Heart Failure
Conditions
Keywords
Heart Failure, Exercise Intolerance, Ejection Fraction
Brief summary
This trial seeks to assess if potassium nitrate (KNO3) therapy improves exercise capacity and oxygen uptake in heart failure patients with preserved ejection fraction (HFpEF).
Detailed description
Approximately 50% of heart failure patients exhibit preserved left ventricular (LV) ejection fraction (EF), and therefore have HF with preserved EF (HFpEF). There are currently no proven effective pharmacologic interventions. Exercise intolerance with reduced aerobic capacity is the hallmark of HFpEF and greatly impairs quality of life (QOL). During exercise, blood vessels within active muscle vasodilator, increasing perfusion to the muscle bed. Nitric oxide is a chief mediator of this process. Inorganic nitrate can ultimately be converted to nitric oxide. This conversion occurs preferentially at the site of exercising muscle, allowing for vasodilation to occur, hence increasing blood flow to the working muscle. Preliminary data suggest that inorganic nitrate improves exercise tolerance in HFpEF. The investigator will aim to test this hypothesis in a larger group.
Interventions
DRUGPotassium Nitrate (KNO3)
The effect of potassium nitrate (KNO3) supplementation on exercise capacity and peak oxygen consumption in HFpEF will be assessed.
Potassium Chloride (KCl) is the matching placebo control drug in this trial.
Sponsors
Northwestern University
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Adults aged 18-90 years of age 2. A diagnosis of heart failure with NYHA Class II-III symptoms 3. LV ejection fraction \>50% during baseline echocardiography 4. Stable medical therapy: no addition/removal/changes in antihypertensive medications, or beta-blockers in the preceding 30 days 5. Elevated filling pressures as evidenced by at least 1 of the following: 1. Mitral E/e' ratio \> 8 (either lateral or septal), with low e' velocity (septal e'\<7 cm/sec or lateral e'\< 10 cm/sec), in addition to one of the following: i Enlarged left atrium (LA volume index \>34 ml/m2) ii Chronic loop diuretic use for control of symptoms iii Elevated natriuretic peptides (BNP levels \>100 ng/L or NT-proBNP levels \>300 ng/L) 2. Mitral E/e' ratio \> 14 (either lateral or septal) 3. Elevated invasively-determined filling pressures previously (resting LVEDP\>16 mmHg or mean pulmonary capillary wedge pressure \[PCWP\] \> 12 mmHg; or PCWP/LVEDP≥25 mmHg with exercise) 4. Acute heart failure decompensation requiring IV diuretics
Exclusion criteria
1. Supine systolic blood pressure \<100 mm Hg 2. Pregnancy: Women of childbearing potential will undergo a pregnancy test during the screening visit 3. Orthostatic hypotension defined as \>20 mm Hg decrease in systolic blood pressure 3-5 minutes following the transition from the supine to standing position 4. Uncontrolled atrial fibrillation, as defined by a resting heart rate\>100 beats per minute 5. Hemoglobin \< 10 g/dL 6. Inability/unwillingness to exercise 7. Moderate or greater left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), any degree of mitral stenosis, severe right-sided valvular disease, or presence of a prosthetic valve in the mitral position 8. Hypertrophic, infiltrative, or inflammatory cardiomyopathy 9. Clinically significant pericardial disease, as per investigator judgement. 10. Current angina 11. Acute coronary syndrome or coronary intervention within the past 2 months 12. Primary pulmonary arteriopathy 13. Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary Disease meeting Stage III or greater GOLD criteria, treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, or the use of daytime supplemental oxygen 14. Ischemia on stress testing without either (1) subsequent revascularization, or; (2) a subsequent angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgement. 15. Left ventricular ejection fraction \<45% in any prior echocardiogram or cardiac MRI, unless this was in the setting of uncontrolled atrial fibrillation. 16. Treatment with phosphodiesterase inhibitors that cannot be withheld 17. Treatment with organic nitrates 18. Significant liver disease impacting synthetic function or volume control (ALT/AST \> 3x ULN, Albumin \<3.0 g/dL) 19. eGFR \< 30 mL/min/1.73m2 20. G6PD deficiency. In males of African, Asian or Mediterranean decent, this will be formally evaluated by enzyme testing prior to drug administration. A negative screening test for G6PD will be required in these subjects for inclusion in the study. If a quantitative test is being performed, a clinically significant reduction in G6PD activity (\<60% of normal) will exclude subjects. 21. Methemoglobinemia - baseline methemoglobin level \>5% 22. Serum K\>5.0 mEq/L 23. Severe right ventricular dysfunction 24. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study. 25. Contraindications to MRI (except as noted below), including the presence of a pacemaker, metal implants, claustrophobia, or that have known medical conditions which can be exacerbated by stress such as anxiety or panic attacks. Inability to lie flat in the MRI scanner for 90 minutes is also an exclusion criterion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases | 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | Subjects will perform a maximal-effort peak oxygen consumption test using a supine bicycle exercise test with expired gas analysis. |
| Change in Total Work Performed During a Maximal-effort Exercise Test From Phase 1 to Phase 2 | 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | Subjects will perform a maximal-effort supine bicycle exercise test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Potassium Nitrate (KNO3) on Muscle Phosphocreatine (PCr) Recovery Kinetics Following a Standardized Plantar Flexor Exercise Protocol | 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | Muscle PCr recovery kinetics were measured using MRI and a standardized plantar flexor exercise protocol with a high resolution spatial mapping of creatine in muscle to analyze creatine chemical exchange saturation transfer and quantify the recovery kinetics of creatine levels. Exercise induces increases in the rate of O2 consumption, which upon cessation of exercise, declines towards baseline in a mono-exponential fashion. This is characterized by a time constant (τ, tau) that corresponds to the time constant of PCr recovery kinetics. Muscle PCr is a marker of oxidative capacity. This outcome measure relates to the half-time derived from linear regression, where a lower value depicts a faster PCr recovery. |
| Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: E/e' Ratio | All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | E/e' ratio is a standard echo parameter that was measured at rest during each visit and calculated using the mitral E, septal e', and lateral e'. This index is parameter for noninvasive left ventricular diastolic function assessment, where an E/e' ratio \< 8 is considered to be normal, and a ratio \> 15 is considered to reflect an increase in the LV filling pressure. |
| Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: Left Atrial Volume Index | All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | Left atrial volume index is a standard echo parameter that was measured at rest during each visit and calculated the body surface area (Dubois and Dubois equation) and left atrial volume from both the two chamber and four chamber views. |
| Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Longitudinal Strain | All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | Peak global systolic myocardial longitudinal strain was evaluated with resting echocardiograms at each visit. Strain was analyzed at the four chamber, two chamber, and three chamber views of the left ventricle and averaged. |
| Effect of Potassium Nitrate (KNO3) on Quality of Life (QOL) | All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | QOL will be assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ). The overall summary score from the KCCQ ranges from 0-100, where higher scores indicate a better quality of life. |
| Effect of Potassium Nitrate (KNO3) on Arterial Wave Reflections as Assessed by Wave Separation Analysis Using Tonometry and Doppler Flow Data | All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | Arterial Wave reflections were assessed via wave separation analysis, using arterial tonometry and Doppler echocardiography. The pulse wave generated by the left ventricle travels forward in arteries and is partially reflected at sites of impedance mismatch (i.e., bifurcations, points of change in arterial size or wall stiffness, predominantly in middle-sized conduit arteries). Wave reflections travel back to the heart, merging into a discrete reflected wave and arrive while the LV is still ejecting blood in mid-to-late systole. Wave reflections increase the late systolic workload of the LV and profoundly impact the LV loading sequence (late relative to early systolic load). |
| Effect of Potassium Nitrate (KNO3) on Augmentation Index | All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | Aortic augmentation index was assessed via comprehensive aortic pressure-flow relations, using arterial tonometry and Doppler echocardiography. It is an indirect measure of arterial stiffness, where a higher value would indicate greater arterial stiffness risk. |
| Effect of Potassium Nitrate (KNO3) on Muscle Blood Flow During Exercise: Muscle Blood Flow During Exercise, Measured With Arterial MRI Spin Labeling During a Standardized Plantar Flexion Exercise Test | 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | MRI studies will be performed at rest and immediately after a standardized plantar flexion exercise. Arterial spin labeling using the flow-sensitive alternating inversion recovery (FAIR) technique will be used to image muscle perfusion with high temporal resolution. |
| Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Circumferential Strain | All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | — |
| Effect of Potassium Nitrate (KNO3) on Late Systolic Wall Stress as Assessed by the Arts Formula Using Echocardiographic and Tonometry Recordings | All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | Late systolic wall stress is assessed via comprehensive aortic pressure-flow relations, using arterial tonometry and Doppler echocardiography. Myocardial wall stress was calculated with the following formula =: Stress = P / \[1/3 In (1 + VW/VLV)\], where ln is the natural logarithm, P is aortic pressure obtained with arterial tonometry, VW is the volume of the LV wall obtained with echocardiography and VLV is the cavity volume obtained with echocardiography |
| Effect of KNO3 on the Percent Change of Systemic Vasodilatory Response to Exercise: The Change in Systemic Vascular Resistance Reserve During Exercise During a Maximal Effort Exercise Test | 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control) | We measured the Systematic vasodilatory response at rest and peak maximal exercise using corresponding echo parameters and blood pressures for each visit. This measure depicts the change from rest and exercise. |
Countries
United States
Participant flow
Pre-assignment details
Following the endpoint assessment of the first phase, subjects will enter a 1-week washout period during which they will not receive any study medications.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Potassium Nitrate (KNO3) Then Potassium Chloride (KCl) Participants were randomized and first received potassium nitrate (KNO3) capsules, providing 6 millimoles of inorganic nitrate per capsule, to be taken three times daily for 6 weeks. Potassium nitrate is the active drug in this trial.
After a washout period of 1 week, participant crossed over to receive potassium chloride (KCl), the matching placebo (control drug) in this trial. Potassium Chloride (KCl) capsules were administered at a dose of 6 millimoles (1 capsule) three times daily for 6 week. | 41 |
| Experimental: Potassium Chloride (KCl) Then Potassium Nitrate (KNO3) Participants were randomized and first received potassium chloride (KCl), the matching placebo (control drug) in this trial. Potassium Chloride (KCl) capsules were administered at a dose of 6 millimoles (1 capsule) three times daily for 6 weeks.
After a washout period of 1 week, participants cross over to receive potassium nitrate (KNO3) capsules, providing 6 millimoles of inorganic nitrate per capsule, to be taken three times daily for 6 weeks. | 43 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase 1 | Physician Decision | 1 | 3 |
| Phase 1 | Withdrawal by Subject | 4 | 0 |
| Phase 2 (Crossover) | Adverse Event | 0 | 1 |
| Phase 2 (Crossover) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Experimental: Potassium Nitrate (KNO3) Then Potassium Chloride (KCl) | Experimental: Potassium Chloride (KCl) Then Potassium Nitrate (KNO3) | Total |
|---|---|---|---|
| 6 Minute Walk Test: Total Meters Walk | 338 meters STANDARD_DEVIATION 102 | 333 meters STANDARD_DEVIATION 94.2 | 336 meters STANDARD_DEVIATION 97.3 |
| Age, Continuous | 69.7 years STANDARD_DEVIATION 7.55 | 67.7 years STANDARD_DEVIATION 11.2 | 68.7 years STANDARD_DEVIATION 9.58 |
| Albumin, total | 4.30 g/dL STANDARD_DEVIATION 0.291 | 4.24 g/dL STANDARD_DEVIATION 0.339 | 4.27 g/dL STANDARD_DEVIATION 0.319 |
| Alkaline phophatase | 78.5 U/L STANDARD_DEVIATION 36.4 | 72.3 U/L STANDARD_DEVIATION 19.4 | 75.3 U/L STANDARD_DEVIATION 29 |
| ALT (alanine transaminase) | 19.0 U/L STANDARD_DEVIATION 8.24 | 22.2 U/L STANDARD_DEVIATION 13.4 | 20.6 U/L STANDARD_DEVIATION 11.2 |
| Anion gap | 8.76 mmol/L STANDARD_DEVIATION 1.39 | 8.59 mmol/L STANDARD_DEVIATION 2.24 | 8.67 mmol/L STANDARD_DEVIATION 1.87 |
| AST (aspartate transferase) | 20.5 U/L STANDARD_DEVIATION 7.93 | 24.0 U/L STANDARD_DEVIATION 11.5 | 22.3 U/L STANDARD_DEVIATION 10 |
| Bilirubin, total | 0.590 mg/dL STANDARD_DEVIATION 0.241 | 0.564 mg/dL STANDARD_DEVIATION 0.195 | 0.577 mg/dL STANDARD_DEVIATION 0.218 |
| Blood Oxygen Saturation | 97.4 percent (%) oxygen saturation STANDARD_DEVIATION 1.23 | 97.5 percent (%) oxygen saturation STANDARD_DEVIATION 1.4 | 97.5 percent (%) oxygen saturation STANDARD_DEVIATION 1.31 |
| Body Mass Index (BMI) | 35.3 kg/m2 STANDARD_DEVIATION 7.89 | 37.1 kg/m2 STANDARD_DEVIATION 7.86 | 36.2 kg/m2 STANDARD_DEVIATION 7.88 |
| Calcium | 9.67 mg/dL STANDARD_DEVIATION 0.398 | 9.65 mg/dL STANDARD_DEVIATION 0.435 | 9.66 mg/dL STANDARD_DEVIATION 0.415 |
| Carbon dioxide | 28.5 mmol/L STANDARD_DEVIATION 2.84 | 28.7 mmol/L STANDARD_DEVIATION 3.02 | 28.6 mmol/L STANDARD_DEVIATION 2.91 |
| Carboxyhemoglobin | 1.82 Percent in blood STANDARD_DEVIATION 0.3777 | 1.67 Percent in blood STANDARD_DEVIATION 0.354 | 1.75 Percent in blood STANDARD_DEVIATION 0.37 |
| Chloride | 101 mmol/L STANDARD_DEVIATION 2.59 | 101 mmol/L STANDARD_DEVIATION 3.15 | 101 mmol/L STANDARD_DEVIATION 2.88 |
| COPD/Asthma | 14 Participants | 11 Participants | 25 Participants |
| Creatinine | 1.01 mg/dL STANDARD_DEVIATION 0.23 | 1.00 mg/dL STANDARD_DEVIATION 0.29 | 1.01 mg/dL STANDARD_DEVIATION 0.261 |
| Current Medications ACE Inhibitors | 13 Participants | 7 Participants | 20 Participants |
| Current Medications Angiotensin Receptor Blockers (ARB) | 15 Participants | 16 Participants | 31 Participants |
| Current Medications Anti Arrythmia | 1 Participants | 2 Participants | 3 Participants |
| Current Medications Anti Coagulation | 2 Participants | 0 Participants | 2 Participants |
| Current Medications Anti Platelet | 28 Participants | 29 Participants | 57 Participants |
| Current Medications Beta Blockers | 26 Participants | 21 Participants | 47 Participants |
| Current Medications Calcium Channel Blockers (CCB) | 15 Participants | 15 Participants | 30 Participants |
| Current Medications Diuretics | 39 Participants | 34 Participants | 73 Participants |
| Current Medications Insulin | 5 Participants | 8 Participants | 13 Participants |
| Current Medications Statins | 27 Participants | 30 Participants | 57 Participants |
| Current Smoker No | 41 Participants | 43 Participants | 84 Participants |
| Current Smoker Yes | 0 Participants | 0 Participants | 0 Participants |
| Diabetes | 17 Participants | 21 Participants | 38 Participants |
| Diastolic Pressure | 74.7 mmHg STANDARD_DEVIATION 8.97 | 74.7 mmHg STANDARD_DEVIATION 10.2 | 74.7 mmHg STANDARD_DEVIATION 9.58 |
| eGFR | 66.4 mL/min/1.73m^2 STANDARD_DEVIATION 16.6 | 70.6 mL/min/1.73m^2 STANDARD_DEVIATION 18.7 | 68.5 mL/min/1.73m^2 STANDARD_DEVIATION 17.7 |
| Ejection Fraction | 61.8 Percent total blood STANDARD_DEVIATION 3.92 | 61.2 Percent total blood STANDARD_DEVIATION 3.57 | 61.5 Percent total blood STANDARD_DEVIATION 3.74 |
| Former smoker No | 17 Participants | 29 Participants | 46 Participants |
| Former smoker Yes | 24 Participants | 14 Participants | 38 Participants |
| Glucose | 108 mg/dL STANDARD_DEVIATION 30.9 | 112 mg/dL STANDARD_DEVIATION 49.6 | 110 mg/dL STANDARD_DEVIATION 41.3 |
| Hematocrit | 39.8 Percent of blood STANDARD_DEVIATION 4.23 | 40.5 Percent of blood STANDARD_DEVIATION 2.98 | 40.1 Percent of blood STANDARD_DEVIATION 3.63 |
| Hemoglobin | 13.4 g/dL STANDARD_DEVIATION 1.48 | 13.6 g/dL STANDARD_DEVIATION 1.18 | 13.3 g/dL STANDARD_DEVIATION 1.28 |
| High Cholesterol | 27 Participants | 33 Participants | 60 Participants |
| Hypertension | 36 Participants | 36 Participants | 72 Participants |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Clinical Summary Score | 68.3 scores on a scale of 0-100 STANDARD_DEVIATION 14 | 62.4 scores on a scale of 0-100 STANDARD_DEVIATION 18.5 | 65.3 scores on a scale of 0-100 STANDARD_DEVIATION 16.6 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Overall Score | 64.9 scores on a scale of 0-100 STANDARD_DEVIATION 14.9 | 58.1 scores on a scale of 0-100 STANDARD_DEVIATION 18.4 | 61.4 scores on a scale of 0-100 STANDARD_DEVIATION 17 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Physical Limitations Score | 67.3 scores on a scale of 0-100 STANDARD_DEVIATION 16.2 | 62.0 scores on a scale of 0-100 STANDARD_DEVIATION 22.7 | 64.6 scores on a scale of 0-100 STANDARD_DEVIATION 19.9 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Quality of Life Score | 65.0 scores on a scale of 0-100 STANDARD_DEVIATION 22.1 | 56.8 scores on a scale of 0-100 STANDARD_DEVIATION 25.8 | 60.8 scores on a scale of 0-100 STANDARD_DEVIATION 24.3 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Self-efficacy Score | 80.2 scores on a scale of 0-100 STANDARD_DEVIATION 22 | 76.5 scores on a scale of 0-100 STANDARD_DEVIATION 30.3 | 78.3 scores on a scale of 0-100 STANDARD_DEVIATION 26.5 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Social Limitation Summary Score | 57.9 scores on a scale of 0-100 STANDARD_DEVIATION 27.5 | 52.7 scores on a scale of 0-100 STANDARD_DEVIATION 23.1 | 55.3 scores on a scale of 0-100 STANDARD_DEVIATION 25.4 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Symptom Frequency Score | 69.0 scores on a scale of 0-100 STANDARD_DEVIATION 21.3 | 62.2 scores on a scale of 0-100 STANDARD_DEVIATION 24.2 | 65.5 scores on a scale of 0-100 STANDARD_DEVIATION 22.9 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Symptom Stability Score | 50.6 scores on a scale of 0-100 STANDARD_DEVIATION 14.2 | 52.3 scores on a scale of 0-100 STANDARD_DEVIATION 17.1 | 51.5 scores on a scale of 0-100 STANDARD_DEVIATION 15.7 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Sympton Burden Score | 69.7 scores on a scale of 0-100 STANDARD_DEVIATION 20.4 | 63.6 scores on a scale of 0-100 STANDARD_DEVIATION 21.4 | 66.6 scores on a scale of 0-100 STANDARD_DEVIATION 21 |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Results Total Symptom Score | 69.3 scores on a scale of 0-100 STANDARD_DEVIATION 19.6 | 62.9 scores on a scale of 0-100 STANDARD_DEVIATION 21 | 66 scores on a scale of 0-100 STANDARD_DEVIATION 20.5 |
| Lateral E/e' Ratio | 10.1 Ratio STANDARD_DEVIATION 3.5 | 11.3 Ratio STANDARD_DEVIATION 5.34 | 10.7 Ratio STANDARD_DEVIATION 4.55 |
| Left Atrial Volume Index | 28.4 mL/m^2 STANDARD_DEVIATION 9.45 | 26.5 mL/m^2 STANDARD_DEVIATION 8.4 | 27.4 mL/m^2 STANDARD_DEVIATION 8.93 |
| MCHC (mean corpuscular hemoglobin concentration) | 33.1 g/dL STANDARD_DEVIATION 0.952 | 33.1 g/dL STANDARD_DEVIATION 0.93 | 33.1 g/dL STANDARD_DEVIATION 0.935 |
| MCH (mean corpuscular hemoglobin) | 29.4 pg STANDARD_DEVIATION 2.74 | 19.3 pg STANDARD_DEVIATION 2 | 19.4 pg STANDARD_DEVIATION 2.37 |
| MCV (mean corpuscular volume) | 88.6 fL STANDARD_DEVIATION 7.4 | 88.8 fL STANDARD_DEVIATION 5.06 | 88.7 fL STANDARD_DEVIATION 6.26 |
| Methemeglobin | 0.729 Percent in blood STANDARD_DEVIATION 0.593 | 0.642 Percent in blood STANDARD_DEVIATION 0.379 | 0.685 Percent in blood STANDARD_DEVIATION 0.494 |
| NT Pro-BNP | 263 pg/mL STANDARD_DEVIATION 332 | 213 pg/mL STANDARD_DEVIATION 359 | 238 pg/mL STANDARD_DEVIATION 344 |
| NYHA Class I | 0 Participants | 0 Participants | 0 Participants |
| NYHA Class II | 33 Participants | 25 Participants | 58 Participants |
| NYHA Class III | 8 Participants | 18 Participants | 26 Participants |
| NYHA Class IV | 0 Participants | 0 Participants | 0 Participants |
| O2 Count | 14.5 mL/dL STANDARD_DEVIATION 2.64 | 15.1 mL/dL STANDARD_DEVIATION 3.96 | 14.8 mL/dL STANDARD_DEVIATION 3.36 |
| Obstructive sleep apnea (OSA) CPAP Use | 17 Participants | 17 Participants | 34 Participants |
| Obstructive sleep apnea (OSA) Obstructive sleep apnea (OSA) | 23 Participants | 23 Participants | 46 Participants |
| Osteoarthritis | 20 Participants | 17 Participants | 37 Participants |
| Oxyhemoglobin | 78.5 Percent in blood STANDARD_DEVIATION 12.9 | 77.4 Percent in blood STANDARD_DEVIATION 16.7 | 77.9 Percent in blood STANDARD_DEVIATION 14.8 |
| Peripheral vascular disease | 3 Participants | 2 Participants | 5 Participants |
| Platelets | 135 THO/uL STANDARD_DEVIATION 69.1 | 247 THO/uL STANDARD_DEVIATION 63.7 | 241 THO/uL STANDARD_DEVIATION 66.2 |
| Potassium | 4.17 mmol/L STANDARD_DEVIATION 0.435 | 4.17 mmol/L STANDARD_DEVIATION 0.391 | 4.17 mmol/L STANDARD_DEVIATION 0.411 |
| Prior Acute Coronary Syndrome or Myocardial infarction | 2 Participants | 5 Participants | 7 Participants |
| Prior Angina | 3 Participants | 11 Participants | 14 Participants |
| Prior Arrythmia | 15 Participants | 17 Participants | 32 Participants |
| Prior CABG | 2 Participants | 3 Participants | 5 Participants |
| Prior CVA/TIA | 3 Participants | 4 Participants | 7 Participants |
| Prior Pulmonary embolism/DVT | 4 Participants | 2 Participants | 6 Participants |
| Prior significant valvular disease or valve surgery in the past | 1 Participants | 2 Participants | 3 Participants |
| Protein, total | 7.13 g/dL STANDARD_DEVIATION 0.59 | 7.07 g/dL STANDARD_DEVIATION 0.501 | 7.10 g/dL STANDARD_DEVIATION 0.544 |
| Race/Ethnicity, Customized Black | 9 Participants | 11 Participants | 20 Participants |
| Race/Ethnicity, Customized White | 32 Participants | 32 Participants | 64 Participants |
| RDW (red blood cell distribution width) | 14.3 Percent red blood cells STANDARD_DEVIATION 1.51 | 14.4 Percent red blood cells STANDARD_DEVIATION 1.31 | 14.3 Percent red blood cells STANDARD_DEVIATION 1.4 |
| Red Blood Cells | 4.52 MIL/uL STANDARD_DEVIATION 0.525 | 4.56 MIL/uL STANDARD_DEVIATION 0.383 | 4.54 MIL/uL STANDARD_DEVIATION 0.455 |
| Region of Enrollment United States | 41 participants | 43 participants | 84 participants |
| Septal E/e' Ratio | 14 Ratio STANDARD_DEVIATION 5.79 | 13.3 Ratio STANDARD_DEVIATION 5.39 | 13.6 Ratio STANDARD_DEVIATION 5.56 |
| Septal Lateral Mean E/e' Ratio | 11.5 Ratio STANDARD_DEVIATION 4.07 | 12.1 Ratio STANDARD_DEVIATION 4.9 | 11.8 Ratio STANDARD_DEVIATION 4.49 |
| Sex: Female, Male Female | 29 Participants | 29 Participants | 58 Participants |
| Sex: Female, Male Male | 12 Participants | 14 Participants | 26 Participants |
| Sodium | 139 mmol/L STANDARD_DEVIATION 2.58 | 129 mmol/L STANDARD_DEVIATION 2.07 | 129 mmol/L STANDARD_DEVIATION 2.32 |
| Systolic Blood Pressure | 130 mmHg STANDARD_DEVIATION 16.9 | 133 mmHg STANDARD_DEVIATION 17.4 | 132 mmHg STANDARD_DEVIATION 17.1 |
| Urea Nitrogen | 20.6 mg/dL STANDARD_DEVIATION 7.76 | 10.0 mg/dL STANDARD_DEVIATION 7.2 | 20.3 mg/dL STANDARD_DEVIATION 7.43 |
| White Blood Cells | 6.68 THO/uL STANDARD_DEVIATION 2.01 | 7.41 THO/uL STANDARD_DEVIATION 1.53 | 7.06 THO/uL STANDARD_DEVIATION 1.81 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 77 | 0 / 74 | 0 / 84 |
| other Total, other adverse events | 43 / 77 | 45 / 74 | 61 / 84 |
| serious Total, serious adverse events | 1 / 77 | 1 / 74 | 1 / 84 |
Outcome results
Primary
Change in Total Work Performed During a Maximal-effort Exercise Test From Phase 1 to Phase 2
Subjects will perform a maximal-effort supine bicycle exercise test.
Time frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Population: Total work was calculated at each phase of the crossover trial. However, the analysis for the t-tests including the reported mean and standard deviation only includes cases in which Phase 1 and Phase 2 were completed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Change in Total Work Performed During a Maximal-effort Exercise Test From Phase 1 to Phase 2 | 26.74341 KJ | Standard Deviation 32.15162 |
| Potassium Chloride (KCl) | Change in Total Work Performed During a Maximal-effort Exercise Test From Phase 1 to Phase 2 | 23.76294 KJ | Standard Deviation 29.8868 |
Comparison: A two-sided α=0.05 was determined by the power calculation.p-value: 0.287195% CI: [-1.910612, 6.3459261]t-test, 2 sided
Comparison: The mixed model analysis provided an assessment of the treatment effect on each continuous outcome of interest while controlling for effects of other covariates such as period, sequence, and a random subject effect. Randomization sequence was not included in the final model due to lack of evidence for a carry over effect. Phase 1 data for participants that did not crossover due to IDS were considered for the model (N=74).p-value: 0.293595% CI: [-6.12, 1.88]Mixed Models Analysis
Primary
Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases
Subjects will perform a maximal-effort peak oxygen consumption test using a supine bicycle exercise test with expired gas analysis.
Time frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Population: As this is a crossover trial, participants received both KNO3 and KCl in different phase, and the sequence of which was dependent on a double blinded randomization. Only participants with outcome data were analyzed. The mean, SD, and t-tests were calculated based on the number of completed cases with successful crossover (N=60), but the mixed model included phase 1 data as well (N=74).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases | 10.31714 L/min/kg | Standard Deviation 3.851249 |
| Potassium Chloride (KCl) | Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases | 10.215172 L/min/kg | Standard Deviation 3.823188 |
Comparison: We considered an increase in peak VO2 of \~0.6 ml/kg/min to be the minimum clinically significant change. Assuming a 90% retention rate, enrolling 84 subjects in this cross-over trial will have 80% power to detect such an effect size in the intervention induced change of our study endpoints with a two-sided α=0.05. PASS11157 was used to perform power calculations.p-value: 0.619195% CI: [-0.6552259, 0.3934043]t-test, 2 sided
Comparison: The mixed model analysis provided an assessment of the treatment effect on each continuous outcome of interest while controlling for effects of other covariates such as period, sequence, and a random subject effect.p-value: 0.71195% CI: [-0.043, 0.62]Mixed Models Analysis
Secondary
Effect of KNO3 on the Percent Change of Systemic Vasodilatory Response to Exercise: The Change in Systemic Vascular Resistance Reserve During Exercise During a Maximal Effort Exercise Test
We measured the Systematic vasodilatory response at rest and peak maximal exercise using corresponding echo parameters and blood pressures for each visit. This measure depicts the change from rest and exercise.
Time frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Effect of KNO3 on the Percent Change of Systemic Vasodilatory Response to Exercise: The Change in Systemic Vascular Resistance Reserve During Exercise During a Maximal Effort Exercise Test | -23.92288 % change | Standard Deviation 23.39527 |
| Potassium Chloride (KCl) | Effect of KNO3 on the Percent Change of Systemic Vasodilatory Response to Exercise: The Change in Systemic Vascular Resistance Reserve During Exercise During a Maximal Effort Exercise Test | -22.13564 % change | Standard Deviation 24.6715 |
p-value: 0.490595% CI: [-5.264221, 10.817366]t-test, 2 sided
Comparison: The mixed model analysis provided an assessment of the treatment effect on each continuous outcome of interest while controlling for effects of other covariates such as period, sequence, and a random subject effect.p-value: 0.79695% CI: [-7.3, 9.48]Mixed Models Analysis
Secondary
Effect of Potassium Nitrate (KNO3) on Arterial Wave Reflections as Assessed by Wave Separation Analysis Using Tonometry and Doppler Flow Data
Arterial Wave reflections were assessed via wave separation analysis, using arterial tonometry and Doppler echocardiography. The pulse wave generated by the left ventricle travels forward in arteries and is partially reflected at sites of impedance mismatch (i.e., bifurcations, points of change in arterial size or wall stiffness, predominantly in middle-sized conduit arteries). Wave reflections travel back to the heart, merging into a discrete reflected wave and arrive while the LV is still ejecting blood in mid-to-late systole. Wave reflections increase the late systolic workload of the LV and profoundly impact the LV loading sequence (late relative to early systolic load).
Time frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Effect of Potassium Nitrate (KNO3) on Arterial Wave Reflections as Assessed by Wave Separation Analysis Using Tonometry and Doppler Flow Data | 0.3681837 unitless | Standard Deviation 0.08317293 |
| Potassium Chloride (KCl) | Effect of Potassium Nitrate (KNO3) on Arterial Wave Reflections as Assessed by Wave Separation Analysis Using Tonometry and Doppler Flow Data | 0.372307 unitless | Standard Deviation 0.0786807 |
| Baseline | Effect of Potassium Nitrate (KNO3) on Arterial Wave Reflections as Assessed by Wave Separation Analysis Using Tonometry and Doppler Flow Data | 0.3804 unitless | Standard Deviation 0.07106 |
p-value: 0.14595% CI: [-0.0454871, 0.0069404]t-test, 2 sided
p-value: 0.304795% CI: [-0.01, 0.04]Mixed Models Analysis
Secondary
Effect of Potassium Nitrate (KNO3) on Augmentation Index
Aortic augmentation index was assessed via comprehensive aortic pressure-flow relations, using arterial tonometry and Doppler echocardiography. It is an indirect measure of arterial stiffness, where a higher value would indicate greater arterial stiffness risk.
Time frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Effect of Potassium Nitrate (KNO3) on Augmentation Index | 122.6139 Index | Standard Deviation 25.40388 |
| Potassium Chloride (KCl) | Effect of Potassium Nitrate (KNO3) on Augmentation Index | 122.5160 Index | Standard Deviation 28.58736 |
| Baseline | Effect of Potassium Nitrate (KNO3) on Augmentation Index | 126.3574 Index | Standard Deviation 26.08744 |
p-value: 0.4495% CI: [-12.598617, 5.585256]t-test, 2 sided
p-value: 0.3991195% CI: [-4.66, 11.44]Mixed Models Analysis
Secondary
Effect of Potassium Nitrate (KNO3) on Late Systolic Wall Stress as Assessed by the Arts Formula Using Echocardiographic and Tonometry Recordings
Late systolic wall stress is assessed via comprehensive aortic pressure-flow relations, using arterial tonometry and Doppler echocardiography. Myocardial wall stress was calculated with the following formula =: Stress = P / \[1/3 In (1 + VW/VLV)\], where ln is the natural logarithm, P is aortic pressure obtained with arterial tonometry, VW is the volume of the LV wall obtained with echocardiography and VLV is the cavity volume obtained with echocardiography
Time frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Effect of Potassium Nitrate (KNO3) on Late Systolic Wall Stress as Assessed by the Arts Formula Using Echocardiographic and Tonometry Recordings | 32.36347 dynes·cm-2·s | Standard Deviation 7.46401 |
| Potassium Chloride (KCl) | Effect of Potassium Nitrate (KNO3) on Late Systolic Wall Stress as Assessed by the Arts Formula Using Echocardiographic and Tonometry Recordings | 34.31358 dynes·cm-2·s | Standard Deviation 7.837627 |
| Baseline | Effect of Potassium Nitrate (KNO3) on Late Systolic Wall Stress as Assessed by the Arts Formula Using Echocardiographic and Tonometry Recordings | 33.95494 dynes·cm-2·s | Standard Deviation 7.746475 |
p-value: 0.0798495% CI: [-4.4966754, 0.2638017]t-test, 2 sided
p-value: 0.13595% CI: [-0.54, 3.9]Mixed Models Analysis
Secondary
Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: E/e' Ratio
E/e' ratio is a standard echo parameter that was measured at rest during each visit and calculated using the mitral E, septal e', and lateral e'. This index is parameter for noninvasive left ventricular diastolic function assessment, where an E/e' ratio \< 8 is considered to be normal, and a ratio \> 15 is considered to reflect an increase in the LV filling pressure.
Time frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Population: All participants were expected to undergo an echocardiogram at each visit (baseline, Phase 1, and Phase 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: E/e' Ratio | 11.84599 Ratio | Standard Deviation 3.981865 |
| Potassium Chloride (KCl) | Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: E/e' Ratio | 11.61516 Ratio | Standard Deviation 4.265457 |
| Baseline | Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: E/e' Ratio | 11.7999 Ratio | Standard Deviation 4.48822 |
p-value: 0.563695% CI: [-0.4959279, 0.9014918]t-test, 2 sided
Comparison: The mixed model analysis provided an assessment of the treatment effect on each continuous outcome of interest while controlling for effects of other covariates such as period, sequence, and a random subject effect.p-value: 0.36195% CI: [-0.99, 0.37]Mixed Models Analysis
Secondary
Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: Left Atrial Volume Index
Left atrial volume index is a standard echo parameter that was measured at rest during each visit and calculated the body surface area (Dubois and Dubois equation) and left atrial volume from both the two chamber and four chamber views.
Time frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: Left Atrial Volume Index | 26.63060 mL/m2 | Standard Deviation 7.812431 |
| Potassium Chloride (KCl) | Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: Left Atrial Volume Index | 27.65687 mL/m2 | Standard Deviation 9.931385 |
| Baseline | Effect of Potassium Nitrate (KNO3) on Left Ventricle (LV) Diastolic Function: Left Atrial Volume Index | 27.4408 mL/m2 | Standard Deviation 8.9284 |
p-value: 0.770795% CI: [-1.1998786, 0.8934502]t-test, 2 sided
Comparison: The mixed model analysis provided an assessment of the treatment effect on each continuous outcome of interest while controlling for effects of other covariates such as period, sequence, and a random subject effect.p-value: 0.72495% CI: [-0.88, 1.25]Mixed Models Analysis
Secondary
Effect of Potassium Nitrate (KNO3) on Muscle Blood Flow During Exercise: Muscle Blood Flow During Exercise, Measured With Arterial MRI Spin Labeling During a Standardized Plantar Flexion Exercise Test
MRI studies will be performed at rest and immediately after a standardized plantar flexion exercise. Arterial spin labeling using the flow-sensitive alternating inversion recovery (FAIR) technique will be used to image muscle perfusion with high temporal resolution.
Time frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Population: Analysis could not be performed as the MRI studies were not able to extract this measure.
Secondary
Effect of Potassium Nitrate (KNO3) on Muscle Phosphocreatine (PCr) Recovery Kinetics Following a Standardized Plantar Flexor Exercise Protocol
Muscle PCr recovery kinetics were measured using MRI and a standardized plantar flexor exercise protocol with a high resolution spatial mapping of creatine in muscle to analyze creatine chemical exchange saturation transfer and quantify the recovery kinetics of creatine levels. Exercise induces increases in the rate of O2 consumption, which upon cessation of exercise, declines towards baseline in a mono-exponential fashion. This is characterized by a time constant (τ, tau) that corresponds to the time constant of PCr recovery kinetics. Muscle PCr is a marker of oxidative capacity. This outcome measure relates to the half-time derived from linear regression, where a lower value depicts a faster PCr recovery.
Time frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Population: MRI was not completed throughout the duration of the study and only completed at one site (University of Pennsylvania).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Effect of Potassium Nitrate (KNO3) on Muscle Phosphocreatine (PCr) Recovery Kinetics Following a Standardized Plantar Flexor Exercise Protocol | 159.5455 seconds | Standard Deviation 99.54442 |
| Potassium Chloride (KCl) | Effect of Potassium Nitrate (KNO3) on Muscle Phosphocreatine (PCr) Recovery Kinetics Following a Standardized Plantar Flexor Exercise Protocol | 219.8485 seconds | Standard Deviation 149.41312 |
p-value: 0.401795% CI: [-133.63637, 57.41259]t-test, 2 sided
p-value: 0.18395% CI: [-34.15, 157.69]Mixed Models Analysis
Secondary
Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Circumferential Strain
Time frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Population: Peak Global Systolic Myocardial Circumferential Strain was not analyzed in the echocardiogram as this measure was not quantified at all during the study; instead, other strain measurements were evaluated alternatively that are considered to be more reliable.
Secondary
Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Longitudinal Strain
Peak global systolic myocardial longitudinal strain was evaluated with resting echocardiograms at each visit. Strain was analyzed at the four chamber, two chamber, and three chamber views of the left ventricle and averaged.
Time frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Population: All participants underwent an echocardiogram at each visit; however, participants in which these echo measures could not be reliably quantified were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Longitudinal Strain | 18.04317 % (change in length) | Standard Deviation 2.812165 |
| Potassium Chloride (KCl) | Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Longitudinal Strain | 17.273221 % (change in length) | Standard Deviation 3.003472 |
| Baseline | Effect of Potassium Nitrate (KNO3) on Myocardial Systolic Strain: Peak Global Systolic Myocardial Longitudinal Strain | 17.7164 % (change in length) | Standard Deviation 2.289224 |
p-value: 0.168082595% CI: [-0.1421806, 0.7947447]t-test, 2 sided
p-value: 0.09395% CI: [-0.88, 0.07]Mixed Models Analysis
Secondary
Effect of Potassium Nitrate (KNO3) on Quality of Life (QOL)
QOL will be assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ). The overall summary score from the KCCQ ranges from 0-100, where higher scores indicate a better quality of life.
Time frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)
Population: As this is a crossover trial, participants received both KNO3 and KCl in different phases, the sequence of which was dependent on a double blinded randomization. Only participants with KCCQ results were analyzed. The mean, SD, and t-tests were calculated based on the number of completed cases with successful crossover (N=66), but the mixed model included phase 1 data as well. Baseline scores for all participants were analyzed in the mixed model as a predictive value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Potassium Nitrate (KNO3) | Effect of Potassium Nitrate (KNO3) on Quality of Life (QOL) | 66.06147 score on a scale | Standard Deviation 18.99883 |
| Potassium Chloride (KCl) | Effect of Potassium Nitrate (KNO3) on Quality of Life (QOL) | 62.77142 score on a scale | Standard Deviation 18.95087 |
| Baseline | Effect of Potassium Nitrate (KNO3) on Quality of Life (QOL) | 61.4335 score on a scale | Standard Deviation 17.02081 |
p-value: 0.17195% CI: [-0.9674467, 5.3392901]t-test, 2 sided
Comparison: The mixed model analysis provided an assessment of the treatment effect on each continuous outcome of interest while controlling for effects of other covariates such as period, sequence, and a random subject effect.p-value: 0.11395% CI: [-5.62, 0.61]Mixed Models Analysis