Friedreich's Ataxia
Conditions
Keywords
Interferon gamma
Brief summary
The purpose of this phase 3 randomized, multi-center, double-blind, placebo-controlled study is to evaluate the efficacy and safety of ACTIMMUNE® (interferon-γ 1b) in the treatment of Friedreich's Ataxia (FA) and to evaluate the pharmacokinetic (PK) characteristics of ACTIMMUNE® in FA patients.
Detailed description
Study with completed results acquired from Horizon in 2024.
Interventions
DRUGInterferon γ-1b
The study drug dose is planned to be escalated on a weekly basis over the first 4 weeks of treatment (from 10 µg/m² to 25, 50, and 100 µg/m²). The dose may be reduced, interrupted, or held based on tolerability. By Week 13, all participants are to be on a stable tolerated dose of study drug in order to continue study participation; the dose may not be further increased after week 13, however, it may be reduced on a case-by-case basis to manage drug-related adverse events (AEs).
DRUGPlacebo
The volume of placebo is planned to correspond with volume of study drug that would be given to the participant if the participant was randomized to the study drug arm.
Sponsors
Friedreich's Ataxia Research Alliance
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
10 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent and child assent, if applicable. * FA confirmed by genetic testing with two expanded guanine-adenine-adenine (GAA) repeats. * FA functional stage of \>1 to \<5 and ability to walk 25 feet with or without an assistive device. * Male or female subject between the ages of 10 and 25 years, inclusive. * If female, the subject is not pregnant or lactating or intending to become pregnant during the study, or within 30 days after the last dose of study drug. Female subjects of child-bearing potential must have a negative serum pregnancy test result at Screening, a negative urine pregnancy test result at Baseline, and agree to use a reliable method of contraception throughout the study and for 30 days after the last dose of study drug.
Exclusion criteria
* Any unstable illness that in the investigator's opinion precludes participation in the study. * Use of any investigational product within 30 days prior to randomization. * A history of substance abuse. * Presence of clinically significant cardiac disease (as determined by the investigator based on electrocardiogram \[ECG\] and echocardiogram results at Screening). Specifically, an ejection fraction of \<40% or a prolonged QT interval (\>50% of cycle duration) will result in exclusion. If the investigator notes any other clinically significant abnormalities on the ECG or echocardiogram, the subject may be eligible if they are provided clearance from a cardiologist. * History of hypersensitivity to interferon (IFN)-ɣ or E. coli-derived products. * Presence of moderate or severe renal disease (estimated creatinine clearance \<50 mL/min) or hepatic disease (aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\] \>2x the upper limit of normal) as evidenced by laboratory results at Screening. * Clinically significant abnormal white blood cell count, hemoglobin, or platelet count as evidenced by laboratory test results at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 26 in the Friedreich's Ataxia Rating Scale (FARS)-mNeuro Score | Baseline, Week 26 | The FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions were assessed. The FARS-mNeuro score excludes the peripheral nervous system subscale score and the facial and tongue atrophy and fasciculations from the bulbar subscale score. Scores range from 0 (normal) to 93 (most impairment). A negative change from baseline is an improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 26 in Activities of Daily Living (ADL) Score | Baseline, Week 26 | Participants and/or their caregivers rated 9 areas of daily living skills (speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function) on a 5-point scale (0=normal, 4=greatest loss of function) with allowable increments of 0.5 if the participant or caregiver strongly felt that a task falls between 2 scores. ADL scores can range from 0 (normal) to 36 (greatest loss of function). A negative change from baseline indicates improvement. |
| Change From Baseline at Week 26 in Timed 25-Foot Walk (T25FW) | Baseline, Week 26 | The T25FW is a quantitative measure of lower extremity function. Participants are directed to 1 end of a clearly marked 25-foot course and instructed to walk 25 feet as quickly as possible, but safely. The task is immediately administered again by having the participant walk back the same distance, and the score for the test is the average of the 2 walks (after reciprocal transformation). Participants may use assistive devices when performing this task, with the same assistive device used at each assessment. A negative change from Baseline indicates improvement. |
| Number of FARS-mNeuro Responders and Non-Responders at Week 26 | Week 26 | A participant was considered a responder if they had an improvement (decrease) of at least 3 points from Baseline at Week 26 for the FARS-mNeuro score. The FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions were assessed. The FARS-mNeuro score excludes the peripheral nervous system subscale score and the facial and tongue atrophy and fasciculations from the bulbar subscale score. Scores range from 0 (normal) to 93 (most impairment). |
| Change From Baseline to Week 26 in Total Friedreich Ataxia Rating Scale Score (FARStot) | Baseline, Week 26 | The FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions are assessed. FARStot scores range from 0 (normal) to 125 (most impairment). A negative change from baseline indicates improvement. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Interferon γ-1b SC doses of ACTIMMUNE® TIW for a total of 26 weeks. | 47 |
| Placebo SC doses of placebo TIW for a total of 26 weeks. | 45 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Interferon γ-1b | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 16.5 years STANDARD_DEVIATION 4.41 | 16.1 years STANDARD_DEVIATION 3.75 | 16.3 years STANDARD_DEVIATION 4.08 |
| Sex: Female, Male Female | 26 Participants | 26 Participants | 52 Participants |
| Sex: Female, Male Male | 21 Participants | 19 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 47 | 37 / 45 |
| serious Total, serious adverse events | 1 / 47 | 2 / 45 |
Outcome results
Primary
Change From Baseline to Week 26 in the Friedreich's Ataxia Rating Scale (FARS)-mNeuro Score
The FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions were assessed. The FARS-mNeuro score excludes the peripheral nervous system subscale score and the facial and tongue atrophy and fasciculations from the bulbar subscale score. Scores range from 0 (normal) to 93 (most impairment). A negative change from baseline is an improvement.
Time frame: Baseline, Week 26
Population: Intent-to-Treat (ITT) Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro) and at Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon γ-1b | Change From Baseline to Week 26 in the Friedreich's Ataxia Rating Scale (FARS)-mNeuro Score | -0.6 units on a scale | Standard Deviation 4.61 |
| Placebo | Change From Baseline to Week 26 in the Friedreich's Ataxia Rating Scale (FARS)-mNeuro Score | -1.0 units on a scale | Standard Deviation 4.41 |
Comparison: The primary and secondary efficacy endpoints were tested in a hierarchical manner. Each endpoint was tested in sequential order and the current endpoint must have shown statistical significance (p \< 0.05) prior to performing testing the next endpoint. The primary endpoint, FARS-mNeuro, was to be tested first, followed by the key secondary endpoint, ADL, followed by the other secondary endpoints, T25FW, FARS-mNeuro responder rate, and FARStot.p-value: 0.5442ANCOVA
Secondary
Change From Baseline at Week 26 in Timed 25-Foot Walk (T25FW)
The T25FW is a quantitative measure of lower extremity function. Participants are directed to 1 end of a clearly marked 25-foot course and instructed to walk 25 feet as quickly as possible, but safely. The task is immediately administered again by having the participant walk back the same distance, and the score for the test is the average of the 2 walks (after reciprocal transformation). Participants may use assistive devices when performing this task, with the same assistive device used at each assessment. A negative change from Baseline indicates improvement.
Time frame: Baseline, Week 26
Population: ITT Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro), and T25FW data at Baseline and Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon γ-1b | Change From Baseline at Week 26 in Timed 25-Foot Walk (T25FW) | -0.006 1/seconds | Standard Deviation 0.0247 |
| Placebo | Change From Baseline at Week 26 in Timed 25-Foot Walk (T25FW) | -0.003 1/seconds | Standard Deviation 0.0181 |
Secondary
Change From Baseline to Week 26 in Activities of Daily Living (ADL) Score
Participants and/or their caregivers rated 9 areas of daily living skills (speech, swallowing, cutting food and handling utensils, dressing, personal hygiene, falling, walking, quality of sitting position, and bladder function) on a 5-point scale (0=normal, 4=greatest loss of function) with allowable increments of 0.5 if the participant or caregiver strongly felt that a task falls between 2 scores. ADL scores can range from 0 (normal) to 36 (greatest loss of function). A negative change from baseline indicates improvement.
Time frame: Baseline, Week 26
Population: ITT Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro) and ADL data at Baseline and Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon γ-1b | Change From Baseline to Week 26 in Activities of Daily Living (ADL) Score | 0.64 units on a scale | Standard Deviation 2.938 |
| Placebo | Change From Baseline to Week 26 in Activities of Daily Living (ADL) Score | 0.01 units on a scale | Standard Deviation 2.595 |
Secondary
Change From Baseline to Week 26 in Total Friedreich Ataxia Rating Scale Score (FARStot)
The FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions are assessed. FARStot scores range from 0 (normal) to 125 (most impairment). A negative change from baseline indicates improvement.
Time frame: Baseline, Week 26
Population: ITT Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro) and FARStot data at Baseline and Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon γ-1b | Change From Baseline to Week 26 in Total Friedreich Ataxia Rating Scale Score (FARStot) | -0.2 units on a scale | Standard Deviation 5.53 |
| Placebo | Change From Baseline to Week 26 in Total Friedreich Ataxia Rating Scale Score (FARStot) | -0.6 units on a scale | Standard Deviation 5.19 |
Secondary
Number of FARS-mNeuro Responders and Non-Responders at Week 26
A participant was considered a responder if they had an improvement (decrease) of at least 3 points from Baseline at Week 26 for the FARS-mNeuro score. The FARS assessment includes neurological signs that specifically reflect neural substrates affected in FA. Based on a neurological examination, bulbar, upper limb, lower limb, peripheral nerve, and upright stability/gait functions were assessed. The FARS-mNeuro score excludes the peripheral nervous system subscale score and the facial and tongue atrophy and fasciculations from the bulbar subscale score. Scores range from 0 (normal) to 93 (most impairment).
Time frame: Week 26
Population: ITT Population: All randomized participants with a valid baseline (including Screening) and at least 1 valid post baseline measurement in the primary efficacy outcome (FARS-mNeuro) and data at Week 26. A valid FARS-mNeuro score was defined as no missing values in the questionnaire.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Interferon γ-1b | Number of FARS-mNeuro Responders and Non-Responders at Week 26 | Responder | 14 Participants |
| Interferon γ-1b | Number of FARS-mNeuro Responders and Non-Responders at Week 26 | Non-responder | 32 Participants |
| Placebo | Number of FARS-mNeuro Responders and Non-Responders at Week 26 | Responder | 16 Participants |
| Placebo | Number of FARS-mNeuro Responders and Non-Responders at Week 26 | Non-responder | 28 Participants |