A Phase 2a Study of NAD+ Precursor Supplementation in Friedreich's Ataxia
Phase: PHASE2
Conditions: Friedreich Ataxia
Sponsor: Metro International Biotech, LLC

Title: A Phase 2a Study of NAD+ Precursor Supplementation in Friedreich’s Ataxia 
 
 
NCT Number: NCT04817111 
Document Date: May 6, 2022 
 

 
 
 
 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
A Phase 2a Study of NAD+ Precursor Supplementation in 
Friedreich’s Ataxia 
Funder 
Friedreich’s Ataxia Research Alliance (FARA) 
Clinical Phase 
Open Label, Safety and Tolerability 
Study Rationale 
Frataxin supports the function of the mitochondrial electron 
transport chain (ETC) because it facilitates the formation of iron-
sulfur clusters, which are essential to multiple ETC components. 
Cardiac muscle has a high energy requirement, and the role of 
impaired mitochondrial oxidative phosphorylation capacity in the 
pathogenesis of FA-related cardiomyopathy is a focus of ongoing 
investigations. In animal models, there is evidence for disruption of 
the physiologic coupling between mitochondria and sarcomeres in 
cardiomyocytes, as well as iron accumulation and mitochondrial 
proliferation.16 Similar phenomena may be observable in skeletal 
muscle in humans.3,17 
 
We hypothesize that MIB-626 therapy will be feasible, well-
tolerated, and may increase cardiac mitochondrial bioenergetic 
capacity, as reflected by the phosphocreatine (PCr) to ATP ratio 
measured via cardiac 31Phosphorus magnetic resonance 
spectroscopy (31P- MRS). 
Study Objective(s) 
Primary  
 
To test the safety and tolerability of short-term MIB-626 therapy 
in adults with FA without overt heart failure. 
Secondary 
 
To use cardiac 31P-MRS to measure the within-participant 
change in PCr/ATP-γ ratio before and after treatment with MIB-
626. 
 
To 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.  
 
To assess within-participant changes in grip strength (via hand 
grip dynamometry) before and after treatment with MIB-626. 
 
To measure the concentration of NAD+ (and associated 
metabolites) in whole blood before and after treatment with 
MIB-626.  
 
To assess within-participant change in the FARS-ADL, before 
and after treatment with MIB-626. 
 
To assess within-participant change in overall well-being, 

 
 
 
 
 
 
 
 
 
 
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assessed via CGI scales (CGI-S and CGI-C), before and after 
treatment with MIB-626. 
Test Article(s) 
 
MIB-626 two (2) 500 mg tablets, po daily 
Study Design 
 
Open Label, Single Arm, Assess Safety and Tolerability 
Subject Population 
key criteria for 
Inclusion and Exclusion: 
Inclusion Criteria 
1. Molecular diagnosis of Friedreich’s Ataxia (FA). 
2. Males and females, ages 18y to < 65y. 
Exclusion Criteria 
1. Known sensitivity to nicotinamide-containing compounds. 
2. Concurrent use of vitamin B3 supplements and/or any 
medications likely to increase risk of MIB-626 toxicity. 
3. HGbA1c > 8.5% and/or DM requiring insulin or insulin 
secretagogue. 
4. Kidney disease (eGFR < 60 ml/min/1.73 m2) using serum 
creatinine and MDRD equation. The eGFR levels will be 
calculated using the MDRD (Modified Diet in Renal Disease 
study) equation, which is the equation used by the CHOP 
laboratory. 
5. Liver disease (AST/ALT > 3x ULN) 
6. Severe co-existing cardiac disease as manifest by a reduced 
LV ejection fraction to < 40%, moderate or greater valve 
disease, presence of a congenital heart defect, and/or 
evidence of pulmonary hypertension on an echocardiogram 
or cardiac MRI within 12 months of screening. 
7. History of clinically significant arrhythmias (atrial 
fibrillation, atrial flutter, or ventricular tachycardia) or an 
increased potential for arrhythmias on the screening ECG as 
evidenced by:  
 Prolonged QTc (>480 ms for females or >460 msec for 
males) 
 Any rhythm other than sinus on the baseline ECG, 
excluding sinus arrhythmia. 
 Multiple PACs (>2) or PVCs on the baseline ECG 
8. Prior history of heart failure. 
9. Any contraindication to MRI, including spinal rods (related 
to unknown safety considerations for cardiac 31P-MRS). 

 
 
 
 
 
 
 
 
 
 
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10. Use of any investigational agent within 4 weeks of 
enrollment. 
11. Females: Pregnant/lactating or planning to become pregnant 
during their participation. 
12. Any medical condition that, in the opinion of the 
investigator, will interfere with the safe completion of the 
study. 
Number Of Subjects  
 
N =10 screened at CHOP with an aim to enroll and obtain complete 
data for 6 participants. 
 
2 Sites: The Children's Hospital of Philadelphia and the Hospital of 
the University of Pennsylvania 
 
Study procedures will be completed at The Children's Hospital of 
Philadelphia and The Hospital of the University of Pennsylvania. 
Study Duration 
Each individual’s participation will last up to 15 weeks.   
 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
Participants will undergo a telephone screening to assess eligibility 
and then, within 90 days, complete an in-person screening to 
confirm eligibility. Participants with confirmed eligibility will be 
included and begin 14 (+/- 2) days of test article (MIB-626).  
Participants will complete a follow-up visit at the conclusion of 14 
(+/- 2) days of MIB-626.  
Efficacy Evaluations 
PCr/ATP-γ ratio via cardiac 31P-MRS 
Skeletal muscle CrCEST and NAD+ (1H-MRS) 
NAD+ analysis of metabolites in whole blood 
Grip strength (hand grip dynamometry)  
FARS-ADL scale 
Clinician/participant clinical global impression (CGI) scales (CGI-
S, CGI-C) 
Safety Evaluations 
Safety will be monitored through the collection of laboratory 
assessments at baseline and follow-up.  Participants will also be 
monitored using a standardized assessment of symptoms (see 
attachment).   
 
We will use the Common Terminology Criteria for Adverse Events 
(CTCAE, version 5.0, U.S. Department of Health and Human 
Services) to grade adverse events.  
 
Individuals who experience a new Grade 3 or higher AE will be 
required to stop study participation. 

 
 
 
 
 
 
 
 
 
 
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Statistical And Analytic 
Plan 
We will focus primarily on safety and tolerability. We will note the 
number of participants who complete the protocol, monitor 
adherence, and systematically collected adverse events. We will also 
use paired t-tests and/or Wilcoxon signed rank tests to assess 
within-participant changes in cardiac and skeletal muscle 
bioenergetics, NAD+ metabolites, grip strength, FARS-ADL, and 
clinician/participant reported overall clinical status.  
 
To estimate statistical power, we used data from a previous study 
comparing cardiac 31P-MRS assessments of tissue bioenergetics in 
individuals with FA as compared to control participants.1 With an 
expected initial mean of adjusted PCr/ATP ratio in individuals with 
FA of 1.42 (SD 0.52) 1, and assuming a conservative short-term 
(i.e., over 14 (+/- 2) days) within-subject correlation of at least 0.6 
between repeated measures, a sample of 6 individuals has 80% 
power to detect an improvement in PCr/ATP to 2.09 (normal = 
2.20). This initial experience will generate estimates regarding the 
distribution of the candidate mechanistic/efficacy outcomes in FA 
and treatment responses, and may provide a basis for longer Phase 
2/3 interventional studies of MIB-626 supplementation. 
DATA AND SAFETY 
MONITORING PLAN 
The PI is responsible for data quality management and continuous 
monitoring of study participants to ensure safety.  Data will be 
reviewed at regularly scheduled team meetings. The PI and study 
team will report findings as required to the local Institutional 
Review Board and medical monitor.