Safety, Tolerability and Efficacy of ACTIMMUNE® Dose Escalation in Friedreich's Ataxia Study

Study Overview
=================
Brief Summary
-----------------
The purpose of this phase 3 multi-center, open-label extension study is to evaluate the long-term safety of ACTIMMUNE® (interferon-γ 1b) in participants with Friedreich's Ataxia.

Detailed Description
-----------------
Participants who complete 26 weeks of blinded treatment in HZNP-ACT-301 (NCT02415127), will be eligible to enter this 6-month study. All participants will receive ACTIMMUNE® 3 times a week (TIW) for 26 weeks. In order to maintain the study blind in HZNP-ACT-301 (NCT02415127), all participants in this open-label extension study will undergo ACTIMMUNE® titration, regardless if they received ACTIMMUNE® or placebo in HZNP-ACT-301 (NCT02415127). The Week 26 Visit from HZNP-ACT-301 (NCT02415127) will serve as the Baseline Visit (Day 1) for this study. During the treatment period, additional clinic visits are scheduled at Weeks 4, 13, and 26; in between clinic visits, participants (and/or caregivers) will be monitored via emails/phone calls on a weekly basis until participants reach their maximum tolerated dose, and on a monthly basis thereafter.

Official Title
-----------------
Multicenter, Safety and Efficacy, Open-Label Extension Study of ACTIMMUNE® (Interferon γ-1b) in Children and Young Adults With Friedreich's Ataxia

Conditions
-----------------
Friedreich's Ataxia

Intervention / Treatment
-----------------
* Drug: Interferon γ-1b


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent and child assent, if applicable. Completed 26 weeks of blinded treatment in Study HZNP-ACT-301 (NCT02415127). 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 urine pregnancy test result at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301 [NCT02415127]), 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: Subjects will be ineligible if, in the opinion of the Investigator, they are unlikely to comply with the study protocol or have a concomitant disease or condition that could interfere with the conduct of the study or potentially put the subject at unacceptable risk. NOTE: Additional inclusion/exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 10 Years
Maximum Age: 26 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: interferon γ-1b<br>Subcutaneous (SC) doses of ACTIMMUNE® TIW for a total of 26 weeks. | Drug: Interferon γ-1b<br>* 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).<br>* Other names: ACTIMMUNE®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs | An adverse event (AE) is any untoward medical occurrence, whether or not the event is considered related to the investigational product. A TEAE is any adverse change from the subject's baseline condition, including any laboratory test value abnormality judged as clinically significant by the investigator, that occurs on or after the date of the first dose of study drug administered at home and throughout the duration of the clinical study, whether the adverse event is considered related to the treatment or not. An SAE is an AE that results in death, is life-threatening, results in persistent or significant disability or incapacity, inpatient hospitalization or prolongation of an existing hospitalization, is a congenital anomaly or birth defect, or other medically important event. | Baseline/Day 1 (Week 26 of Study HZNP-ACT-301 [NCT02415127]) through Week 28 (follow-up safety visit) | 
| Number of Participants With Positive/Negative Neutralizing Antibody (NAb) and Anti-Drug Antibody (ADA) Tests | NAb testing only for those participants with a positive ADA test. Baseline is defined as the last non-missing measurement/assessment on the date of Week 26 Visit from study HZNP-ACT-301 (NCT02415127). If this measurement was missing or otherwise unavailable, it was the last non-missing measurement/assessment on or prior to first dose in this study. If the participant discontinued the study, then premature withdrawal assessments were mapped to the nearest scheduled visit based on schedule of the assessment and the study day. If the mapped visit was already available then the visit was mapped to the next schedule visit. Last on study assessment is the last non-missing post-baseline assessment for each participant. | Baseline/Day 1 (Week 26 of Study HZNP-ACT-301 [NCT02415127]), Week 4, Week 13, Week 26, and Week 28 (follow-up safety visit) | 
| 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. | From Baseline to Week 26 for all participants and from Baseline of HZNP-ACT-301 (NCT02415127)to Week 26 of HZNP-ACT-302 (52-week treatment duration) for participants receiving active treatment in both studies. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From Baseline to Week 26 for all participants and from Baseline of HZNP-ACT-301 (NCT02415127)to Week 26 of HZNP-ACT-302 (52-week treatment duration) for participants receiving active treatment in both studies. | 
| 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. | From Baseline to Week 26 for all participants and from Baseline of HZNP-ACT-301 (NCT02415127)to Week 26 of HZNP-ACT-302 (52-week treatment duration) for participants receiving active treatment in both studies. | 
| 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). | Week 26 | 
| 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. | From Baseline to Week 26 for all participants and from Baseline of HZNP-ACT-301 (NCT02415127)to Week 26 of HZNP-ACT-302 (52-week treatment duration) for participants receiving active treatment in both studies. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Interferon gamma