Friedreich's Ataxia
Conditions
Brief summary
The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of RT001 in patients with Friedreich's ataxia.
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.
Interventions
DRUGLow dose cohort
RT001 is encapsulated di-deutero synthetic homologue of linoleic acid ethyl ester. Each capsule contains 900 mg of RT001.
DRUGHigh dose cohort
RT001 comparator is encapsulated non-deuterated linoleic acid ethyl ester.
Sponsors
Biojiva LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Patients With Adverse Events | 28 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics - Maximum Observed Plasma Concentration After a Single Dose | 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 |
| Pharmacokinetics - Time to Reach Maximum Plasma Concentration After a Single Dose | 24 hours | TMax measured for the low and high dose cohorts |
| Pharmacokinetics - Maximum Observed Plasma Concentration After Final Dose on Day 28 | 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 |
| Pharmacokinetics - Area Under the Concentration-time Curve After a Single Dose | 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 |
| Change From Baseline at 28 Days in the Timed 25 Foot Walk (T25FW) | 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. |
| Change From Baseline at 28 Days in the Friedreich Ataxia Rating Scale (FARS) - Neurological Score (Minimum Score 0, Maximum Score 125, Lower is Better) | 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. |
| Change From Baseline at 28 Days in Peak Workload for the Treated Population vs. the Comparator Population | 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. |
| Pharmacokinetics - Terminal Half-life Estimation After Final Dose on Day 28 | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - RT001 RT001 - 2 capsules/day (1.8 g/day) | 6 |
| Cohort 1 - Comparator RT001 comparator - 2 capsules/day | 3 |
| Cohort 2 - RT001 RT001 - 10 capsules/day (9 g/day) | 7 |
| Cohort 2 - Comparator RT001 comparator - 10 capsules/day | 3 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 - RT001 | Cohort 1 - Comparator | Cohort 2 - RT001 | Cohort 2 - Comparator | Total |
|---|---|---|---|---|---|
| Age, Continuous | 39.5 years STANDARD_DEVIATION 7.61 | 45.3 years STANDARD_DEVIATION 2.08 | 28.6 years STANDARD_DEVIATION 7.46 | 26.3 years STANDARD_DEVIATION 4.16 | 34.3 years STANDARD_DEVIATION 9.47 |
| Body Mass Index (BMI) | 22.82 kg/m^2 STANDARD_DEVIATION 3.857 | 26.17 kg/m^2 STANDARD_DEVIATION 2.798 | 21.63 kg/m^2 STANDARD_DEVIATION 3.096 | 24.63 kg/m^2 STANDARD_DEVIATION 7.931 | 23.47 kg/m^2 STANDARD_DEVIATION 4.128 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 6 participants | 3 participants | 7 participants | 3 participants | 19 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 5 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 3 | 0 / 7 | 0 / 3 |
| other Total, other adverse events | 5 / 6 | 2 / 3 | 5 / 7 | 2 / 3 |
| serious Total, serious adverse events | 0 / 6 | 0 / 3 | 1 / 7 | 0 / 3 |
Outcome results
Primary
Number of Patients With Adverse Events
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - RT001 (1.8 g/Day) | Number of Patients With Adverse Events | 5 participants |
| Cohort 1 - Comparator | Number of Patients With Adverse Events | 2 participants |
| Cohort 2 - RT001 (9 g/Day) | Number of Patients With Adverse Events | 5 participants |
| Cohort 2 - Comparator | Number of Patients With Adverse Events | 2 participants |
Secondary
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.
Time frame: 28 days
Population: Subjects unable to start or complete the test were excluded from analysis. Treatment and comparator cohorts were pooled to allow for statistical analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - RT001 (1.8 g/Day) | Change From Baseline at 28 Days in Peak Workload for the Treated Population vs. the Comparator Population | .08 watts/kg |
| Cohort 1 - Comparator | Change From Baseline at 28 Days in Peak Workload for the Treated Population vs. the Comparator Population | -.08 watts/kg |
p-value: 0.008Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - RT001 (1.8 g/Day) | Change From Baseline at 28 Days in the Friedreich Ataxia Rating Scale (FARS) - Neurological Score (Minimum Score 0, Maximum Score 125, Lower is Better) | -6.22 units on a scale maximum 125 | Standard Deviation 2.796 |
| Cohort 1 - Comparator | Change From Baseline at 28 Days in the Friedreich Ataxia Rating Scale (FARS) - Neurological Score (Minimum Score 0, Maximum Score 125, Lower is Better) | -6.47 units on a scale maximum 125 | Standard Deviation 4.768 |
| Cohort 2 - RT001 (9 g/Day) | Change From Baseline at 28 Days in the Friedreich Ataxia Rating Scale (FARS) - Neurological Score (Minimum Score 0, Maximum Score 125, Lower is Better) | -3.3 units on a scale maximum 125 | Standard Deviation 2.08 |
| Cohort 2 - Comparator | Change From Baseline at 28 Days in the Friedreich Ataxia Rating Scale (FARS) - Neurological Score (Minimum Score 0, Maximum Score 125, Lower is Better) | -2 units on a scale maximum 125 | Standard Deviation 3.464 |
Secondary
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.
Time frame: 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - RT001 (1.8 g/Day) | Change From Baseline at 28 Days in the Timed 25 Foot Walk (T25FW) | .503 sec | Standard Deviation 3.7751 |
| Cohort 1 - Comparator | Change From Baseline at 28 Days in the Timed 25 Foot Walk (T25FW) | -1.87 sec | Standard Deviation 1.1653 |
| Cohort 2 - RT001 (9 g/Day) | Change From Baseline at 28 Days in the Timed 25 Foot Walk (T25FW) | -7.475 sec | Standard Deviation 28.6458 |
| Cohort 2 - Comparator | Change From Baseline at 28 Days in the Timed 25 Foot Walk (T25FW) | .608 sec | Standard Deviation 2.4182 |
Secondary
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
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - RT001 (1.8 g/Day) | Pharmacokinetics - Area Under the Concentration-time Curve After a Single Dose | 524 ug*h/mL | Standard Deviation 86 |
| Cohort 1 - Comparator | Pharmacokinetics - Area Under the Concentration-time Curve After a Single Dose | 915 ug*h/mL | Standard Deviation 251 |
Secondary
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
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - RT001 (1.8 g/Day) | Pharmacokinetics - Maximum Observed Plasma Concentration After a Single Dose | 35.9 ug/mL | Standard Deviation 9.8 |
| Cohort 1 - Comparator | Pharmacokinetics - Maximum Observed Plasma Concentration After a Single Dose | 58.6 ug/mL | Standard Deviation 16 |
Secondary
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
Time frame: Day 28-Day 31 (3 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - RT001 (1.8 g/Day) | Pharmacokinetics - Maximum Observed Plasma Concentration After Final Dose on Day 28 | 91 ug/mL | Standard Deviation 44.6 |
| Cohort 1 - Comparator | Pharmacokinetics - Maximum Observed Plasma Concentration After Final Dose on Day 28 | 359.9 ug/mL | Standard Deviation 31.6 |
Secondary
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
Time frame: Day 28-Day 31 (3 days)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - RT001 (1.8 g/Day) | Pharmacokinetics - Terminal Half-life Estimation After Final Dose on Day 28 | 42.3 h | Standard Deviation 9.77 |
| Cohort 1 - Comparator | Pharmacokinetics - Terminal Half-life Estimation After Final Dose on Day 28 | 30.3 h | Standard Deviation 18.3 |
Secondary
Pharmacokinetics - Time to Reach Maximum Plasma Concentration After a Single Dose
TMax measured for the low and high dose cohorts
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 - RT001 (1.8 g/Day) | Pharmacokinetics - Time to Reach Maximum Plasma Concentration After a Single Dose | 6.05 h | Standard Deviation 0 |
| Cohort 1 - Comparator | Pharmacokinetics - Time to Reach Maximum Plasma Concentration After a Single Dose | 8.0 h | Standard Deviation 0 |