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

Systemic Lupus Erythematosus (Sle) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06032923
• Other study ID #: 10001621
• Secondary ID: 001621-H
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 13, 2024
• Est. completion date: August 1, 2028

Study information

• Verified date: May 21, 2024
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Rebecca D Huffstutler, C.R.N.P.
• Phone: (301) 594-1281
• Email: rebecca.huffstutler[@]nih.gov
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 78
• Est. completion date: August 1, 2028
• Est. primary completion date: August 1, 2028
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 120 Years

Eligibility

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

SLE subjects:

• Female subjects 18 years or older who meets > 3 of 11 modified Am. Coll. of Rheumatology (ACR) (1997) Revised Criteria for SLE and mild/moderate disease activity defined as an SLE Disease Activity Index 2000(SLEDAI 2K) between zero and less than or equal to 14 at screening;

• If on glucocorticoids, the dose must be less than or equal to 20 mg daily and stable for at least 4 weeks prior to screening;

• If on hydroxychloroquine or other antimalarials such as chloroquine or quinacrine, dose must have been stable for the 12 weeks prior to screening. The max. allowed doses
• hydroxychloroquine 400 mg/day, chloroquine phosphate 500 mg/day and quinacrine 100 mg/day;

• If on immunosuppressive drugs (methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus); dose must have been stable for the 12 weeks prior to screening

• Subjects of childbearing potential must agree to practice effective birth control for the duration of the study;

• Stated willingness to comply with all study procedures and availability for the duration of the study;

• Agreement to adhere to Lifestyle Considerations throughout study duration;

• Ability of subject to understand and the willingness to sign a written informed consent document.

Control subjects:

• Female subjects 18 years or older

• No history of autoimmune or inflammatory disease;

EXCLUSION CRITERIA:

SLE Subjects:

• Active renal or central nervous system disease or major renal or hepatic dysfunction;

• Treatment with rituximab, belimumab or any other biologic agent within the 6 months prior to screening

• Treatment with cyclophosphamide or IVIG within the 6 months prior to screening and or increase in glucocorticoid dose within 4 weeks of screening;

• Dietary vitamin B3 or tryptophan supplementation within 6 weeks of screening.

• Pregnancy or lactation (nursing)

• Treatment with another investigational drug or other intervention within 6 months of screening

Control Subjects:

• Inability to sign consent

• Dietary vitamin B3 or tryptophan supplementation within 6 weeks

• Pregnancy or nursing

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.

Related Conditions & MeSH terms

• Lupus Erythematosus, Systemic
• Systemic Lupus Erythematosus (Sle)

Intervention

Dietary Supplement:
• Nicotinamide Riboside
The dietary supplement Nicotinamide Riboside or a placebo capsule in subjects with SLE. Niagen(R) is a commercially available form of nicotinamide riboside (NR)

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	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.	4 years

External Links

•   NIH Clinical Center Detailed Web Page