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| ID | Type | Description | Link |
|---|---|---|---|
| 1R21HL126209-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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Mitochondrial dysfunction has been implicated in heart failure (HF), and is associated with an imbalance in intracellular ratio of reduced nicotinamide-adenine dinucleotide (NADH) to oxidized nicotinamide-adenine dinucleotide (NAD), or the NADH/NAD ratio. In mouse models of HF, we have found that normalization of the NADH/NAD, through supplementation with NAD+ precursors, is associated with improvement in cardiac function. This Study will randomize participants with systolic HF (ejection fraction ≤40%) to treatment with the NAD precursor, nicotinamide riboside (NR) or matching placebo, uptitrated to a final oral dose of 1000mg twice daily, to determine the safety and tolerability of NR in participants with systolic HF.
Aim 1: Determine the safety and tolerability of NR in patients with clinically stable, systolic heart failure (LVEF <40%). To accomplish this Aim:
A) a total of 30 participants with clinically stable, systolic heart failure (LVEF <40%) will undergo 2:1 randomization to NR 250mg PO twice daily or matching placebo B) NR (or matching placebo), will be increased weekly by 250mg/dose (500mg/day) to a final dose of 1000mg PO twice daily. Clinic visits with labs bi-weekly during dose escalation will assess HF symptoms and monitor labs [B-type natriuretic peptide (BNP), complete blood count (CBC), glycosylated hemoglobin, alanine aminotransferase (ALT), creatine kinase (CK), insulin/glucose, uric acid, electrolytes, blood urea nitrogen (BUN) and creatinine (Cr).
C) to ensure intermediate-term safety and tolerability, participants will continue on their maximum tolerated dose (of NR or placebo) through Study Week 12
Aim 2: Determine whether, at the doses employed, NR and NAD are detectable in whole blood.
Aim 3 (Exploratory): Assess the range of potential effect sizes of NR on HF surrogate endpoints using:
A) Six-minute walk tests (6MWTs) at each visit (including Screening) to assess functional capacity B) Echocardiography at Baseline and Week 12 to assess LV systolic function (by real-time, 3D echocardiography) and diastolic function (by integrated Doppler and tissue Doppler imaging)](streamdown:incomplete-link)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nicotinamide Riboside | Experimental | Nicotinamide riboside will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12. |
|
| Placebo | Placebo Comparator | Matching placebo will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| nicotinamide riboside | Dietary Supplement | nicotinamide riboside capsule |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Adverse Events | up to 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| On-Trial Change in Whole Blood NAD+ Levels | Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels | Week 12-Week 0 |
| Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Exploratory Endpoint: Effect of NR on Functional Capacity | Change in Six Minute Walk Distance | Week 12 - Week 0 |
| Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function | Change in Left Ventricular Ejection Fraction by 3D-Transthoracic Echocardiography |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kevin D O'Brien, MD | University of Washington | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Washington | Seattle | Washington | 98195 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36644285 | Derived | Wang DD, Airhart SE, Zhou B, Shireman LM, Jiang S, Melendez Rodriguez C, Kirkpatrick JN, Shen DD, Tian R, O'Brien KD. Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction. JACC Basic Transl Sci. 2022 Sep 14;7(12):1183-1196. doi: 10.1016/j.jacbts.2022.06.012. eCollection 2022 Dec. |
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A de-identified, public access database will be made available two years after publication of the primary study results. Data files will be delivered in electronic format, providing meta-data that completely describes the tables, variables and coding. Both the raw data and the primary analysis files will be included. Primary analysis files are a compilation of key variables used to generate the statistical results, to help assure that investigators reach consistent conclusions when analyzing the data to published results. Data, documentation and all other materials will be delivered to NHLBI, as well as a document that fully describes the data, steps taken to de-identify the data, and quality control procedures. A document summarizing data tables and other files that are being delivered and describing the data manipulations applied to the data to assure data anonymity, including an annotated clinical study report providing the database variable names.
2 years following Study completion
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| ID | Title | Description |
|---|---|---|
| FG000 | Nicotinamide Riboside | Nicotinamide riboside will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12. nicotinamide riboside: nicotinamide riboside capsule |
| FG001 | Placebo | Matching placebo will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12. Placebo: matching placebo capsule |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Nicotinamide Riboside | Nicotinamide riboside will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12. nicotinamide riboside: nicotinamide riboside capsule |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Adverse Events | Total Adverse Events, per participant | Posted | Mean | Full Range | events/participant | up to 12 weeks |
|
16 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Nicotinamide Riboside | Nicotinamide riboside will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12. nicotinamide riboside: nicotinamide riboside capsule |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Myalgia, severe | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nervous system disorders | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Kevin O'Brien, Study PI | University of Washington | 206-529-7802 | cardiac@uw.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 29, 2018 | Oct 26, 2022 | Prot_002.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 27, 2022 | Sep 27, 2022 | SAP_003.pdf |
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| ID | Term |
|---|---|
| D054143 | Heart Failure, Systolic |
| ID | Term |
|---|---|
| D006333 | Heart Failure |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C018613 | nicotinamide-beta-riboside |
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2:1 randomization to nicotinamide riboside vs. matching placebo
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Randomization and dispensing of matching placebo will be performed by Investigational Drug Services at the University of Washington
| Placebo | Drug | matching placebo capsule |
|
Incidence of On-Trial Abnormal Laboratory Values and/or Adverse Events that Are Related to Treatment
| 16 weeks |
| Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate) | Mitochondrial Respiration in Isolated Peripheral Blood Mononuclear Cells by the Seahorse (R) Assay | Week 12 - Week 0 |
| Week 12 - Week 0 |
| Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function | Tissue Doppler Imaging, e' | Week 12 - Week 0 |
| BG001 | Placebo | Matching placebo will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12. Placebo: matching placebo capsule |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Sitting Blood Pressure Systolic | Mean | Full Range | mmHg |
|
| Sitting Blood Pressure Diastolic | Mean | Full Range | mmHg |
|
| Heart rate | Mean | Full Range | beats/min |
|
| Weight | Mean | Full Range | kg |
|
| Height | Mean | Full Range | cm |
|
| Smoking: Never | Count of Participants | Participants |
|
| Alcohol: Never | Count of Participants | Participants |
|
| Non-ischemic heart failure | Count of Participants | Participants |
|
| Left ventricular (LV) ejection fraction [LV stroke volume (SV)/LV end-diastolic volume (LVEDV)] | Mean | Full Range | percentage of ejection fraction |
|
| Previous myocardial infarction | Count of Participants | Participants |
|
| Previous coronary artery bypass surgery | Count of Participants | Participants |
|
| Previous percutaneous coronary intervention | Count of Participants | Participants |
|
| History of hypertension | Count of Participants | Participants |
|
| History of dyslipidemia | Count of Participants | Participants |
|
| History of atherosclerotic disease (coronary, peripheral or carotid) | Count of Participants | Participants |
|
| History of atrial fibrillation | Count of Participants | Participants |
|
| History of atrial flutter | Count of Participants | Participants |
|
| History of diabetes | Count of Participants | Participants |
|
| Liver disease | Count of Participants | Participants |
|
| Emphysema | Count of Participants | Participants |
|
| Serum potassium | Mean | Full Range | mEq/L |
|
| Serum glucose | Mean | Full Range | mg/dL |
|
| Serum creatinine | Mean | Full Range | mg/dL |
|
| Alanine aminotransferase, U/L | Mean | Full Range | U/L |
|
| Body temperature | Mean | Full Range | degrees Celsius |
|
| White blood count | Mean | Full Range | cells x 1000/uL |
|
| Hematocrit | Mean | Full Range | % |
|
| Hemoglobin | Mean | Full Range | g/dL |
|
| Platelet count, thousand/uL | Mean | Full Range | cells x 1000/uL |
|
| Aspartate aminotransferase | Mean | Full Range | U/L |
|
| Insulin resistance (homeostasis model assessment) | Mean | Full Range | units |
|
| Estimated glomerular filtration rate | Mean | Full Range | mL/min/1.73_m2 |
|
| Placebo |
Matching placebo will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12. Placebo: matching placebo capsule |
|
|
| Secondary | On-Trial Change in Whole Blood NAD+ Levels | Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels | Post enrollment, one of the study participants randomized to NR withdraw before the study drug was dispensed. | Posted | Mean | Standard Error | uM | Week 12-Week 0 |
|
|
|
|
| Secondary | Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment | Incidence of On-Trial Abnormal Laboratory Values and/or Adverse Events that Are Related to Treatment | Posted | Number | participants | 16 weeks |
|
|
|
|
| Secondary | Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate) | Mitochondrial Respiration in Isolated Peripheral Blood Mononuclear Cells by the Seahorse (R) Assay | One study subject randomized to NR withdrew post enrollment. | Posted | Mean | Standard Error | pmol/min/1,000,000 cells | Week 12 - Week 0 |
|
|
|
|
| Other Pre-specified | Exploratory Endpoint: Effect of NR on Functional Capacity | Change in Six Minute Walk Distance | Posted | Mean | Standard Error | meters | Week 12 - Week 0 |
|
|
|
|
| Other Pre-specified | Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function | Change in Left Ventricular Ejection Fraction by 3D-Transthoracic Echocardiography | One study subject randomized to NR withdrew post-enrollment. We were unable to obtain the LVEF for one of the enrolled patient randomized to NR. | Posted | Mean | Standard Error | percentage of ejection fraction | Week 12 - Week 0 |
|
|
|
|
| Other Pre-specified | Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function | Tissue Doppler Imaging, e' | Posted | Mean | Standard Error | cm/sec | Week 12 - Week 0 |
|
|
|
|
| 0 |
| 20 |
| 1 |
| 20 |
| 19 |
| 20 |
| EG001 | Placebo | Matching placebo will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12. Placebo: matching placebo capsule | 0 | 10 | 2 | 10 | 9 | 10 |
| Acute pulmonary edema | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Heart failure | Cardiac disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Infections and infestations | Infections and infestations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Renal and urinary disorders | Renal and urinary disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Musculoskeletal and connective tissue disorders | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| General disorders and administration site conditions | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Gastrointestinal disorders | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Respiratory, thoracic and mediastinal disorders | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Skin and subcutaneous tissue disorders | Skin and subcutaneous tissue disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Metabolism and nutrition disorders | Metabolism and nutrition disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Cardiac disorders | Cardiac disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
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