NAD+ Precursor Supplementation in Friedreich's Ataxia
Study Details
Study Description
Brief Summary
The primary objective is to test the safety and tolerability of short-term therapy with a nicotinamide adenine dinucleotide (NAD+) precursor (MIB-626) in adults with Friedreich's Ataxia (FA) without overt heart failure and with a left ventricular ejection fraction ≥ 40%. A key secondary objective is to test the effects of MIB-626 on cardiac and skeletal muscle bioenergetics.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
The primary focus for this protocol is safety and tolerability. We will systematically assess for adverse events using a safety monitoring uniform report form. We will also use cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS) to measure the Phosphocreatine(PCr)/Adenosine triphosphate (ATP)- γ ratio before and after treatment with MIB-626. In addition, if time permits we will use proton (1H)-MRS to measure skeletal muscle nicotinamide adenine dinucleotide (NAD+) before and after treatment.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Open Label - MIB-626 MIB-626 |
Drug: MIB-626
Two (2) 500 mg Tablets, By Mouth, Daily
|
Outcome Measures
Primary Outcome Measures
- Incidence of treatment-emergent adverse events as assessed by Common Terminology Criteria for Adverse Events version 5.0. [14 Days]
Safety will be monitored through collection of laboratory assessments (CBC, CMP, lipid profile, HbA1c), vital signs (heart rate, blood pressure), and ECG, all of which will be reviewed for clinically relevant abnormalities, and standardized assessment of symptoms.
Secondary Outcome Measures
- Cardiac 31-Phosphorus-MRS: PCr/ATP Ratio [Change from baseline to 14 days.]
Measure the within-participant change in PCr/ATP-γ ratio before and after treatment with MIB-626.
- Post-Exercise CrCEST [Change from baseline to 14 days.]
Assess the within-participant change in skeletal muscle post-exercise CrCEST recovery (an index of skeletal muscle mitochondrial oxidative phosphorylation capacity) and the within-participant change skeletal muscle NAD+ via 1H-MRS before and after treatment with MIB-626.
- Grip Strength [Change from baseline to 14 days.]
Assess within-participant changes in grip strength (via hand grip dynamometry) before and after treatment with MIB-626.
- Concentration of NAD+ in Whole Blood [Change from baseline to 14 days.]
Measure the concentration of NAD+ (and associated metabolites) in whole blood before and after treatment with MIB-626.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Molecular diagnosis of Friedreich's Ataxia (FA).
-
Males and females, ages 18 years to < 65 years.
Exclusion Criteria:
-
Known sensitivity to nicotinamide-containing compounds.
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Concurrent use of Vitamin B3 supplements and/or any medications likely to increase risk of MIB-626 toxicity.
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HgbA1c > (great than or equal to) 8.5% and or Diabetes Mellitus (DM) requiring insulin or insulin secretagogue.
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Kidney disease (Estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1.73 m2) using serum creatinine and MDRD equation. The eGFR levels will be calculated using the Modified Diet in Renal Disease Study (MDRD) equation, which is the equation used by the Children's Hospital Of Philadelphia laboratory.
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Liver disease (Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) > 3 x Upper Limit of Normal)
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Severe co-existing cardiac disease (Ejection Fraction (EF) < 40%, known arrhythmia) as demonstrated by an echocardiogram within 12 months of screening.
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Any contraindication to MRI, including spinal rods (related to unknown safety considerations for cardiac 31-Phosphorus -MRS).
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Use of any investigational agent within 4 weeks of enrollment.
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Females: Pregnant/lactating or planning to become pregnant during their participation.
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Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | The Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
Sponsors and Collaborators
- Metro International Biotech, LLC
- Children's Hospital of Philadelphia
Investigators
- Principal Investigator: Shana E McCormack, MD, Children's Hospital of Philadelphia
Study Documents (Full-Text)
None provided.More Information
Publications
- Bagga P, Wilson N., DeBrosse D., Hariharan H., Reddy R., editor. In vivo detection of NAD+ in human calf muscle at 7T using 28-channel knee volume coil. International Society for Magnetic Resonance in Medicine; 2019; Montreal, Canada.
- DeBrosse C, Nanga RPR, Wilson N, D'Aquilla K, Elliott M, Hariharan H, Yan F, Wade K, Nguyen S, Worsley D, Parris-Skeete C, McCormick E, Xiao R, Cunningham ZZ, Fishbein L, Nathanson KL, Lynch DR, Stallings VA, Yudkoff M, Falk MJ, Reddy R, McCormack SE. Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders. JCI Insight. 2016 Nov 3;1(18):e88207. doi: 10.1172/jci.insight.88207.
- Patel M, Isaacs CJ, Seyer L, Brigatti K, Gelbard S, Strawser C, Foerster D, Shinnick J, Schadt K, Yiu EM, Delatycki MB, Perlman S, Wilmot GR, Zesiewicz T, Mathews K, Gomez CM, Yoon G, Subramony SH, Brocht A, Farmer J, Lynch DR. Progression of Friedreich ataxia: quantitative characterization over 5 years. Ann Clin Transl Neurol. 2016 Jul 25;3(9):684-94. doi: 10.1002/acn3.332. eCollection 2016 Sep.
- 19-016525
- MIB-626-201