Nicotinamide Riboside for Systemic Lupus Erythematosus (SLE)

Overseen By Michael N Sack, M.D.

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must not be taking: Biologics, Cyclophosphamide, IVIG, others

Disqualifiers: Active renal, CNS disease, pregnancy, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks

78 Participants Needed

Trial Summary

What is the purpose of this trial?

Study Description: Systemic lupus erythematosus (SLE) occurs predominantly in women and is driven by type I interferon dysregulation and neutrophil hyperresponsiveness. Neutrophils in females have reduced mitochondrial bioenergetic capacity which affects immunometabolism. Nicotinamide adenine dinucleotide (NAD)+ boosting with nicotinamide riboside blunts type 1 IFN activation in-vivo in monocytes of healthy subjects and ex-vivo in SLE subjects. These findings support the proposal of the hypothesis that NAD+ boosting by NR supplementation will modulate metabolic pathways in lupus and blunt type 1 interferon signaling. Moreover, as type 1 interferon drives endothelial dysfunction, linked to increased cardiovascular risk, the effect of NR on endothelial function will be examined. Objectives: Primary Objective: Evaluate the effect of NR vs. placebo on immunometabolic and inflammatory remodeling in female SLE subjects: Exploratory Objective: Compare and characterize myeloid cell bioenergetic and immunometabolic profiles in healthy control and SLE female subjects Endpoints: Primary Endpoint: The primary end point will be to assess the effect of NR on blunting type I IFN signaling by measuring monocytic secretion of IFN-beta secretion compared to baseline in response to placebo vs. NR supplemented in SLE study subjects. Exploratory Endpoints: Healthy control vs. SLE subjects: * Compare type I IFN transcript profiles in monocytes and neutrophils at baseline and in response to activation. * Assess cell bioenergetics including: 1) monocyte and neutrophil metabolic flux mass spectroscopy of 13C-glucose and 13Cglutamine analysis to investigate their metabolic fates; (iii) Mitochondrial oxygen consumption (using glucose, amino acid, and fatty acid substrates) and glycolysis rates. SLE baseline vs. NR/placebo supplementation: Baseline vs. 6 weeks of NR/placebo: -Assess effect of NR on bioenergetics by measuring steady-state metabolite levels comparing changes in placebo vs. NR groups in monocytes and neutrophils. Baseline vs. 12 weeks of NR/placebo: * Whole blood NAD+ levels (batched and measured at the end of study enrollment period) * Explore effects of NR on gene regulation using monocyte and neutrophils by RNA-seq and chromatin remodeling analysis. * Determine the effect of NR vs placebo on endothelial dysfunction in SLE subjects

Will I have to stop taking my current medications?

The trial requires that if you are taking vitamin B3 or tryptophan supplements, you must stop them at least 6 weeks before the baseline visit. Other medications like glucocorticoids, antimalarials, and immunosuppressive drugs must have stable doses for a certain period before screening.

How is the drug Nicotinamide Riboside different from other treatments for systemic lupus erythematosus (SLE)?

Nicotinamide Riboside (NR) is unique because it is a form of vitamin B3 that may boost cellular energy production and repair, which is different from traditional treatments like cyclophosphamide that suppress the immune system. This novel approach could potentially offer a less toxic alternative for managing SLE. ^{1 2 3 4 5}

Research Team

Michael N Sack, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

This trial is for women over 18 with mild to moderate Systemic Lupus Erythematosus (SLE), meeting specific criteria, and not on certain immunosuppressive drugs or recent biologic agents. They must have stable medication doses, agree to effective birth control, and commit to the study's duration without major organ dysfunction.

Inclusion Criteria

I am willing and able to follow all study rules and attend all appointments.

The subject must demonstrate comprehension and agree to sign a formalized informed consent document.

I am a woman aged 18 or older.

Exclusion Criteria

I haven't taken vitamin B3 or tryptophan supplements in the last 6 weeks.

Pregnant women are excluded from participation on this study. Self-reported pregnancy status may be accepted from female control participants of child-bearing potential for a blood draw which is considered a minimal risk procedure.

I am unable to give my consent for treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Nicotinamide Riboside or placebo for 12 weeks to evaluate its effect on immunometabolism and immunity in SLE subjects

12 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Nicotinamide Riboside

Trial Overview The trial tests if Nicotinamide Riboside (NR) can improve immune system metabolism in SLE by boosting NAD+ levels. It compares NR's effects on inflammatory responses and energy production in cells against a placebo over a period of up to 12 weeks.

Participant Groups

Group I: Healthy controls Active Control 1 Intervention

This group will not receive the dietary supplement or placebo.

Group II: Subjects with SLE - Active Active Control 1 Intervention

This study group will take the dietary supplement Nicotinamide Riboside capsules.

Group III: Subjects with SLE - Placebo Placebo Group 1 Intervention

This study group will take the Placebo.

Nicotinamide Riboside is already approved in United States, European Union for the following indications:

Approved in United States as Niagen for:

• Dietary supplement for general health and wellness

Approved in European Union as Niagen for:

• Dietary supplement for general health and wellness

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a clinical trial involving 51 patients with proliferative lupus nephritis, leflunomide (LEF) showed an 80% total response rate and a 40% complete remission rate, comparable to 75% and 25% respectively for IV cyclophosphamide, indicating LEF's efficacy as an induction therapy.

LEF was generally well-tolerated, though some patients experienced adverse events like infections and alopecia, highlighting the need for further research on its long-term safety and effectiveness in maintenance therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of proliferative lupus nephritis with leflunomide and steroid: a prospective multi-center controlled clinical trial]. Cui, TG., Hou, FF., Ni, ZH., et al.[2018]

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) that requires tailored treatment based on the specific type of LN, with traditional therapies including cyclophosphamide and prednisone being effective but associated with significant side effects.

Recent clinical trials are exploring new treatment options for LN that aim to improve efficacy while reducing toxicity, addressing the urgent need for safer alternatives given the high risk of progression to end-stage renal disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of proliferative and membranous lupus nephritis: review of key clinical trials. Alshayeb, H., Wall, BM., Gosmanova, EO.[2011]

Early administration of low-dose linomide significantly reduced autoantibody levels by 50-64% in an animal model of systemic lupus erythematosus (SLE), indicating its potential efficacy in preventing disease progression when given before disease onset.

Linomide was ineffective when administered during later stages of SLE, suggesting that its therapeutic benefits are limited to early intervention, and the effects diminished after treatment cessation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of experimental systemic lupus erythematosus with linomide. Zandman-Goddard, G., George, J., Levy, Y., et al.[2017]

This study involves a prospective randomized trial with 12 patients suffering from systemic lupus erythematosus (SLE) and nephritis, focusing on the effects of monthly intravenous cyclophosphamide administration.

Preliminary data suggests that cyclophosphamide may be a potential treatment option for managing SLE-related nephritis, although further results are needed to assess its efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cyclophosphamide pulse therapy of systemic lupus erythematosus with renal involvement]. Hein, R., Neumann, KH., Koch, KM., et al.[2014]

In a study involving mice with established lupus nephritis, ribavirin significantly improved survival rates and reduced harmful antibodies against DNA, indicating its potential as a therapeutic option for this condition.

Ribavirin also reversed proteinuria, a common symptom of kidney damage in lupus nephritis, while other antiviral agents tested did not show effectiveness at the dosages used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribavirin: efficacy in the treatment of murine autoimmune disease. Klassen, LW., Budman, DR., Williams, GW., et al.[2019]

References

1. China pubmed.ncbi.nlm.nih.gov

[Treatment of proliferative lupus nephritis with leflunomide and steroid: a prospective multi-center controlled clinical trial]. [2018]

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

Treatment of proliferative and membranous lupus nephritis: review of key clinical trials. [2011]

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

Modulation of experimental systemic lupus erythematosus with linomide. [2017]

4. Germany pubmed.ncbi.nlm.nih.gov

[Cyclophosphamide pulse therapy of systemic lupus erythematosus with renal involvement]. [2014]

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

Ribavirin: efficacy in the treatment of murine autoimmune disease. [2019]