NAD+ Precursor Supplementation in Friedreich's Ataxia

• ClinicalTrials.gov Identifier: NCT04817111
• Recruitment Status: Active, not recruiting
• First Posted: March 25, 2021
• Last Update Posted: October 28, 2022
• Sponsor: Metro International Biotech, LLC
• Collaborator: Children's Hospital of Philadelphia
• Information provided by (Responsible Party): Shana McCormack, Children's Hospital of Philadelphia

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
Friedreich Ataxia	Drug: MIB-626	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

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open Label, 14 Days (+/- 2 Days)
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase 2a Study of NAD+ Precursor Supplementation in Friedreich's Ataxia
• Actual Study Start Date: May 17, 2021
• Actual Primary Completion Date: May 19, 2022
• Estimated Study Completion Date: May 19, 2023

Arms and Interventions

Arm	Intervention/treatment
Open Label - MIB-626; MIB-626	Drug: MIB-626; Two (2) 500 mg Tablets, By Mouth, Daily

Outcome Measures

Primary Outcome Measures :

1. Incidence of treatment-emergent adverse events as assessed by Common Terminology Criteria for Adverse Events version 5.0. [ Time Frame: 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 :

1. Cardiac 31-Phosphorus-MRS: PCr/ATP Ratio [ Time Frame: Change from baseline to 14 days. ]
   Measure the within-participant change in PCr/ATP-γ ratio before and after treatment with MIB-626.
2. Post-Exercise CrCEST [ Time Frame: 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.
3. Grip Strength [ Time Frame: Change from baseline to 14 days. ]
   Assess within-participant changes in grip strength (via hand grip dynamometry) before and after treatment with MIB-626.
4. Concentration of NAD+ in Whole Blood [ Time Frame: 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

• Ages Eligible for Study: 18 Years to 64 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Pennsylvania

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)

Documents provided by Shana McCormack, Children's Hospital of Philadelphia:

Informed Consent Form  [PDF] October 20, 2021

More Information

Publications:

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.

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.

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.

• Responsible Party: Shana McCormack, Attending Physician, Children's Hospital of Philadelphia
• ClinicalTrials.gov Identifier: NCT04817111
• Other Study ID Numbers: 19-016525; MIB-626-201 ( Other Identifier: Metro International Biotech, LLC )
• First Posted: March 25, 2021
• Last Update Posted: October 28, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: IPD may be available with appropriate regulatory approvals.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Ataxia; Cerebellar Ataxia; Friedreich Ataxia; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Spinocerebellar Degenerations; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Mitochondrial Diseases; Metabolic Diseases