Double-blind Placebo Controlled Study to Evaluate the Effect of NAD+ Boosting With Nicotinamide Riboside on Immunometabolism and Immunity in Systemic Lupus Erythematosus

Phase 1

Recruiting

• Conditions: Systemic Lupus Erythematosus (Sle)

• Registration Number: NCT06032923
• Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Brief Summary

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

Detailed Description

Study Description:

Systemic lupus erythematosus (SLE) occurs predominantly in women and is driven by type I interferon dysregulation and neutrophil hyper-responsiveness. 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 13C-glutamine 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

Study Timeline

• Study First Submitted: 2023-09-09
• Study First Submitted QC: 2023-09-11
• Study First Posted: 2023-09-13
• Study Start: 2024-03-13
• Status Verified: 2025-06-05
• Last Update Submitted: 2025-06-06
• Last Update Posted: 2025-06-08
• Primary Completion: 2028-08-01
• Study Completion: 2028-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 78

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
The primary end point will be to assess the effect of NR on blunting type I IFN signaling and cytokine secretion from placebo vs. NR supplemented subjects in monocytes comparing baseline (visit 1 to visit 3).	4 years	Type 1 IFN dysregulation is present in SLE. NAD+ boosting blunts type 1 interferon in healthy subjects in-vivo and in monocytes of SLE subjects ex-vivo. Completion of data collection time is by 01/2027.

Trial Locations

Locations (1)

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States