NR Supplementation for Bone Marrow Transplant Engraftment Improvement

Overseen By Ronald Sobecks, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Case Comprehensive Cancer Center

Disqualifiers: Myelofibrosis, Pregnancy, Allergy to niacin, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 21 days

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks a safe method to enhance recovery after a bone marrow transplant. Researchers are testing whether adding nicotinamide riboside, a vitamin B supplement, to donor cells can increase blood stem cell numbers and accelerate recovery. The trial seeks participants planning to undergo a specific type of bone marrow transplant with a matching human donor. Individuals with certain allergies or conditions that might interfere with the trial requirements are not suitable for this study. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to contribute to groundbreaking medical advancements.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that nicotinamide riboside is likely to be safe for humans?

Research has shown that nicotinamide riboside (NR), a type of vitamin B3, is generally safe. Some studies indicate that NR is as safe as nicotinamide, another form of vitamin B3. Even in high amounts, the main concerns involve effects on the liver and kidneys, but these effects were not serious.

NR is also sold as a dietary supplement, suggesting it is safe for most people. However, this study is in an early stage, so researchers are still carefully monitoring its safety. While NR appears promising, participants should know it is still under testing, and any potential risks are being closely observed. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Nicotinamide Riboside (NR) because it offers a fresh approach to improving bone marrow transplant engraftment. Unlike traditional treatments that focus on immune suppression or support, NR works by boosting cellular energy and enhancing cell repair through a unique mechanism that increases NAD+ levels, a vital molecule for cell function and resilience. This could potentially lead to faster and more effective engraftment, providing a significant advantage over existing therapies.

What evidence suggests that nicotinamide riboside might be an effective treatment for improving engraftment?

Research suggests that nicotinamide riboside (NR), a type of vitamin B3, might enhance the success of bone marrow transplants. In this trial, participants will receive NR to evaluate its effects on transplant outcomes. Studies have found that NR can increase the number of blood stem cells, potentially speeding up the time for new cells to grow in the body after a transplant. This could reduce the risk of complications and lead to better long-term health. Specifically, NR has increased the number of early-stage cells without exhausting them, significantly improving survival rates. Overall, NR shows promise in supporting healthier cell growth and recovery after a bone marrow transplant. ^{4 6 7 8 9}

Who Is on the Research Team?

Ronald Sobecks, MD

Principal Investigator

Cleveland Clinic, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals who are eligible for a bone marrow transplant with myeloablative conditioning and have an HLA-identical donor. It's not suitable for pregnant or breastfeeding women, those with uncontrolled illnesses or psychiatric conditions that could affect compliance, or anyone allergic to NR compounds like niacin.

Inclusion Criteria

Subjects must provide a written informed consent

I have a matching donor for my bone marrow transplant.

I am eligible and planning to undergo a bone marrow transplant with intensive preparation.

Exclusion Criteria

History of allergy or intolerance to NR precursor compounds, including niacin or nicotinamide

I am not pregnant or breastfeeding.

Subjects with uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nicotinamide riboside supplementation to improve engraftment after allogeneic hematopoietic cell transplantation

Up to 21 days

Frequent monitoring visits during treatment

Engraftment Monitoring

Participants are monitored for engraftment, defined as the process during which transplanted stem cells begin to grow in the bone marrow

14-24 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neutrophil and platelet recovery

Up to 100 days

What Are the Treatments Tested in This Trial?

Interventions

• Nicotinamide Riboside (NR)

Trial Overview

The study is testing the addition of Nicotinamide Riboside (NR), a vitamin B supplement, to donor cells in bone marrow transplants. The goal is to see if it can safely increase stem cell numbers and speed up engraftment after the transplant.

How Is the Trial Designed?

Group I: Nicotinamide riboside (NR) Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Published Research Related to This Trial

A single oral dose of nicotinamide riboside (NR) can significantly increase blood NAD+ levels, with a reported rise of up to 2.7-fold in an individual, indicating its potential efficacy as an NAD+ precursor.

In a clinical trial involving various doses (100, 300, and 1,000 mg), NR was shown to produce dose-dependent increases in blood NAD+ metabolites, and the formation of nicotinic acid adenine dinucleotide (NAAD) from NR was identified as a sensitive biomarker for effective NAD+ repletion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Trammell, SA., Schmidt, MS., Weidemann, BJ., et al.[2021]

Primitive hematopoietic cells, including myeloid progenitors and hematopoietic stem cells (HSCs), can resist the toxic effects of the antifolate drug trimetrexate (TMTX) by salvaging extracellular nucleotide precursors like thymidine and hypoxanthine.

Using nucleoside transport inhibitors, such as nitrobenzylmercaptopurineriboside phosphate (NBMPR-P), significantly sensitized these progenitor cells and HSCs to TMTX in vivo, leading to a dramatic reduction in their numbers and bone marrow repopulating activity, suggesting a potential strategy to enhance the efficacy of antifolate therapies in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sensitization of hematopoietic stem and progenitor cells to trimetrexate using nucleoside transport inhibitors. Allay, JA., Spencer, HT., Wilkinson, SL., et al.[2021]

A gene therapy strategy using the MeiIRG vector can protect bone marrow cells from severe myelosuppression caused by the combination of antifolate drugs and the nucleoside transport inhibitor NBMPR, as shown in both in vitro and in vivo studies.

Mice treated with MeiIRG-transduced bone marrow cells exhibited reduced toxicity, improved blood cell counts, and a survival advantage, suggesting that this approach allows for higher doses of chemotherapy while safeguarding healthy cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retroviral transfer of the hENT2 nucleoside transporter cDNA confers broad-spectrum antifolate resistance in murine bone marrow cells. Patel, DH., Allay, JA., Belt, JA., et al.[2021]

Anabolic steroids have been shown to effectively stimulate the recovery of blood cell production (granulopoiesis and erythropoiesis) in patients after chemotherapy, potentially reducing the need for expensive supportive therapies.

Lithium and hypertransfusion may also enhance blood cell recovery, but more research is needed to confirm their effectiveness and safety before they can be widely recommended for clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hematopoietic stimulation for enhanced bone marrow regeneration after chemotherapy (author's transl)]. Labedzki, L., Noack, D.[2019]

In an 8-week clinical trial with overweight but healthy participants, nicotinamide riboside (NR) significantly increased whole blood NAD+ levels in a dose-dependent manner, with increases of 22%, 51%, and 142% for doses of 100, 300, and 1000 mg, respectively.

The study found NR to be safe, with no significant adverse effects reported compared to placebo, and it did not negatively impact cholesterol levels or 1-carbon metabolism, supporting its potential as a dietary supplement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Conze, D., Brenner, C., Kruger, CL.[2023]

Nicotinamide riboside (NR) is a promising NAD+ precursor that has shown potential health benefits in treating various conditions, including cardiovascular, neurodegenerative, and metabolic disorders, based on numerous animal and human studies.

Research indicates that NR may also have therapeutic applications against infections, such as SARS-CoV-2, but challenges related to its bioavailability and safety need to be addressed for effective translation into clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. Mehmel, M., Jovanović, N., Spitz, U.[2021]

N-acetylneuraminic acid (N-ANA) significantly stimulates erythropoiesis (red blood cell production) in mice after irradiation, with a total dose of 150 mg/kg administered over three days showing reliable increases in erythroid cell formation.

The mechanism behind this stimulation appears to involve enhancing the microenvironment of the bone marrow, which supports increased production of erythroid precursors and overall hemopoiesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The stimulating effect of sialic acid on the processes of postradiation hemopoietic regeneration]. Agafonov, VI., Dygaĭ, AM., Boldyshev, DA., et al.[2013]

The study demonstrated that retroviral-mediated gene transfer of a dihydrofolate reductase (DHFR) variant (L22Y) can effectively select for transduced myeloid cells in mice, providing a potential strategy to protect against chemotherapy-induced myelosuppression.

To achieve significant protection from neutropenia, at least 10% of myeloid cells need to express the modified gene, with optimal protection occurring when over 30% of cells are modified, indicating the need for improved gene transfer methods for adult cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retroviral vectors containing a variant dihydrofolate reductase gene for drug protection and in vivo selection of hematopoietic cells. Allay, JA., Galipeau, J., Blakley, RL., et al.[2017]

Nicotinamide (NAM), a form of vitamin B-3, enhances the engraftment efficacy of cord blood-derived CD34(+) cells by delaying their differentiation and increasing their ability to migrate to the bone marrow, which is crucial for effective transplantation.

The study suggests that NAM's effects are specifically linked to the inhibition of the SIRT1 enzyme, highlighting its potential clinical utility in improving the expansion and functionality of hematopoietic stem cells for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Peled, T., Shoham, H., Aschengrau, D., et al.[2022]

Nicotinamide riboside (NR) is a form of vitamin B3 that effectively increases NAD+ levels, which may help counteract age-related declines in this important metabolite.

In a 90-day safety study on Sprague Dawley rats, NR-E showed no significant adverse effects at doses up to 1,200 mg/kg/d, establishing a no-observed-adverse-effect-level (NOAEL) of 500 mg/kg/d for males and 1,200 mg/kg/d for females.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Assessment of High-Purity, Synthetic Nicotinamide Riboside (NR-E) in a 90-Day Repeated Dose Oral Toxicity Study, With a 28-Day Recovery Arm. Marinescu, AG., Chen, J., Holmes, HE., et al.[2021]

Citations

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Here, the authors show nicotinamide riboside treatment shrinks the age-enlarged stem cell pool and shifts aged HSC functionally, metabolically ...

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Research studies have shown that adding nicotinamide riboside to donor cells has the potential to increase blood stem cell numbers and potentially decrease the ...

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Nicotinamide riboside may help decrease the time to engraftment, thereby decrease the risk of complications and improve long-term health status. Eligibility ...

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The NAD-Booster Nicotinamide Riboside Potently ...

NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80%, ...

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pmc.ncbi.nlm.nih.gov/articles/PMC10459282/

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Safety assessment of nicotinamide riboside, a form of ...

Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested. Target organs of toxicity were liver, kidney, ...

7.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/26791540/

Safety assessment of nicotinamide riboside, a form ...

Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested. Target organs of toxicity were liver, kidney, ...

8.

nature.com

nature.com/articles/s41467-021-22863-0

Nicotinamide riboside attenuates age-associated ...

Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways.

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clinicaltrials.gov

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Study of Nicotinamide Riboside Supplementation in ...

The purpose of this study is to find a safe and tolerable way to improve engraftment after transplant. Research studies have shown that adding nicotinamide ...