Clinical trial NCT04817111: NAD+ Precursor Supplementation in Friedreich's Ataxia
Official title: A Phase 2a Study of NAD+ Precursor Supplementation in Friedreich's Ataxia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Friedreich Ataxia
Lead sponsor: Metro International Biotech, LLC
Sponsor class: INDUSTRY
Collaborators: name: Children's Hospital of Philadelphia
First posted: 2021-03-25
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open Label, 14 Days (+/- 2 Days)
Primary purpose: OTHER

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.

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.

Eligibility 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.
* Concurrent use of Vitamin B3 supplements and/or any medications likely to increase risk of MIB-626 toxicity.
* HgbA1c \> (great than or equal to) 8.5% and or Diabetes Mellitus (DM) requiring insulin or insulin secretagogue.
* 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.
* Liver disease (Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) \> 3 x Upper Limit of Normal)
* Severe co-existing cardiac disease (Ejection Fraction (EF) \< 40%, known arrhythmia) as demonstrated by an echocardiogram within 12 months of screening.
* Any contraindication to MRI, including spinal rods (related to unknown safety considerations for cardiac 31-Phosphorus -MRS).
* Use of any investigational agent within 4 weeks of enrollment.
* Females: Pregnant/lactating or planning to become pregnant during their participation.
* Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study.

Primary outcomes:
measure: Percentage of Individuals With Treatment-emergent Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 5.0.
timeFrame: 14 Days
Secondary outcomes:
measure: Cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS): Phosphocreatine (PCr)/Adenosine Tri-Phosphate (ATP) Ratio
timeFrame: Change from baseline to 14 days.
measure: Post-Exercise Creatine Chemical Exchange Saturation Transfer (CrCEST) Magnetic Resonance Imaging (MRI)
timeFrame: Change from baseline to 14 days.
measure: Grip Strength
timeFrame: Change from baseline to 14 days.
measure: Concentration of Nicotinamide Adenine Dinucleotide (NAD+) in Whole Blood
timeFrame: Change from baseline to 14 days.
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Shana E McCormack, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.