Pilot Study to Evaluate the Effect of NAD+ Boosting With Nicotinamide Riboside on Immunometabolism and Immunity in Systemic Lupus Erythematosus
Study Details
Study Description
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:
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Compare type I IFN transcript profiles in monocytes and neutrophils at baseline and in response to activation.
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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)
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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
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 1/Phase 2 |
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 Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
No Intervention: Healthy controls This group will not receive the dietary supplement or placebo. |
|
Active Comparator: Subjects with SLE - Active This study group will take the dietary supplement Nicotinamide Riboside capsules. |
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)
|
Placebo Comparator: Subjects with SLE - Placebo This study group will take the Placebo. |
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)
|
Outcome Measures
Primary Outcome Measures
- 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.
Eligibility Criteria
Criteria
- 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) more than or equal to 2 and less than or equal to 14 at screening;
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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;
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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
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hydroxychloroquine 400 mg/day, chloroquine phosphate 500 mg/day and quinacrine 100 mg/day;
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Subjects of childbearing potential must agree to practice effective birth control for the duration of the study;
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Stated willingness to comply with all study procedures and availability for the duration of the study;
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Agreement to adhere to Lifestyle Considerations throughout study duration;
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Ability of subject to understand and the willingness to sign a written informed consent document.
Control subjects:
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Female subjects 18 years or older
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No history of autoimmune or inflammatory disease;
EXCLUSION CRITERIA:
SLE Subjects:
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Active renal or central nervous system disease or major renal or hepatic dysfunction;
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Treatment with rituximab, belimumab or any other biologic agent within the 6 months prior to screening
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Current treatment with specific immunosuppressive drugs (methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus);
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Treatment with cyclophosphamide or IVIG within the 6 months prior to screening and or increase in glucocorticoid dose within 4 weeks of screening;
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Dietary vitamin B3 or tryptophan supplementation within 6 weeks of screening.
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Pregnancy or lactation (nursing)
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Treatment with another investigational drug or other intervention within 6 months of screening
Control Subjects:
-
Inability to sign consent
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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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | National Institutes of Health Clinical Center | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Michael N Sack, M.D., National Heart, Lung, and Blood Institute (NHLBI)
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 10001621
- 001621-H