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

Trial Summary

What is the purpose of this trial?

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 riboside to donor cells has the potential to increase blood stem cell numbers and potentially decrease the time to engraftment. Also, nicotinamide riboside, TRU NIAGEN (the study drug) is a type of vitamin B supplement that the general public can get without a prescription and is well tolerated.

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 Nicotinamide Riboside (NR) safe for human use?

Nicotinamide Riboside (NR) has been studied in humans and is generally recognized as safe, with no significant differences in adverse events compared to a placebo in clinical trials. It has been tested at various doses and shown to be well-tolerated, with no reports of serious side effects. ^{1 2 3 4 5}

How does the NR supplementation treatment differ from other treatments for bone marrow transplant engraftment improvement?

NR supplementation is unique because it focuses on enhancing the body's natural processes to improve bone marrow transplant outcomes, potentially offering a novel approach compared to traditional methods that often involve drugs or gene therapy to protect or stimulate bone marrow cells. ^{6 7 8 9 10}

Research Team

Ronald Sobecks, MD

Principal Investigator

Cleveland Clinic, Case Comprehensive Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 (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]

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]

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]

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]

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]

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]

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]

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]

References

1. England 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. [2023]

2. Netherlands 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. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. [2021]

4. United States 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. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

[Hematopoietic stimulation for enhanced bone marrow regeneration after chemotherapy (author's transl)]. [2019]

7. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[The stimulating effect of sialic acid on the processes of postradiation hemopoietic regeneration]. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Retroviral vectors containing a variant dihydrofolate reductase gene for drug protection and in vivo selection of hematopoietic cells. [2017]

9. United States pubmed.ncbi.nlm.nih.gov

Retroviral transfer of the hENT2 nucleoside transporter cDNA confers broad-spectrum antifolate resistance in murine bone marrow cells. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Sensitization of hematopoietic stem and progenitor cells to trimetrexate using nucleoside transport inhibitors. [2021]