A First in Human Study of RT001 in Patients With Friedreich's Ataxia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of RT001 in patients with Friedreich's ataxia.

Detailed Description
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Study RT001-002 is a randomized, double-blind, controlled, ascending dose study to evaluate the safety, tolerability, pharmacokinetic, disease state, and exploratory endpoints in patients with Friedreich's ataxia after oral administration. The study includes 2 dose levels of RT001.

Official Title
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A Randomized, Double-blind, Controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of RT001 in Patients With Friedreich's Ataxia

Conditions
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Friedreich's Ataxia

Intervention / Treatment
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* Drug: Low dose cohort
* Drug: High dose cohort


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female 18 to 50 years of age Medical history consistent with the symptoms of FRDA at ≤ 25 years of age Homozygous for GAA repeat expansions in the Frataxin gene in the affected range for FRDA FARS-Neurological score of 20-90 points Ambulatory (with or without assistive device) and capable of performing assessments/evaluations Body Mass Index ≤ 29.9 kg/m2 Agrees to dietary restrictions and agrees to receive calls from a dietary coach Signed the informed consent form prior to entry into the study Agrees to spend the required number of overnight clinic days Able to provide the necessary repeated blood samples Exclusion Criteria: Received treatment with other experimental therapies within the last 30 days prior to the first dose Known point mutation in the FXN gene History of malignancies (other than basal cell carcinomas) Impaired renal function at screening Alanine transaminase (ALT) or aspartate transaminase (AST) laboratory values > 2 x upper limit of normal (ULN) at screening Known hepatitis B surface antigen (HBsAg)-positive, or known or suspected active hepatitis C infection, or is known to be human immunodeficiency virus (HIV) positive Female who is breastfeeding or has a positive pregnancy test Male participant or female participant of child bearing potential, who is sexually active and unwilling/unable to use a medically acceptable and effective double barrier birth control method throughout the study Unwilling or unable to comply with the requirements of the protocol Clinically significant cardiac abnormalities at screening that, in the opinion of the Investigator, would make the patient unsuitable for enrollment Diabetes mellitus (Type 1 or 2) Suicidal ideation as determined by the Columbia-Suicide Severity Rating Scale History, within the last 2 years, of alcohol abuse, significant mental illness, or physical opioid dependence Cannot adhere to the dietary guidance required to be followed by the protocol Cannot take the medication due to impairment in swallowing capsules

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RT001, oral, 1.8 g/day<br>RT001, oral, 1.8 g QD for 28 days or matching comparator | Drug: Low dose cohort<br>* RT001 is encapsulated di-deutero synthetic homologue of linoleic acid ethyl ester. Each capsule contains 900 mg of RT001.<br>* Other names: RT001 comparator 1.8 g/d (2 capsule per day);Drug: High dose cohort<br>* RT001 comparator is encapsulated non-deuterated linoleic acid ethyl ester.<br>* Other names: RT001 comparator 9.0 g/d (9 capsule per day);|
| Experimental: RT001, oral, 9 g/day<br>RT001, oral, 4.5 g BID for 28 days or matching comparator | Drug: Low dose cohort<br>* RT001 is encapsulated di-deutero synthetic homologue of linoleic acid ethyl ester. Each capsule contains 900 mg of RT001.<br>* Other names: RT001 comparator 1.8 g/d (2 capsule per day);Drug: High dose cohort<br>* RT001 comparator is encapsulated non-deuterated linoleic acid ethyl ester.<br>* Other names: RT001 comparator 9.0 g/d (9 capsule per day);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Area Under the Concentration-time Curve After a Single Dose | AUC 0-24 hours post-dose (Hours -1.0 to -0.5 (pre-breakfast, pre-dose), 0.5 (± 5 min), 1 (± 5 min), 1.5 (± 5 min), 2 (± 10 min), 4 (± 10 min) (pre-lunch), 6 (± 10 min), 8 (± 10 min), 12 (± 10 min), and 16 (± 30 min) Day 2: 24 hours following dosing on Day 1 (± 30 min; pre-breakfast, pre-dose) was measured for the low and high dose cohorts after a single dose of RT001 | 24 hours | 
| Pharmacokinetics - Maximum Observed Plasma Concentration After a Single Dose | Plasma levels were measured for the following time points: Day 1: Hours -1.0 to -0.5 (pre-breakfast, pre-dose), 0.5 (± 5 min), 1 (± 5 min), 1.5 (± 5 min), 2 (± 10 min), 4 (± 10 min) (pre-lunch), 6 (± 10 min), 8 (± 10 min), 12 (± 10 min), and 16 (± 30 min) Day 2: 24 hours following dosing on Day 1 (± 30 min; pre-breakfast, pre-dose) PK curves were constructed from these data and CMax measured on the curves for the low and high dose cohorts | 24 hours | 
| Pharmacokinetics - Time to Reach Maximum Plasma Concentration After a Single Dose | TMax measured for the low and high dose cohorts | 24 hours | 
| Pharmacokinetics - Maximum Observed Plasma Concentration After Final Dose on Day 28 | After 28 days of dosing, the final dose of RT001 was administered, and PK samples were obtained at the following timepoints (all timepoints refer to final dose on Day 28): Day 28: Hours -1.0 to -0.5 (pre-breakfast, pre-dose on Day 28), 0.5 (± 5 min), 1 (± 5 min), 1.5 (± 5 min), 2 (± 10 min), 4 (± 10 min) (pre-lunch), 6 (± 10 min), 8 (± 10 min), 12 (± 10 min), and 16 (± 30 min) Day 29: Hours 24 (± 30 min; pre-breakfast) and 32 (± 30 min) hours following final dose on Day 28 Day 30: 48 hours following final dose on Day 28 (± 30 min; pre-breakfast) Day 31: 72 hours following final dose on Day 28 (± 30 min; pre-breakfast) PK curves were constructed, and CMax at 28 days was determined from these curves | Day 28-Day 31 (3 days) | 
| Pharmacokinetics - Terminal Half-life Estimation After Final Dose on Day 28 | After 28 days of dosing, the final dose of RT001 was administered, and PK samples were obtained at the following timepoints (all timepoints refer to final dose on Day 28): Day 28: Hours -1.0 to -0.5 (pre-breakfast, pre-dose on Day 28), 0.5 (± 5 min), 1 (± 5 min), 1.5 (± 5 min), 2 (± 10 min), 4 (± 10 min) (pre-lunch), 6 (± 10 min), 8 (± 10 min), 12 (± 10 min), and 16 (± 30 min) Day 29: Hours 24 (± 30 min; pre-breakfast) and 32 (± 30 min) hours following final dose on Day 28 Day 30: 48 hours following final dose on Day 28 (± 30 min; pre-breakfast) Day 31: 72 hours following final dose on Day 28 (± 30 min; pre-breakfast) PK curves were constructed, and T1/2 at 28 days was determined from these curves | Day 28-Day 31 (3 days) | 
| Change From Baseline at 28 Days in the Timed 25 Foot Walk (T25FW) | The T25FW is a quantitative mobility and leg function performance test based on a timed 25-foot walk. T25FW was measured at baseline and at 28 days. These data were compared. | 28 days | 
| Change From Baseline at 28 Days in the Friedreich Ataxia Rating Scale (FARS) - Neurological Score (Minimum Score 0, Maximum Score 125, Lower is Better) | The FARS-neurological rating scale specifically developed and validated for Friedreich's Ataxia. The FARS-Neurological included evaluations of the neurological signs that specifically reflect neural substrates affected in patients with FA. Based on a neurological examination bulbar (11 points), upper limb coordination (36 points), lower limb coordination (16 points), peripheral nervous system (26 points), and upright stability (36 points) functions were assessed for individual sub-scores (11, 36, 16, 26, and 36) with a maximum score of 125 (Friedreich's Ataxia Study Group, Subramony et al., 2005, Lynch et al., 2006). FARS-Neurologic examinations were conducted by a qualified physician or health professional trained in the use of the FARS format. A lower score is better. The minimum score is 0, the maximum score is 125. | 28 days | 
| Change From Baseline at 28 Days in Peak Workload for the Treated Population vs. the Comparator Population | Peak workload was measured using cardiopulmonary exercise testing at baseline and after 28 days of treatment. The results of treatment were compared to baseline examination. | 28 days |