higher KCCQ score indicates an improved KCCQ score in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.3---secondary-endpoint-%5C%233"> |
| 9.3 - Secondary Endpoint #3</h2> |
| <div>Endpoint Description: NYHA class<br> |
| Response Variable Definition: Visit 2 and Visit 3 NYHA class, classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Baseline NYHA class, period effect, sequence effect, and random effect of patient<br> |
| Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Sensitivity Analysis: Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the NYHA class was assessed.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on NYHA class. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A lower NYHA class indicates an improved heart failure symptoms in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.4---secondary-endpoint-%5C%234"> |
| 9.4 - Secondary Endpoint #4</h2> |
| <div>Endpoint Description: Patient preference for study phase (inorganic nitrite vs. placebo)<br> |
| Response Variable Definition: Patient preferred study phase (active, placebo, no preference).<br> |
| Statistical Tests: No formal testing will be done.<br> |
| Interpretation of Results: For patients with a preference, a higher percentage of patients favoring the inorganic nitrite period vs placebo indicate a positive treatment experience.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.5---secondary-endpoint-%5C%235"> |
| 9.5 - Secondary Endpoint #5</h2> |
| <div>Endpoint Description: Medial E/e'</div> |
| <div>Response Variable Definition: Visit 2 and Visit 3 medial E/e', classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Period effect, sequence effect, and random effect of patient</div> |
| <div>Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Sensitivity Analysis: Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the echocardiogram was performed.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on medial E/e'. Secondary analyses will be performed using paired t-tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A lower medial E/e' indicates improvement in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.6---secondary-endpoint-%5C%236"> |
| 9.6 - Secondary Endpoint #6</h2> |
| <div>Endpoint Description: Left atrial (LA) volume index<br> |
| Response Variable Definition: Visit 2 and Visit 3 left atrial volume index, classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Period effect, sequence effect, and random effect of patient<br> |
| Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Sensitivity Analysis: Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the echocardiogram was performed.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on LA volume index. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A lower LA volume index indicates improvement in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.7---secondary-endpoint-%5C%237"> |
| 9.7 - Secondary Endpoint #7</h2> |
| <div>Endpoint Description: Pulmonary artery systolic pressure<br> |
| Response Variable Definition: Visit 2 and Visit 3 PASP, classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Period effect, sequence effect, and random effect of patient<br> |
| Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Sensitivity Analysis: Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the echocardiogram was performed.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on PASP. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A lower PASP indicates improvement in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.8---secondary-endpoint-%5C%238"> |
| 9.8 - Secondary Endpoint #8</h2> |
| <div>Endpoint Description: Core lab NT pro BNP<br> |
| Response Variable Definition: Visit 2 and Visit 3 NT pro BNP, classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Baseline NT pro BNP, period effect, sequence effect, and random effect of patient</div> |
| <div>Handling of Dropouts and Missing Data: No adjustment for missing data will be made.</div> |
| <div>Sensitivity Analysis: Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the biomarkers were drawn.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on NT pro BNP. Secondary analyses will be performed using paired t-tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A lower NT pro BNP indicates improved NT pro BNP in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="9.9---secondary-endpoint-%5C%239"> |
| 9.9 - Secondary Endpoint #9</h2> |
| <div>Endpoint Description: <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="10.033ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4434.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msub"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="TeXAtom" transform="translate(616,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mi"><path data-c="1D438" d="M492 213Q472 213 472 226Q472 230 477 250T482 285Q482 316 461 323T364 330H312Q311 328 277 192T243 52Q243 48 254 48T334 46Q428 46 458 48T518 61Q567 77 599 117T670 248Q680 270 683 272Q690 274 698 274Q718 274 718 261Q613 7 608 2Q605 0 322 0H133Q31 0 31 11Q31 13 34 25Q38 41 42 43T65 46Q92 46 125 49Q139 52 144 61Q146 66 215 342T285 622Q285 629 281 629Q273 632 228 634H197Q191 640 191 642T193 659Q197 676 203 680H757Q764 676 764 669Q764 664 751 557T737 447Q735 440 717 440H705Q698 445 698 453L701 476Q704 500 704 528Q704 558 697 578T678 609T643 625T596 632T532 634H485Q397 633 392 631Q388 629 386 622Q385 619 355 499T324 377Q347 376 372 376H398Q464 376 489 391T534 472Q538 488 540 490T557 493Q562 493 565 493T570 492T572 491T574 487T577 483L544 351Q511 218 508 216Q505 213 492 213Z"></path></g></g></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(1206.2,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(1706.2,0)"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="mi" transform="translate(2475.2,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(3235.2,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> slope<br> |
| Response Variable Definition: Visit 2 and Visit <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="11.165ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4934.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 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d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="mi" transform="translate(2975.2,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(3735.2,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> slope, classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Baseline <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="10.033ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4434.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msub"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="TeXAtom" transform="translate(616,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mi"><path data-c="1D438" d="M492 213Q472 213 472 226Q472 230 477 250T482 285Q482 316 461 323T364 330H312Q311 328 277 192T243 52Q243 48 254 48T334 46Q428 46 458 48T518 61Q567 77 599 117T670 248Q680 270 683 272Q690 274 698 274Q718 274 718 261Q613 7 608 2Q605 0 322 0H133Q31 0 31 11Q31 13 34 25Q38 41 42 43T65 46Q92 46 125 49Q139 52 144 61Q146 66 215 342T285 622Q285 629 281 629Q273 632 228 634H197Q191 640 191 642T193 659Q197 676 203 680H757Q764 676 764 669Q764 664 751 557T737 447Q735 440 717 440H705Q698 445 698 453L701 476Q704 500 704 528Q704 558 697 578T678 609T643 625T596 632T532 634H485Q397 633 392 631Q388 629 386 622Q385 619 355 499T324 377Q347 376 372 376H398Q464 376 489 391T534 472Q538 488 540 490T557 493Q562 493 565 493T570 492T572 491T574 487T577 483L544 351Q511 218 508 216Q505 213 492 213Z"></path></g></g></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(1206.2,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(1706.2,0)"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="mi" transform="translate(2475.2,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(3235.2,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> slope, period effect, sequence effect, and random effect of patient<br> |
| Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Sensitivity Analysis: Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the cardiopulmonary exercise testing was performed.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="10.033ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4434.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msub"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="TeXAtom" transform="translate(616,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mi"><path data-c="1D438" d="M492 213Q472 213 472 226Q472 230 477 250T482 285Q482 316 461 323T364 330H312Q311 328 277 192T243 52Q243 48 254 48T334 46Q428 46 458 48T518 61Q567 77 599 117T670 248Q680 270 683 272Q690 274 698 274Q718 274 718 261Q613 7 608 2Q605 0 322 0H133Q31 0 31 11Q31 13 34 25Q38 41 42 43T65 46Q92 46 125 49Q139 52 144 61Q146 66 215 342T285 622Q285 629 281 629Q273 632 228 634H197Q191 640 191 642T193 659Q197 676 203 680H757Q764 676 764 669Q764 664 751 557T737 447Q735 440 717 440H705Q698 445 698 453L701 476Q704 500 704 528Q704 558 697 578T678 609T643 625T596 632T532 634H485Q397 633 392 631Q388 629 386 622Q385 619 355 499T324 377Q347 376 372 376H398Q464 376 489 391T534 472Q538 488 540 490T557 493Q562 493 565 493T570 492T572 491T574 487T577 483L544 351Q511 218 508 216Q505 213 492 213Z"></path></g></g></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(1206.2,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(1706.2,0)"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="mi" transform="translate(2475.2,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(3235.2,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> slope. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A lower <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="10.033ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 4434.8 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msub"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="TeXAtom" transform="translate(616,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mi"><path data-c="1D438" d="M492 213Q472 213 472 226Q472 230 477 250T482 285Q482 316 461 323T364 330H312Q311 328 277 192T243 52Q243 48 254 48T334 46Q428 46 458 48T518 61Q567 77 599 117T670 248Q680 270 683 272Q690 274 698 274Q718 274 718 261Q613 7 608 2Q605 0 322 0H133Q31 0 31 11Q31 13 34 25Q38 41 42 43T65 46Q92 46 125 49Q139 52 144 61Q146 66 215 342T285 622Q285 629 281 629Q273 632 228 634H197Q191 640 191 642T193 659Q197 676 203 680H757Q764 676 764 669Q764 664 751 557T737 447Q735 440 717 440H705Q698 445 698 453L701 476Q704 500 704 528Q704 558 697 578T678 609T643 625T596 632T532 634H485Q397 633 392 631Q388 629 386 622Q385 619 355 499T324 377Q347 376 372 376H398Q464 376 489 391T534 472Q538 488 540 490T557 493Q562 493 565 493T570 492T572 491T574 487T577 483L544 351Q511 218 508 216Q505 213 492 213Z"></path></g></g></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(1206.2,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 -245T56 -231Q56 -221 230 257T407 740Q411 750 423 750Z"></path></g></g><g data-mml-node="mi" transform="translate(1706.2,0)"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="mi" transform="translate(2475.2,0)"><path data-c="1D436" d="M50 252Q50 367 117 473T286 641T490 704Q580 704 633 653Q642 643 648 636T656 626L657 623Q660 623 684 649Q691 655 699 663T715 679T725 690L740 705H746Q760 705 760 698Q760 694 728 561Q692 422 692 421Q690 416 687 415T669 413H653Q647 419 647 422Q647 423 648 429T650 449T651 481Q651 552 619 605T510 659Q484 659 454 652T382 628T299 572T226 479Q194 422 175 346T156 222Q156 108 232 58Q280 24 350 24Q441 24 512 92T606 240Q610 253 612 255T628 257Q648 257 648 248Q648 243 647 239Q618 132 523 55T319 -22Q206 -22 128 53T50 252Z"></path></g><g data-mml-node="msub" transform="translate(3235.2,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> slope indicates improvement in the inorganic nitrite period vs placebo.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="9.10---secondary-endpoint-%5C%2310"> |
| 9.10 - Secondary Endpoint #10</h3> |
| <div>Endpoint Description: <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="4.454ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 1968.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" transform="translate(769,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> at ventilatory threshold<br> |
| Response Variable Definition: Visit 2 and Visit <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="5.585ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 2468.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g><g data-mml-node="mi" transform="translate(500,0)"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" transform="translate(1269,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> at ventilatory threshold, classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Baseline <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="4.454ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 1968.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" transform="translate(769,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> at ventilatory threshold, period effect, sequence effect, and random effect of patient</div> |
| <div>Handling of Dropouts and Missing Data: No adjustment for missing data will be made.</div> |
| <div>Sensitivity Analysis: Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the cardiopulmonary exercise testing was performed.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="4.454ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 1968.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" transform="translate(769,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> at ventilatory threshold. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A higher <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.339ex;" xmlns="http://www.w3.org/2000/svg" width="4.454ex" height="1.932ex" role="img" focusable="false" viewBox="0 -704 1968.6 854"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" transform="translate(769,0)"><g data-mml-node="mi"><path data-c="1D442" d="M740 435Q740 320 676 213T511 42T304 -22Q207 -22 138 35T51 201Q50 209 50 244Q50 346 98 438T227 601Q351 704 476 704Q514 704 524 703Q621 689 680 617T740 435ZM637 476Q637 565 591 615T476 665Q396 665 322 605Q242 542 200 428T157 216Q157 126 200 73T314 19Q404 19 485 98T608 313Q637 408 637 476Z"></path></g><g data-mml-node="TeXAtom" transform="translate(796,-150) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> at ventilatory threshold indicates improvement in the inorganic nitrite period vs placebo.</div> |
| <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="9.11---secondary-endpoint-%5C%2311"> |
| 9.11 - Secondary Endpoint #11</h3> |
| <div>Endpoint Description: Exercise duration on CPET</div> |
| <div>Response Variable Definition: Visit 2 and Visit 3 exercise duration, classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Baseline exercise duration, period effect, sequence effect, and random effect of patient</div> |
| <div>Handling of Dropouts and Missing Data: No adjustment for missing data will be made.</div> |
| <div>Sensitivity Analysis: Due to the short washout period of the study drug, a separate analysis will be performed removing those patients that discontinued active study treatment prior to the next study visit where the cardiopulmonary exercise testing was performed.</div> |
| <div>Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on exercise duration. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A longer exercise duration indicates improvement in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="10.-tertiary-endpoint-descriptions"> |
| 10. Tertiary Endpoint Descriptions</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="10.1---tertiary-endpoint-%5C%231"> |
| 10.1 - Tertiary Endpoint #1</h2> |
| <div>Endpoint Description: Exercise capacity as assessed by peak <span class="math-inline "> |
| <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.566ex;" xmlns="http://www.w3.org/2000/svg" width="17.519ex" height="2.262ex" role="img" focusable="false" viewBox="0 -750 7743.6 1000"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D449" d="M52 648Q52 670 65 683H76Q118 680 181 680Q299 680 320 683H330Q336 677 336 674T334 656Q329 641 325 637H304Q282 635 274 635Q245 630 242 620Q242 618 271 369T301 118L374 235Q447 352 520 471T595 594Q599 601 599 609Q599 633 555 637Q537 637 537 648Q537 649 539 661Q542 675 545 679T558 683Q560 683 570 683T604 682T668 681Q737 681 755 683H762Q769 676 769 672Q769 655 760 640Q757 637 743 637Q730 636 719 635T698 630T682 623T670 615T660 608T652 599T645 592L452 282Q272 -9 266 -16Q263 -18 259 -21L241 -22H234Q216 -22 216 -15Q213 -9 177 305Q139 623 138 626Q133 637 76 637H59Q52 642 52 648Z"></path></g><g data-mml-node="msub" 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322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(3235.6,0)"><path data-c="1D459" d="M117 59Q117 26 142 26Q179 26 205 131Q211 151 215 152Q217 153 225 153H229Q238 153 241 153T246 151T248 144Q247 138 245 128T234 90T214 43T183 6T137 -11Q101 -11 70 11T38 85Q38 97 39 102L104 360Q167 615 167 623Q167 626 166 628T162 632T157 634T149 635T141 636T132 637T122 637Q112 637 109 637T101 638T95 641T94 647Q94 649 96 661Q101 680 107 682T179 688Q194 689 213 690T243 693T254 694Q266 694 266 686Q266 675 193 386T118 83Q118 81 118 75T117 65V59Z"></path></g><g data-mml-node="TeXAtom" data-mjx-texclass="ORD" transform="translate(3533.6,0)"><g data-mml-node="mo"><path data-c="2F" d="M423 750Q432 750 438 744T444 730Q444 725 271 248T92 -240Q85 -250 75 -250Q68 -250 62 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388T88 425T132 442T175 435T205 417T221 395T229 376L231 369Q231 367 232 367L243 378Q303 442 384 442Q401 442 415 440T441 433T460 423T475 411T485 398T493 385T497 373T500 364T502 357L510 367Q573 442 659 442Q713 442 746 415T780 336Q780 285 742 178T704 50Q705 36 709 31T724 26Q752 26 776 56T815 138Q818 149 821 151T837 153Q857 153 857 145Q857 144 853 130Q845 101 831 73T785 17T716 -10Q669 -10 648 17T627 73Q627 92 663 193T700 345Q700 404 656 404H651Q565 404 506 303L499 291L466 157Q433 26 428 16Q415 -11 385 -11Q372 -11 364 -4T353 8T350 18Q350 29 384 161L420 307Q423 322 423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 181Q151 335 151 342Q154 357 154 369Q154 405 129 405Q107 405 92 377T69 316T57 280Q55 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(6409.6,0)"><path data-c="1D456" d="M184 600Q184 624 203 642T247 661Q265 661 277 649T290 619Q290 596 270 577T226 557Q211 557 198 567T184 600ZM21 287Q21 295 30 318T54 369T98 420T158 442Q197 442 223 419T250 357Q250 340 236 301T196 196T154 83Q149 61 149 51Q149 26 166 26Q175 26 185 29T208 43T235 78T260 137Q263 149 265 151T282 153Q302 153 302 143Q302 135 293 112T268 61T223 11T161 -11Q129 -11 102 10T74 74Q74 91 79 106T122 220Q160 321 166 341T173 380Q173 404 156 404H154Q124 404 99 371T61 287Q60 286 59 284T58 281T56 279T53 278T49 278T41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mi" transform="translate(6754.6,0)"><path data-c="1D45B" d="M21 287Q22 293 24 303T36 341T56 388T89 425T135 442Q171 442 195 424T225 390T231 369Q231 367 232 367L243 378Q304 442 382 442Q436 442 469 415T503 336T465 179T427 52Q427 26 444 26Q450 26 453 27Q482 32 505 65T540 145Q542 153 560 153Q580 153 580 145Q580 144 576 130Q568 101 554 73T508 17T439 -10Q392 -10 371 17T350 73Q350 92 386 193T423 345Q423 404 379 404H374Q288 404 229 303L222 291L189 157Q156 26 151 16Q138 -11 108 -11Q95 -11 87 -5T76 7T74 17Q74 30 112 180T152 343Q153 348 153 366Q153 405 129 405Q91 405 66 305Q60 285 60 284Q58 278 41 278H27Q21 284 21 287Z"></path></g><g data-mml-node="mo" transform="translate(7354.6,0)"><path data-c="29" d="M60 749L64 750Q69 750 74 750H86L114 726Q208 641 251 514T294 250Q294 182 284 119T261 12T224 -76T186 -143T145 -194T113 -227T90 -246Q87 -249 86 -250H74Q66 -250 63 -250T58 -247T55 -238Q56 -237 66 -225Q221 -64 221 250T66 725Q56 737 55 738Q55 746 60 749Z"></path></g></g></g></svg></mjx-container></span> measured during cardiopulmonary exercise testing within the following subgroups:<br> |
| a. Baseline core lab NT Pro BNP <span class="math-inline "> |
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| b. Baseline systolic blood pressure above and below the median<br> |
| c. Age above and below the median<br> |
| d. Male vs female<br> |
| e. Baseline estimated glomerular filtration rate (GFR) by MDRD above and below the median<br> |
| f. On vs off study drug at time of visit based on active study drug phase<br> |
| g. Atrial fibrillation/flutter vs not<br> |
| h. Diabetes vs no diabetes<br> |
| i. BMI above and below the median<br> |
| j. Baseline activity level above and below the median</div> |
| <div>See section 8.1 for analysis details</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="10.2---tertiary-endpoint-%5C%232"> |
| 10.2 - Tertiary Endpoint #2</h2> |
| <div>Endpoint Description: Core lab cystatin C<br> |
| Response Variable Definition: Visit 2 and Visit 3 cystatin C, classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Baseline cystatin C, period effect, sequence effect, and random effect of patient<br> |
| Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on cystatin C. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A lower cystatin C indicates improvement in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="10.3---tertiary-endpoint-%5C%233"> |
| 10.3 - Tertiary Endpoint #3</h2> |
| <div>Endpoint Description: Core lab cyclic guanosine monophosphate (cGMP)<br> |
| Response Variable Definition: Visit 2 and Visit 3 cGMP, classified as to treatment received in prior treatment period.</div> |
| <div>Additional Covariates: Baseline cGMP, period effect, sequence effect, and random effect of patient<br> |
| Handling of Dropouts and Missing Data: No adjustment for missing data will be made.<br> |
| Statistical Tests: A mixed model (PROC MIXED in SAS) will be used to estimate and statistically compare the response to inorganic nitrite versus placebo on cGMP. Secondary analyses will be performed using paired t -tests and appropriate general linear models.</div> |
| <div>Interpretation of Results: A higher cGMP indicates an improvement in the inorganic nitrite period vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="11.-safety-analysis"> |
| 11. Safety analysis</h2> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="11.1---safety-endpoint-%5C%231"> |
| 11.1 - Safety Endpoint #1</h2> |
| <div>Safety Endpoint #1: Comparison of adverse events and serious adverse events</div> |
| <div>Response Variable Definitions: Each unique adverse event (AE) and serious adverse event (SAE) type based on preferred term within body system. The number of patients experiencing adverse events will be counted within each study phase, based on preferred term.</div> |
| <div>Additional Covariates: None<br> |
| Handling of Dropouts and Missing Data:<br> |
| No adjustments for missing data will be made.<br> |
| Statistical Tests:<br> |
| Fisher's mid-p will be calculated for each adverse event within each study phase.<br> |
| Interpretation of Results: Lower event rates indicate a better outcome for inorganic nitrite vs placebo.</div> |
| <h2 type="section" data-unnumbered="true" class="section-title" id="12.-interim-analyses"> |
| 12. Interim Analyses</h2> |
| <div>Interim data analysis for efficacy will not be conducted due to the relatively small size and short duration of this clinical trial. Safety data will be periodically assessed by the Data and Safety Monitoring Board (DSMB) based on the reporting of adverse events. There are no pre-specified guidelines for determining stopping rules due to a safety concern; the clinical opinion from the DSMB deliberations will be sole determinant.</div> |
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| </div> |
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