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| Name | Class |
|---|---|
| American Heart Association | OTHER |
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While preliminary data show that oral nicotinamide riboside (NR) supplementation increases myocardial levels of oxidized nicotine-adenine dinucleotide (NAD+) levels in mice, there has been no direct evidence that suggests oral NR increases NAD+ levels or improves mitochondrial function in human hearts. This Pilot Study is designed to obtain feasibility data for a planned, larger study testing the hypothesis that oral NR supplementation will increase myocardial NAD+ levels and improve cardiomyocyte mitochondrial function in participants with advanced heart failure planned for elective left ventricular assist device (LVAD) implantation. To demonstrate safety and feasibility of NR in this patient population, the investigators propose to enroll 5 participants planned for LVAD implantation in a Pilot Study of NR in which participants will receive NR, up-titrated over 3 days to a final NR dose of 1000mg twice daily. Blood and myocardial tissue analyses collected previously from age- and gender-matched LVAD recipients will serve as controls.
This Pilot Study will examine the following Aims:
Aim 1: Enroll 5 participants scheduled for elective left ventricular assist device (LVAD) placement into an open-label study of nicotinamide riboside (NR).
a. Participants will have labs (including safety panels) drawn at baseline (Day 1), then receive escalating doses of NR to a maximum dose of 1000mg twice daily by Day 3. Participants will be continued on NR at 1000mg twice daily until LVAD implantation surgery.
On the morning of LVAD implantation Surgery (Day 5 or later), participants will have final labs drawn. Samples of fresh cardiac tissue removed from the left ventricular apex during LVAD implantation surgery will be collected in the operating room. The primary analyses will be performed on NR-treated participants who were on the maximum NR dose of 1000mg twice daily for at least 2 days prior to LVAD implantation surgery. The maximum duration of NR administration will be capped at 14 days. If the surgery doesn't happen by then, the participant will be withdrawn from the study.
Aim 2: Determine the effect of NR (as compared to historical controls) on levels of the oxidized and reduced forms of nicotine-adenine dinucleotide (NAD+ and NADH, respectively), mitochondrial function and its regulation through modifications of the epigenome in the failing myocardium.
Aim 3: Test the hypothesis that NR improves mitochondrial function and reduces inflammatory response in heart failure (HF) patients receiving NR (as compared to historical controls).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Open-label nicotinamide riboside | Experimental | Participants scheduled to receive an LVAD will be prescribed nicotinamide riboside (NR) according to the following administration schedule: Dose Escalation Day 1: 250 mg (1 capsule) twice daily (total daily intake = 500 mg) Day 2: 500 mg (2 capsules) twice daily (total daily intake = 1000 mg) Day 3: 1000 mg (4 capsules) twice daily (total daily intake = 2000 mg) Dose Maintenance Day 4: 1000 mg (4 capsules) twice daily Day 5-14 as applicable thru Day Before Surgery: 1000 mg (4 capsules) twice daily Washout Day of LVAD Surgery and/or Day 15: None |
|
| Baseline controls | No Intervention | Patients previously receiving LVADs, in whom blood and myocardial tissue assays for NAD+ levels and mitochondrial function were performed. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nicotinamide riboside | Dietary Supplement | nicotinamide riboside supplied as 250mg capsules |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participates Experiencing Treatment-Emergent Adverse Events (Safety and Tolerability) | Participants experiencing adverse events during the time they are on the study drug. Regarding time frame: Day 1 is the first day that the study subjects start taking the study drug (NR). The participants stop taking the study drug on the day before his/her LVAD surgery (between Days 6 and 14). | from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14) |
| Pre/Post NR Comparison of Maximal Mitochondrial Respiration in PBMCs | Comparison of maximal mitochondrial respiration in PBMCs on the Day of LVAD Surgery Pre- vs Post-NR Administration | from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14) |
| Measure | Description | Time Frame |
|---|---|---|
| Effect of NR on Whole Blood NAD+ Levels | Change in whole blood NAD+ levels from Baseline to Day of Surgery in NR-treated participants | from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14) |
| Between-group Comparison of Mitochondrial Respiration (Seahorse Assay) in Isolated Peripheral Blood Mononuclear Cells (PBMCs) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kevin 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 |
|---|---|---|---|
| 32790648 | Result | Zhou B, Wang DD, Qiu Y, Airhart S, Liu Y, Stempien-Otero A, O'Brien KD, Tian R. Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. J Clin Invest. 2020 Nov 2;130(11):6054-6063. doi: 10.1172/JCI138538. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Open-label Nicotinamide Riboside | Participants scheduled to receive an LVAD will be prescribed nicotinamide riboside (NR) according to the following administration schedule: Dose Escalation Day 1: 250 mg (1 capsule) twice daily (total daily intake = 500 mg) Day 2: 500 mg (2 capsules) twice daily (total daily intake = 1000 mg) Day 3: 1000 mg (4 capsules) twice daily (total daily intake = 2000 mg) Dose Maintenance Day 4: 1000 mg (4 capsules) twice daily Day 5-14 as applicable thru Day Before Surgery: 1000 mg (4 capsules) twice daily Washout Day of LVAD Surgery and/or Day 15: None Nicotinamide riboside: nicotinamide riboside supplied as 250mg capsules |
| FG001 | Baseline Controls | Patients previously receiving LVADs, in whom blood and myocardial tissue assays for NAD+ levels and mitochondrial function were performed. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
We did not have the funding to enroll baseline controls.
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| ID | Title | Description |
|---|---|---|
| BG000 | Open-label Nicotinamide Riboside | Participants scheduled to receive an LVAD will be prescribed nicotinamide riboside (NR) according to the following administration schedule: Dose Escalation Day 1: 250 mg (1 capsule) twice daily (total daily intake = 500 mg) Day 2: 500 mg (2 capsules) twice daily (total daily intake = 1000 mg) Day 3: 1000 mg (4 capsules) twice daily (total daily intake = 2000 mg) Dose Maintenance Day 4: 1000 mg (4 capsules) twice daily Day 5-14 as applicable thru Day Before Surgery: 1000 mg (4 capsules) twice daily Washout Day of LVAD Surgery and/or Day 15: None Nicotinamide riboside: nicotinamide riboside supplied as 250mg capsules |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Number of Participates Experiencing Treatment-Emergent Adverse Events (Safety and Tolerability) | Participants experiencing adverse events during the time they are on the study drug. Regarding time frame: Day 1 is the first day that the study subjects start taking the study drug (NR). The participants stop taking the study drug on the day before his/her LVAD surgery (between Days 6 and 14). | We did not enroll any baseline control subjects. | Posted | Count of Participants | Participants | from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14) |
|
from Day 1 receiving NR to 30 days post-LVAD implantation.
The study patients were on NR for a short period of time and it is extremely difficult to tease out their symptoms of terminal HF versus those from NR administration.
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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 | Open-label Nicotinamide Riboside | Participants scheduled to receive an LVAD will be prescribed nicotinamide riboside (NR) according to the following administration schedule: Dose Escalation Day 1: 250 mg (1 capsule) twice daily (total daily intake = 500 mg) Day 2: 500 mg (2 capsules) twice daily (total daily intake = 1000 mg) Day 3: 1000 mg (4 capsules) twice daily (total daily intake = 2000 mg) Dose Maintenance Day 4: 1000 mg (4 capsules) twice daily Day 5-14 as applicable thru Day Before Surgery: 1000 mg (4 capsules) twice daily Washout Day of LVAD Surgery and/or Day 15: None Nicotinamide riboside: nicotinamide riboside supplied as 250mg capsules |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac Arrest | Cardiac disorders | Systematic Assessment | The cardiac arrest was determined by our DSMB to be independent of NR administration. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Kevin Douglas O'Brien | University of Washington | 2065984300 | 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: Study Protocol | Nov 18, 2018 | Apr 17, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Nov 18, 2018 | Apr 17, 2024 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C018613 | nicotinamide-beta-riboside |
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This single-center, open-label study will compare blood and myocardial NAD+ levels and other mitochondrial endpoints in participants with end-stage heart failure receiving open-label nicotinamide riboside prior to LVAD implantation to similar endpoints from patients previously undergoing LVAD implantation.
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Study biostatistician will be blinded to group (NR vs. untreated controls)
Comparison of mitochondrial respiration (Seahorse assay) in isolated peripheral blood mononuclear cells (PBMCs) on the Day of LVAD Surgery in NR-treated vs. historical control patients |
| Data collected 6-14 days after study intervention (oral NR) has been initiated. |
| Between-group Comparison of Whole Blood NAD+ Levels | Comparison of whole blood NAD+ levels on the Day of LVAD Surgery in NR-treated vs. historical control patients | Data collected 6-14 days after study intervention (oral NR) has been initiated. |
| BG001 | Baseline Controls | Patients previously receiving LVADs, in whom blood and myocardial tissue assays for NAD+ levels and mitochondrial function were performed. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| LV Ejection Fraction | Mean | Full Range | % |
|
| OG001 | Baseline Controls | Patients previously receiving LVADs, in whom blood and myocardial tissue assays for NAD+ levels and mitochondrial function were performed. |
|
|
| Primary | Pre/Post NR Comparison of Maximal Mitochondrial Respiration in PBMCs | Comparison of maximal mitochondrial respiration in PBMCs on the Day of LVAD Surgery Pre- vs Post-NR Administration | We did not have the funds to enroll baseline control subjects. | Posted | Mean | Standard Deviation | pmole/min/million cells (O2 consump rate | from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14) |
|
|
|
| Secondary | Effect of NR on Whole Blood NAD+ Levels | Change in whole blood NAD+ levels from Baseline to Day of Surgery in NR-treated participants | Posted | Mean | Standard Deviation | ug/mL | from Day 1 receiving NR to the day before LVAD surgery (between Day 6-Day 14) |
|
|
|
| Secondary | Between-group Comparison of Mitochondrial Respiration (Seahorse Assay) in Isolated Peripheral Blood Mononuclear Cells (PBMCs) | Comparison of mitochondrial respiration (Seahorse assay) in isolated peripheral blood mononuclear cells (PBMCs) on the Day of LVAD Surgery in NR-treated vs. historical control patients | The control subjects were unfortunately not enrolled so we were unable to make the intergroup comparison. | Posted | Mean | Standard Deviation | pmole/min/million cells (O2 consump rate | Data collected 6-14 days after study intervention (oral NR) has been initiated. |
|
|
|
| Secondary | Between-group Comparison of Whole Blood NAD+ Levels | Comparison of whole blood NAD+ levels on the Day of LVAD Surgery in NR-treated vs. historical control patients | We unfortunately did not enroll any control subjects, hence were unable to make the intergroup comparison. | Posted | Mean | Standard Deviation | ug/mL | Data collected 6-14 days after study intervention (oral NR) has been initiated. |
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| 1 |
| 5 |
| 2 |
| 5 |
| 0 |
| 5 |
| EG001 | Baseline Controls | Patients previously receiving LVADs, in whom blood and myocardial tissue assays for NAD+ levels and mitochondrial function were performed. | 0 | 0 | 0 | 0 | 0 | 0 |
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| Death | Nervous system disorders | Systematic Assessment | The death resulting from post-LVAD CVA was determined to be unrelated to NR administration by our DSMB. |
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