NAD Augmentation for Diabetic Kidney Disease

(DKD Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Shalender Bhasin, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Brigham and Women's Hospital

Must be taking: ACE inhibitors, ARBs

Disqualifiers: Cardiovascular event, Substance use, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing whether NMN, a compound that may improve cell function, can help older adults with type 2 diabetes and high urine protein levels. The goal is to see if NMN can reduce kidney damage by improving cell energy production. Participants will receive NMN to compare the effects.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if your UACR is over 300 mg/g creatinine, you must be using an ACE inhibitor or an ARB. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug MIB-626 for diabetic kidney disease?

Research shows that nicotinamide, a component of MIB-626, can reduce kidney inflammation and slow down kidney disease progression in animal models. Additionally, nicotinamide supplementation has been linked to improved kidney outcomes in other kidney-related conditions. ^{1 2 3 4 5}

Is NAD augmentation with βNMN safe for humans?

Research shows that βNMN, a form of NAD augmentation, is generally safe for humans. In studies, healthy adults taking up to 1250 mg daily for 4 weeks experienced no severe side effects, and similar safety was observed in animal studies with higher doses. ^{1 6 7 8 9}

How is the drug MIB-626 unique for treating diabetic kidney disease?

MIB-626 is unique because it is an oral formulation of a specific form of nicotinamide mononucleotide (βNMN) that increases levels of nicotinamide adenine dinucleotide (NAD+), which is important for energy production and reducing inflammation. This approach is different from other treatments as it targets the underlying metabolic pathways to potentially improve kidney function. ^{1 2 3 4 10}

Research Team

Shalender Bhasin, MD

Principal Investigator

Brigham and Women's Hospital

Eligibility Criteria

This trial is for adults with Type 2 Diabetes and Diabetic Kidney Disease. Participants must have a certain level of kidney function, controlled blood sugar levels, and be on specific medications if their urine shows high protein levels. Pregnant women or those planning pregnancy soon cannot join. People with recent serious health events, severe psychiatric conditions, very high BMI, substance abuse history, or who've been in other drug trials recently are excluded.

Inclusion Criteria

You have type 2 diabetes, high levels of certain blood glucose markers, and are currently taking specific diabetes medications.

Exclusion Criteria

I have not had a major heart problem in the last 3 months.

You have had a problem with alcohol or drugs in the last 2 years.

Your urine test shows a high level of protein first thing in the morning.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either 1000 mg NMN or placebo twice daily to assess improvements in DKD over a 6-month period

24 weeks

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a focus on sustained NAD levels

12 weeks

Treatment Details

Interventions

• Investigational Product - MIB 626 (NAD+ precursor)
• Placebo (Other)

Trial Overview The study tests MIB 626 (a form of NMN) to see if it can improve kidney function in diabetic patients better than a placebo. It's randomized and double-blind meaning neither the researchers nor participants know who gets the real treatment versus a fake one (placebo). Each participant takes either MIB 626 or placebo twice daily.

Participant Groups

Group I: Investigational Product - MIB 626 Active Control 1 Intervention

The MIB-626 will be a GMP-grade microcrystalline solid NMN mixed with inert excipients (including microcrystalline cellulose) and compressed into tablets at a dose strength of 500 mg per tablet, enabling administration of the 1,000 mg twice daily using two tablets taken twice daily.

Group II: Placebo Placebo Group 1 Intervention

Participants randomized to placebo will receive Matching placebo tablets will be provided by Metro International Biotech, LLC.

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Dr. William Curry

Brigham and Women's Hospital

Chief Medical Officer

MD from Columbia University College of Physicians and Surgeons

Dr. Scott Schissel

Brigham and Women's Hospital

Chief Executive Officer since 2021

MD from Columbia University College of Physicians and Surgeons

Boston Medical Center

Collaborator

Trials

410

Recruited

890,000+

Dr. Alastair Bell

Boston Medical Center

Chief Executive Officer since 2023

MD from University of Oxford, MBA from Harvard Business School

Dr. Ravin Davidoff

Boston Medical Center

Chief Medical Officer since 2008

M.B., B.Ch. from University of Witwatersrand, South Africa

Findings from Research

In a study of 167 cardiac bypass surgery patients, a significant decrease in urinary tryptophan and kynurenin was observed in those who developed acute kidney injury (AKI), indicating a potential biomarker for AKI risk.

However, supplementation with nicotinamide (NAM) did not improve kidney function or outcomes in a mouse model of ischaemic AKI, suggesting that NAM may not be an effective treatment for preventing renal damage in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The tryptophan pathway and nicotinamide supplementation in ischaemic acute kidney injury. Piedrafita, A., Balayssac, S., Mayeur, N., et al.[2022]

Modified-release nicotinamide (NAMR) significantly reduced serum phosphate levels in hemodialysis patients over the first 24 weeks, but this effect was not maintained at 52 weeks, indicating potential issues with long-term efficacy.

The treatment was associated with increased risks of side effects such as thrombocytopenia, pruritus, anemia, and diarrhea, as well as herpes zoster occurring only in NAMR patients, highlighting the need for careful monitoring of safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified-release nicotinamide for the treatment of hyperphosphataemia in haemodialysis patients: 52-week efficacy and safety results of the phase 3 randomized controlled NOPHOS trial. Ketteler, M., Wiecek, A., Rosenkranz, AR., et al.[2023]

Supplementation with nicotinamide (Nam), a precursor of NAD+, significantly reduced kidney inflammation and fibrosis in a mouse model of chronic kidney disease (CKD), suggesting it may help prevent disease progression.

Nam supplementation also decreased the buildup of harmful metabolites associated with renal failure by enhancing NAD+ levels, which supports metabolic pathways that are crucial for kidney function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide Attenuates the Progression of Renal Failure in a Mouse Model of Adenine-Induced Chronic Kidney Disease. Kumakura, S., Sato, E., Sekimoto, A., et al.[2021]

In a study of 66 children with newly diagnosed type 1 diabetes, low doses of nicotinamide (1-2 mg/kg per day) were associated with significantly lower insulin requirements over a 24-month period compared to a control group of 37 children who did not receive the treatment.

The findings suggest that nicotinamide therapy may help prolong the honeymoon period in pediatric patients with type 1 diabetes, indicating a potential benefit in managing the disease early after diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of nicotinamide on newly diagnosed type 1 diabetic children. Kamal, M., Abbasy, AJ., Muslemani, AA., et al.[2013]

A study involving 31 healthy adults showed that daily oral administration of 1250 mg of β-NMN for 4 weeks is safe and well-tolerated, with no significant adverse effects reported.

The research indicates that β-NMN does not cause harmful changes in various health parameters, suggesting its potential for further exploration in age-related disease prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. Fukamizu, Y., Uchida, Y., Shigekawa, A., et al.[2022]

The synthetic form of β-nicotinamide mononucleotide (NMN-C®) was found to be safe in a study involving acute and subchronic toxicity tests, with no mutagenic or genotoxic effects observed.

In a 90-day study with doses up to 1500 mg/kg/day, NMN-C® did not show any adverse effects, establishing a No-Observable Adverse Effect Level (NOAEL) of ≥1500 mg/kg/day, indicating its potential safety for short to intermediate-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats. Cros, C., Cannelle, H., Laganier, L., et al.[2021]

Nicotinamide mononucleotide (NMN) significantly enhances insulin secretion in RIN-m5f cells, especially when combined with repaglinide, indicating its potential role in improving insulin response.

NMN treatment increases the mRNA expression of the transcription factor PDX-1, which is crucial for insulin secretion, while not significantly affecting the expression of FoxO1, suggesting a targeted mechanism of action for NMN in insulin regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of nicotinamide mononucleotide on insulin secretion and gene expressions of PDX-1 and FoxO1 in RIN-m5f cells. Sheng, F., Ren, X., Dai, X., et al.[2022]

Oral supplementation of nicotinamide mononucleotide (NMN) at 250 mg/day for 24 weeks was found to be safe for older male patients with diabetes, with no severe adverse events reported.

Despite the safety of NMN, the study showed no significant improvements in grip strength or walking speed compared to the placebo group, although there were indications of reduced frailty and changes in retinal thickness that warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study. Akasaka, H., Nakagami, H., Sugimoto, K., et al.[2023]

Trimethoprim significantly inhibits the transport of metformin and NMN through renal cation transporters, leading to increased plasma levels of metformin by 29.5% and decreased renal clearance of both drugs.

The study suggests that NMN can serve as a useful probe for predicting drug interactions involving renal cation transporters, based on findings from a clinical trial with 12 healthy volunteers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction. Müller, F., Pontones, CA., Renner, B., et al.[2018]

References

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

MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of β-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults. [2023]

2. England pubmed.ncbi.nlm.nih.gov

The tryptophan pathway and nicotinamide supplementation in ischaemic acute kidney injury. [2022]

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

Modified-release nicotinamide for the treatment of hyperphosphataemia in haemodialysis patients: 52-week efficacy and safety results of the phase 3 randomized controlled NOPHOS trial. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Nicotinamide Attenuates the Progression of Renal Failure in a Mouse Model of Adenine-Induced Chronic Kidney Disease. [2021]

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

Effect of nicotinamide on newly diagnosed type 1 diabetic children. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats. [2021]

8. China pubmed.ncbi.nlm.nih.gov

Effect of nicotinamide mononucleotide on insulin secretion and gene expressions of PDX-1 and FoxO1 in RIN-m5f cells. [2022]

9. Japan pubmed.ncbi.nlm.nih.gov

Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study. [2023]

10. Germany pubmed.ncbi.nlm.nih.gov

N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction. [2018]