NAD+ Precursor Supplementation in Friedreich's Ataxia

Study Overview
=================
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.

Official Title
-----------------
A Phase 2a Study of NAD+ Precursor Supplementation in Friedreich's Ataxia

Conditions
-----------------
Friedreich Ataxia

Intervention / Treatment
-----------------
* Drug: MIB-626


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: Open Label, 14 Days (+/- 2 Days)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Open Label - MIB-626<br>MIB-626 | Drug: MIB-626<br>* Two (2) 500 mg Tablets, By Mouth, Daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Individuals With Treatment-emergent Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 5.0. | Safety will be monitored through collection of laboratory assessments (CBC, complete metabolic profile, 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. We report the proportion of individuals who had at least one treatment-emergent adverse event of Grade 1 or higher. | 14 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS): Phosphocreatine (PCr)/Adenosine Tri-Phosphate (ATP) Ratio | Measure the within-participant change in PCr/ATP ratio before and after treatment with MIB-626. | Change from baseline to 14 days. | 
| Post-Exercise Creatine Chemical Exchange Saturation Transfer (CrCEST) Magnetic Resonance Imaging (MRI) | Assess the within-participant change in skeletal muscle post-exercise CrCEST recovery (an index of skeletal muscle mitochondrial oxidative phosphorylation capacity). | Change from baseline to 14 days. | 
| Grip Strength | Assess within-participant changes in grip strength (via hand grip dynamometry) before and after treatment with MIB-626. | Change from baseline to 14 days. | 
| Concentration of Nicotinamide Adenine Dinucleotide (NAD+) in Whole Blood | Measure the concentration of NAD+ in whole blood before and after treatment with MIB-626. | Change from baseline to 14 days. |