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

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ClinicalTrials.gov Identifier: NCT02445794
Recruitment Status : Completed
First Posted : May 15, 2015
Results First Posted : November 27, 2020
Last Update Posted : November 27, 2020
Sponsor:
Information provided by (Responsible Party):
Retrotope, Inc.

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

Condition or disease Intervention/treatment Phase
Friedreich's Ataxia Drug: Low dose cohort Drug: High dose cohort Phase 1 Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Controlled Study to Assess the Safety, Tolerability, and Pharmacokinetics of RT001 in Patients With Friedreich's Ataxia
Study Start Date : August 2015
Actual Primary Completion Date : June 2016
Actual Study Completion Date : July 2016


Arm Intervention/treatment
Experimental: RT001, oral, 1.8 g/day
RT001, oral, 1.8 g QD for 28 days or matching comparator
Drug: Low dose cohort
RT001 is encapsulated di-deutero synthetic homologue of linoleic acid ethyl ester. Each capsule contains 900 mg of RT001.
Other Names:
  • RT001 1.8 g/d (2 capsule per day)
  • RT001 comparator 1.8 g/d (2 capsule per day)

Drug: High dose cohort
RT001 comparator is encapsulated non-deuterated linoleic acid ethyl ester.
Other Names:
  • RT001 9.0 g/d (9 capsule per day)
  • RT001 comparator 9.0 g/d (9 capsule per day)

Experimental: RT001, oral, 9 g/day
RT001, oral, 4.5 g BID for 28 days or matching comparator
Drug: Low dose cohort
RT001 is encapsulated di-deutero synthetic homologue of linoleic acid ethyl ester. Each capsule contains 900 mg of RT001.
Other Names:
  • RT001 1.8 g/d (2 capsule per day)
  • RT001 comparator 1.8 g/d (2 capsule per day)

Drug: High dose cohort
RT001 comparator is encapsulated non-deuterated linoleic acid ethyl ester.
Other Names:
  • RT001 9.0 g/d (9 capsule per day)
  • RT001 comparator 9.0 g/d (9 capsule per day)




Primary Outcome Measures :
  1. Number of Patients With Adverse Events [ Time Frame: 28 days ]

Secondary Outcome Measures :
  1. Pharmacokinetics - Area Under the Concentration-time Curve After a Single Dose [ Time Frame: 24 hours ]
    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

  2. Pharmacokinetics - Maximum Observed Plasma Concentration After a Single Dose [ Time Frame: 24 hours ]
    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

  3. Pharmacokinetics - Time to Reach Maximum Plasma Concentration After a Single Dose [ Time Frame: 24 hours ]
    TMax measured for the low and high dose cohorts

  4. Pharmacokinetics - Maximum Observed Plasma Concentration After Final Dose on Day 28 [ Time Frame: Day 28-Day 31 (3 days) ]

    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


  5. Pharmacokinetics - Terminal Half-life Estimation After Final Dose on Day 28 [ Time Frame: Day 28-Day 31 (3 days) ]

    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


  6. Change From Baseline at 28 Days in the Timed 25 Foot Walk (T25FW) [ Time Frame: 28 days ]

    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.


  7. Change From Baseline at 28 Days in the Friedreich Ataxia Rating Scale (FARS) - Neurological Score (Minimum Score 0, Maximum Score 125, Lower is Better) [ Time Frame: 28 days ]
    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.

  8. Change From Baseline at 28 Days in Peak Workload for the Treated Population vs. the Comparator Population [ Time Frame: 28 days ]
    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.



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female 18 to 50 years of age
  2. Medical history consistent with the symptoms of FRDA at ≤ 25 years of age
  3. Homozygous for GAA repeat expansions in the Frataxin gene in the affected range for FRDA
  4. FARS-Neurological score of 20-90 points
  5. Ambulatory (with or without assistive device) and capable of performing assessments/evaluations
  6. Body Mass Index ≤ 29.9 kg/m2
  7. Agrees to dietary restrictions and agrees to receive calls from a dietary coach
  8. Signed the informed consent form prior to entry into the study
  9. Agrees to spend the required number of overnight clinic days
  10. Able to provide the necessary repeated blood samples

Exclusion Criteria:

  1. Received treatment with other experimental therapies within the last 30 days prior to the first dose
  2. Known point mutation in the FXN gene
  3. History of malignancies (other than basal cell carcinomas)
  4. Impaired renal function at screening
  5. Alanine transaminase (ALT) or aspartate transaminase (AST) laboratory values > 2 x upper limit of normal (ULN) at screening
  6. 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
  7. Female who is breastfeeding or has a positive pregnancy test
  8. 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
  9. Unwilling or unable to comply with the requirements of the protocol
  10. Clinically significant cardiac abnormalities at screening that, in the opinion of the Investigator, would make the patient unsuitable for enrollment
  11. Diabetes mellitus (Type 1 or 2)
  12. Suicidal ideation as determined by the Columbia-Suicide Severity Rating Scale
  13. History, within the last 2 years, of alcohol abuse, significant mental illness, or physical opioid dependence
  14. Cannot adhere to the dietary guidance required to be followed by the protocol
  15. Cannot take the medication due to impairment in swallowing capsules

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02445794


Locations
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United States, California
Collaborative Neuroscience Network, LLC
Long Beach, California, United States, 90806
United States, Florida
University of South Florida
Tampa, Florida, United States, 33612
Sponsors and Collaborators
Retrotope, Inc.
Investigators
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Study Director: Curtis Scribner, MD Retrotope, Inc.
Principal Investigator: Theresa Zesiewicz, MD USF Ataxia Research Center
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Responsible Party: Retrotope, Inc.
ClinicalTrials.gov Identifier: NCT02445794    
Other Study ID Numbers: RT001-002
First Posted: May 15, 2015    Key Record Dates
Results First Posted: November 27, 2020
Last Update Posted: November 27, 2020
Last Verified: September 2020
Additional relevant MeSH terms:
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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