Conditions: Friedreich's Ataxia
Keywords: Interferon gamma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 86
Healthy volunteers: no

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.

Study with completed results acquired from Horizon in 2024.

Arms:
arm 1: Subcutaneous (SC) doses of ACTIMMUNE® TIW for a total of 26 weeks.

Interventions: intervention 1: Interferon γ-1b
Intervention descriptions: intervention 1: 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).

Protocol document:
Prot_000.pdf: 
Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
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Page 1 of 93 
 
 
 
CLINICAL STUDY PROTOCOL  
FOR ACTIMMUNE® 
IND: 123947 
Protocol Number: HZNP-ACT-302 
Version 2.0, incorporating Amendment 1 
 
Multicenter, Safety and Efficacy, Open-Label Extension Study of 
ACTIMMUNE® (interferon γ-1b) in Children and Young Adults with 
Friedreich’s Ataxia 
Short title:  STEADFAST Open-Label Extension 
Safety, Tolerability and Efficacy of ACTIMMUNE® Dose Escalation in 
Friedreich’s Ataxia Study 
Date:  28 September 2016 
Collaborator: 
Friedreich’s Ataxia Research Alliance (FARA) 
Sponsor: 
Horizon Pharma Ireland Ltd. 
Connaught House, 1st Floor 
1 Burlington Road  
Dublin 4, Ireland 
 
This protocol is the confidential information of Horizon Pharma Ireland Ltd. and is intended solely for the guidance of the clinical investigation. 
This protocol may not be disclosed to parties not associated with the clinical investigation or used for any purpose without the prior written 
consent of Horizon Pharma Ireland Ltd. 
CONFIDENTIAL 
 






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Date: 28 September 2016 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
HZNP-ACT-302 
Version: 
2.0, incorporating Amendment 1 
Protocol Title: 
Multicenter, Safety and Efficacy, Open-Label Extension Study of 
ACTIMMUNE® (interferon γ-1b) in Children and Young Adults with 
Friedreich’s Ataxia 
Version Date: 
28 September 2016 
I agree to conduct the study according to the protocol named above. I fully understand that any 
changes instituted by the Principal Investigator without previous discussion with the Sponsor 
constitute a violation of the protocol, unless necessary to eliminate an immediate hazard to the 
safety or well-being of a subject. 
I acknowledge that I have read and understand the protocol named above and agree to carry out 
all of its terms in accordance with applicable regulations and laws. 
I assure that the study drug supplied by the Sponsor will be used only as described in the 
protocol named above. 
 
 
 
 
 
 
 
 
 Name  
Study Center 
Address 
City State 
 
 
Date 
 
 


Horizon Pharma Ireland Ltd. 
 
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SUMMARY OF CHANGES 
Protocol HZNP-ACT-302 
Version 2.0, incorporating Amendment 1 
 
The original protocol was approved on 11 September 2015. This protocol is being further 
amended to collect additional safety data related to cardiac function (echocardiogram) and blood 
coagulation parameters (prothrombin time and activated partial thromboplastin time).  
Since the initiation of this study, there has been a single case report of a study participant who 
developed cardiac hypertrophy (evidenced by respiratory distress and decreased left ventricular 
ejection fraction) and thrombosis in the ventricles, lung, and possibly the superior mesenteric 
artery that resulted in a fatal outcome approximately 5 months after initiating open-label 
treatment with ACTIMMUNE in this study. A detailed review of this event by the investigator 
and Sponsor did not reveal any causality with ACTIMMUNE, and given that Friedreich's Ataxia 
(FA) is associated with various forms of heart disease, such as hypertrophic cardiomyopathy 
[Weidemann et al, 2013], an acute process superimposed on chronic underlying heart disease 
must be considered. This single case report contrasts with a recently published case report 
showing improvement of cardiac hypertrophy and cardiomyopathy in a patient with FA who was 
treated with interferon γ-1b for one year [Wyller et al, 2016]. In addition, off-protocol physician-
prescribed ACTIMMUNE therapy has not been identified to have adverse cardiac events, 
including 8 FA patients treated by the coordinating principal investigator (CPI) of this study for 
at least 6 months. In order to provide clarification regarding the effect of ACTIMMUNE on 
cardiac function and blood coagulation, echocardiogram and blood clotting parameters have been 
included in this amended protocol. 
Echocardiograms, which were not scheduled in the original protocol, will be performed at 
Baseline and Week 26 (or premature withdrawal). In addition, the volume of individual blood 
samples for clinical laboratory safety analyses will be increased from 4.5 mL to 9.3 mL at each 
previously scheduled time point to accommodate the additional coagulation parameter testing. 
In addition, the Sponsor’s local address, employee titles, and signatories were updated, the 
contact person for the Academic Research Organization (ARO) was updated, and the contract 
organization performing statistical analyses was changed from the ARO to Premier Research. 
The following sections of the protocol are affected: 2, 2.1, 4, 6, 9.1, 9.5.3, 9.5.3.5, 9.5.3.7, 
9.5.5.1, 9.5.5.2, 9.5.5.3, 9.5.5.4, 9.6.1, and 17.1. 
2. SYNOPSIS 
Criteria for Evaluation: 
Safety Assessments 
• Vital signs, clinical safety laboratory evaluations (complete blood count, prothrombin 
time [PT], international normalized ratio [INR], activated partial thromboplastin time 
[aPTT], chemistry, and urinalysis), and pregnancy testing (if applicable) at all on-
treatment clinic visits. 


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• Echocardiogram at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Week 26 
(or PW). 
 
Safety Endpoints 
Adverse event and concomitant medication data will be summarized. Clinical laboratory safety 
data, vital sign data, echocardiogram data, and ECG interval data will be summarized with 
descriptive statistics for Baseline, post-dose, and change from Baseline to post-dose values. 
 
2.1 Schedule of Assessments 
Study Phase 
Treatment Period 
Follow-up 
Visit # 
Baseline1 
1 
2 
3 
Safety Visit 
Week 
1 
4 
13 
26 (or PW) 
28 
Study Days (± visit window) 
Day 1  
(Week 26 of Study 
HZNP-ACT-301) 
29 (± 3)  
days 
92 (± 3)  
days 
183 (± 3) 
days 
197 (± 3) 
days 
Safety Assessments 
 
 
 
 
 
TEAE, SAE assessment11 
X 
X 
X 
X 
X 
Immunogenicity testing12 
X 
X 
X 
X 
X 
Echocardiogram 
X 
 
 
X 
 
ECG 
X 
 
X 
X 
 
Physical examination13 
X 
X13 
X 
X 
X13 
Vital Signs: blood pressure, pulse, temperature 
X 
X 
X 
X 
 
Urine pregnancy test 14 
X 
X 
X 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
Clinical laboratory evaluation15  
(hematology, chemistry, urinalysis) 
X 
X 
X 
X 
 
End treatment 
 
 
 
X 
 
11 Adverse events occurring or worsening on or after the date of administration of the first dose of study drug at home through the end of the 
study will be considered treatment-emergent adverse events (TEAEs). All SAEs that occur on or after the date of administration of the first 
dose of study drug at home through two weeks after study discontinuation will be recorded. 
12 If a subject tests positive for anti-drug antibodies (ADA), he/she will be followed until ADA levels revert to baseline. 
13 Brief physical examinations will be performed at the Week 4 and Follow-Up Safety Visits; all other examinations will be complete physical 
examinations.  
14 Only for female subjects of childbearing potential. 
15 Collect blood samples for clinical safety laboratory testing (total 9.3 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, and 
1.8 mL for coagulation) and a urine sample for urinalysis. 
 
4. LIST OF ABBREVIATIONS 
PT, INR, and aPTT abbreviations were added. 
6.  INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Study site monitoring, project management, and data management, and statistical analyses will 
be performed by the Clinical Trials Coordination Center (CTCC), an Academic Research 
Organization (ARO) at the University of Rochester, Rochester, NY. Statistical analyses will be 
performed by Premier Research International, LLC. 


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Table 6.1 Table of Non-Sponsor Study Responsibilities 
Clinical Trials Coordination 
Center (CTCC) (project 
management, clinical 
monitoring, and data 
management, and statistical 
analyses)  
Academic Research Organization (ARO) 
Center for Human Experimental Therapeutics (CHET) 
University of Rochester 
265 Crittenden Avenue 
Rochester, NY  14624 
Statistical Analyses 
Premier Research International, LLC 
One Park Drive, Suite 150 
Durham, NC 27709 
 
9.1 Overall Study Design and Plan 
Safety Assessments 
• Vital signs, clinical safety laboratory evaluations (complete blood count, prothrombin time 
[PT], international normalized ratio [INR], activated partial thromboplastin time [aPTT], 
chemistry, and urinalysis), and pregnancy testing (if applicable) at all on-treatment clinic 
visits. 
• Echocardiogram at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Week 26 (or 
PW). 
9.5.3 Safety Variables 
• Safety will be assessed via AE and concomitant medication use monitoring, immunogenicity 
testing, physical examinations, vital signs, clinical safety laboratory evaluations (complete 
blood count, PT, INR, aPTT, chemistry, and urinalysis), pregnancy testing (if applicable), 
echocardiograms, and ECGs. 
9.5.3.5 Echocardiograms (section added) 
Echocardiograms are scheduled for Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and 
Week 26 (or PW). 
9.5.3.7 Clinical Laboratory Tests 
Samples of blood (9.34.5 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, and 
1.8 mL for PT/INR/aPTT) and urine are scheduled for collection at Baseline/Day 1 (Week 26 of 
Study HZNP-ACT-301), and Weeks 4, 13, and 26 (or PW). 


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The following clinical laboratory tests will be performed:  
• Complete blood count  
• PT (and derivation of INR) and aPTT 
• Chemistry panel 
• Urinalysis 
9.5.5.1 Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) 
• Collect blood (9.34.5 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, and 
1.8 mL for PT/INR/aPTT) and urine samples from all subjects for safety clinical laboratory 
values (including urine pregnancy test [if applicable]). The pregnancy test must be negative 
for those subjects to be eligible for participation in this study. 
• Collect blood samples (2 mL) for immunogenicity testing. 
• Collect blood samples (1 mL) for frataxin analyses. 
• Measure height and weight to calculate dose volume. 
• Educate subjects and caregivers on dosing technique and schedule. 
• Between approximately 7 to 10 AM, administer the last dose of double-blind study drug for 
Study HZNP-ACT-301 or supervise administration of the study drug by either the subject or 
the subject’s caregiver and record date/time of dosing. 
• Perform physical examination, including vital signs. 
• Enquire about AEs and concomitant medications. 
• Perform ADL, and Physician’s and Patient’s Global Assessments. 
• Perform echocardiogram. 
• Perform ECG. 
9.5.5.2 Week 4 and  
9.5.5.3 Week 13 
• Collect blood (9.34.5 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, and 
1.8 mL for PT/INR/aPTT) and urine samples from all subjects for safety clinical laboratory 
values (including urine pregnancy test [if applicable]). 
9.5.5.4 Week 26 (Termination Visit or Premature Withdrawal Visit) 
• Collect blood (9.34.5 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, and 
1.8 mL for PT/INR/aPTT) and urine samples from all subjects for safety clinical laboratory 
values (including urine pregnancy test [if applicable]). 
• Collect blood samples (2 mL) for immunogenicity testing. 
• Collect blood samples (1 mL) for frataxin analyses. 
• Measure height and weight. 




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2. 
SYNOPSIS 
Protocol Title: Multicenter, Safety and Efficacy, Open-Label Extension Study of ACTIMMUNE® (interferon γ-1b) in 
Children and Young Adults with Friedreich’s Ataxia 
Protocol Number:  HZNP-ACT-302 
Phase: 3 
Protocol Version: 2.0, incorporating Amendment 1 
 
Test Drug: ACTIMMUNE (interferon γ-1b) 
Indication: Friedreich’s Ataxia (FA) 
Number and Country of Study Sites: Approximately 4 study centers in the United States. 
Objectives: 
Primary Study Objective 
To evaluate the long-term safety of ACTIMMUNE in subjects with FA. 
Primary Efficacy Objective 
To evaluate the effect of ACTIMMUNE (interferon [IFN]-γ 1b) on the change from Baseline to Week 26 for all 
subjects and from Baseline of HZNP-ACT-301 to Week 26 of HZNP-ACT-302 (52-week treatment duration) for 
subjects receiving active treatment in both studies in neurological outcome as measured by Friedreich’s Ataxia Rating 
Scale (FARS) excluding the peripheral nervous system subscale score and the facial and tongue atrophy and 
fasciculations from the bulbar subscale score (FARS-mNeuro score). 
Secondary Efficacy Objectives 
To evaluate the effect of ACTIMMUNE (interferon [IFN]-γ 1b) on the change from Baseline to Week 26 for all 
subjects and from Baseline of HZNP-ACT-301 to Week 26 of HZNP-ACT-302 (52-week treatment duration) for 
subjects receiving active treatment in both studies for the following: 
• 
Activities of Daily Living (ADL) 
• 
The timed 25-foot-walk test (T25FW) 
• 
Responder rate (≥3 point improvement in the FARS-mNeuro score) 
• 
Neurological outcome as measured by the total FARS score (FARStot) 
Study Design: 
This is a multi-center, dose-escalation, open-label extension study of HZNP-ACT-301 examining the safety and 
efficacy of ACTIMMUNE in the treatment of FA in children and young adults. Subjects who complete 26 weeks of 
blinded treatment in HZNP-ACT-301 will be eligible to enter this 6-month study. All subjects who choose to 
participate will receive ACTIMMUNE three times a week (TIW) for 26 weeks. In order to maintain the study blind in 
HZNP-ACT-301, all subjects in this open-label extension study will undergo ACTIMMUNE titration, regardless if 
they received ACTIMMUNE or placebo in HZNP-ACT-301. 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 100 µg/m2), however, the dose may be reduced, 
interrupted, or held based on tolerability. By Week 13, all subjects 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 subsequent drug-related adverse events (AEs) (e.g., elevated liver function tests). 
The Week 26 Visit from HZNP-ACT-301 will serve as the Baseline Visit (Day 1) for this study. All subjects will 
undergo Baseline assessments and be assigned to the lowest dose (10 µg/m2) of ACTIMMUNE. The first dose of 
study drug will be administered at home before bedtime according to the subject’s TIW dosing schedule. During the 
treatment period, additional clinic visits are scheduled at Weeks 4, 13, and 26; in between clinic visits, subjects 
(and/or caregivers) will be monitored via emails/phone calls on a weekly basis until subjects reach their maximum 
tolerated dose and on a monthly basis thereafter. 
Subjects will return to the clinic two weeks after the last dose of study drug for a Follow-Up Safety Visit. 
An overview of the study design is presented in the schematic below, and details of study activities are provided in 
Section 2.1, Schedule of Assessments. 


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Schematic of Study Design 
 
 
 
<–––––––––– ACTIMMUNE (10 µg/m2 to 100 µg/m2) TIW SC –––––––––> 
(26 weeks) 
 
 
 
Baseline 1 
Visit 1 
Visit 2 
Visit 3 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1eek 
 
Week 4 
Week 13 
Week 26 
Week 28 
 
 
 
First dose 
 
 
 
 
 
 
 
at home 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<–– Dose escalation 2 ––> 
 
<––––– Stable dose 2 ––––––> 
 
 
 
 
 
 
<–– Weekly contact 3 ––> <–––––––––––– Monthly contact 3 –––––––––––––> 
 
 
 
 
1 Week 26 of HZNP-ACT-301 will serve as the Baseline Visit (Day 1) for this study. Subjects will receive the last dose of the randomized drug 
from HZNP-ACT-301in a double-blind fashion, and the first dose of study drug for the open-label extension study (10 µg/m2) will be distributed 
for administration at home according to the planned TIW dosing schedule. 
2 The planned dose escalation consists of two doses of ACTIMMUNE 10 µg/m2 in the first week, followed by weekly escalation to 25, 50, and 
100 µg/m2 TIW on Days 8, 15, and 22, respectively; however, the dose may be reduced, interrupted, or held based on tolerability. All subjects are 
to be on a stable tolerated dose of study drug by Week 13 in order to continue study participation. 
3 Subjects and/or caregivers will be contacted by email or phone to monitor safety and dosing logistics on a weekly basis from Day 1 (Week 26 of 
HZNP-ACT-301) through Week 4 (or until stable tolerated dose is achieved) and on a monthly basis after Week 4 (or after dose stabilization) 
through Week 26. 
Subject Population: 
Male and non-pregnant female subjects who completed 26 weeks of blinded treatment in Study HZNP-ACT-301 will 
be enrolled. 
Inclusion Criteria: 
Eligible subjects must meet all of the following criteria: 
1. Written informed consent and child assent, if applicable. 
2. Completed 26 weeks of blinded treatment in Study HZNP-ACT-301. 
3. 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), 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. 
Dose Regimen/Route of Administration: 
Subjects will receive SC doses of ACTIMMUNE TIW for 26 weeks. The volume of study drug will be determined 
using the subject’s body surface area (BSA) at the appropriate clinic visit. The planned dose escalation consists of two 
doses of ACTIMMUNE 10 µg/m2 in the first week, followed by weekly escalation to 25, 50, and 100 µg/m2 TIW on 
Days 8, 15, and 22, respectively; however, dose escalation will only occur if the previous dose is tolerated. If, in the 
opinion of the investigator, severe reactions occur during dose escalation, the dose will be reduced to the previous 
dose level or will be interrupted until the adverse reaction resolves and then restarted at the previous or a lower dose 
level. By Week 13 of the study, subjects must be receiving a stable tolerated dose of study drug; the dose should not 
be further increased but should be maintained for the remaining 13 weeks of the study, however, dose reductions will 
be allowed on a case-by-case basis to manage subsequent drug-related AEs. 
Dosage Form and Strength Formulation: 
The commercial formulation of ACTIMMUNE will be used in this study. Each 0.5 mL of ACTIMMUNE contains 
100 µg (2 million international units [IU]) of IFN-γ 1b. 


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Duration of Treatment and Follow-Up: 
The planned treatment duration is 26 weeks (6 months), with a Follow-Up Safety Visit two weeks following the last 
dose of study drug. 
Criteria for Evaluation: 
Safety Assessments 
• 
Adverse event (AE) monitoring, concomitant medication monitoring, and physical examinations throughout 
the study. 
• 
Immunogenicity testing pre-dose at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), and Weeks 4, 13, 
26 (or premature withdrawal [PW]), and 28. 
• 
Vital signs, clinical safety laboratory evaluations (complete blood count, prothrombin time [PT], international 
normalized ratio [INR], activated partial thromboplastin time [aPTT], chemistry, and urinalysis), and 
pregnancy testing (if applicable) at all on-treatment clinic visits. 
• 
Echocardiogram at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Week 26 (or PW). 
• 
Electrocardiogram (ECG) at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), with additional ECGs at 
Weeks 13 and 26 (or PW). 
Efficacy Assessments 
• 
FARS, ADL assessment, T25FW, and 9-hole peg test (9-HPT) at Baseline/Day 1 (Week 26 of Study HZNP-
ACT-301) and 4 to 6 hours post-dose at Weeks 13 and 26 (or PW). 
• 
Low-contrast Sloan letter chart (LCSLC) Vision Test at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) 
and post-dose at Week 26 (or PW). 
• 
For all subjects with a normal audiogram result at Screening in Study HZNP-ACT-301, Listening in 
Spatialized Noise-Sentences Auditory Test (LiSN-S) at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) 
and post-dose at Week 26 (or PW). 
• 
Frataxin protein levels in whole blood, muscle biopsies (optional), and buccal cells at Baseline/Day 1 (Week 
26 of Study HZNP-ACT-301) and post-dose at Weeks 13 and 26 (or PW).  
• 
Functional staging of ataxia at Baseline/Day 1 (Week 26 of study HZNP-ACT-301), and post-dose at Weeks 
13 and 26 (or PW). 
• 
Physician Global Assessment and Patient Global Assessment at Baseline/Day 1 (Week 26 of Study HZNP-
ACT-301) and post-dose at Weeks 13 and 26 (or PW). 
Quality of Life Assessments 
• 
Quality of life assessments (Modified Fatigue Impact Score [MFIS], and Pediatric Quality of Life [PedsQL] 
questionnaire or 36-item short-form health survey [SF-36]) at Baseline/Day 1 (Week 26 of Study HZNP-
ACT-301) and Weeks 13 and 26 (or PW). The MFIS will be completed for all subjects. Subjects who 
completed the PedsQL during Study HZNP-ACT-301 will continue to complete the PedsQL in this study.  
Subjects who completed the SF-36 during Study HZNP-ACT-301 will continue to complete the SF-36 in this 
study. 
Statistical Analyses: 
All summaries will be presented by both the treatment received in HZNP-ACT-301 as well as overall. 
Safety Endpoints 
Adverse event and concomitant medication data will be summarized. Clinical laboratory safety data, vital sign data, 
echocardiogram data, and ECG interval data will be summarized with descriptive statistics for Baseline, post-dose, 
and change from Baseline to post-dose values. Shift tables will be presented for clinical laboratory values and ECG 
categorical results from Baseline to each post-dose visit. Physical examination findings will be listed by subject. 
Results of immunogenicity testing will be presented in tabular format. 


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Efficacy Endpoints 
The primary efficacy endpoint is the observed change from Baseline to Week 26 for all subjects and from Baseline of 
HZNP-ACT-301 to Week 26 of HZNP-ACT-302 (52-week treatment duration) for subjects receiving active treatment 
in both studies in the FARS-mNeuro score. Results will be summarized descriptively.  
Secondary Efficacy Endpoints 
The observed mean change from Baseline to Week 26 for all subjects and from Baseline of HZNP-ACT-301 to Week 
26 of HZNP-ACT-302 (52-week treatment duration) for subjects receiving active treatment in both studies in ADL, 
T25FW, FARS-mNeuro responder rate, and FARStot results will be summarized descriptively. 
Exploratory Efficacy/Quality of Life Endpoints 
The observed mean changes from Baseline will be summarized descriptively for the following endpoints: 
• 
Change from Baseline to Week 13 in the FARS-mNeuro, ADL, T25FW, and FARStot scores. 
• 
Change from Baseline to Weeks 13 and 26 for all subjects and from Baseline of HZNP-ACT-301 to Week 26 
of HZNP-ACT-302 (52-week treatment duration) for subjects receiving active treatment in both studies in 
9-HPT, remaining FARS subscale scores, FA stage, frataxin protein levels, MFIS, SF-36, PedsQL, and 
Physician and Patient Global Assessments. 
• 
Change from Baseline to Week 26 for all subjects and from Baseline of HZNP-ACT-301 to Week 26 of 
HZNP-ACT-302 (52-week treatment duration) for subjects receiving active treatment in both studies in 
LCSLC and LiSN-S. 
Sample Size Estimate: 
Subjects who complete 26 weeks of blinded treatment in Study HZNP-ACT-301 will be eligible for enrollment. The 
sample size is not based on statistical considerations. 
 


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2.1 
Schedule of Assessments  
Study Phase 
Treatment Period 
Follow-up 
Visit # 
Baseline1 
1 
2 
3 
Safety Visit 
Week 
1 
4 
13 
26 (or PW) 
28 
Study Days (± visit window) 
Day 1  
(Week 26 of Study 
HZNP-ACT-301) 
29 (± 3)  
days 
92 (± 3)  
days 
183 (± 3) 
days 
197 (± 3) 
days 
Informed consent/assent 
X 
 
 
 
 
Review of inclusion/exclusion criteria 
X 
 
 
 
 
Weight/height, BSA2 
X 
X 
X 
X 
 
Educate on dosing technique and schedule3 
X 
X 
X 
 
 
Dose given at study visit4 
 
X 
X 
X 
 
Dispense study drug5 
X 
X 
X 
 
 
Drug compliance 
 
X 
X 
X 
 
Phone (email) contact for safety and dosing logistics6 
X 
X 
X 
 
 
Efficacy assessments7 
 
 
 
 
 
Functional staging of FA7 
X 
 
X 
X 
 
FARS7 
X 
 
X 
X 
 
T25FW7  
X 
 
X 
X 
 
9-HPT7 
X 
 
X 
X 
 
Vision testing (LCSLC) 
X 
 
 
X 
 
Auditory testing (LiSN-S)8 
X 
 
 
X 
 
Frataxin protein:  whole blood, muscle biopsy 
(optional)9, and buccal cells 
X 
 
X 
X 
 
Physician and Patient Global assessments  
X 
 
X 
X 
 
ADL 
X 
 
X 
X 
 
Quality of Life (QOL) Assessments 
 
 
 
 
 
PedsQL or SF-3610 
X 
 
X 
X 
 
MFIS  
X 
 
X 
X 
 
Safety Assessments 
 
 
 
 
 
TEAE, SAE assessment11 
X 
X 
X 
X 
X 
Immunogenicity testing12 
X 
X 
X 
X 
X 
Echocardiogram 
X 
 
 
X 
 
ECG 
X 
 
X 
X 
 
Physical examination13 
X 
X13 
X 
X 
X13 
Vital Signs: blood pressure, pulse, temperature 
X 
X 
X 
X 
 
Urine pregnancy test 14 
X 
X 
X 
X 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
Clinical laboratory evaluation15  
(hematology, chemistry, urinalysis) 
X 
X 
X 
X 
 
End treatment 
 
 
 
X 
 
9-HPT=9-hole peg test, ADL=activities of daily living, BSA=body surface area, ECG=electrocardiogram, FA=Friedreich’s Ataxia, 
FARS=Friedreich’s Ataxia Rating Scale, IFN=interferon, LCSLC=Low-contrast Sloan letter chart, LiSN-S=Listening in Spatialized Noise-
Sentences Auditory Test, MFIS=Modified Fatique Impact Scale, PedsQL=Pediatric Quality of Life, PW=premature withdrawal, QOL=quality of 
life, SAE=serious adverse event, SF-36=36-item short form health survey, T25FW=timed 25-foot walk, TEAE=treatment-emergent adverse 
event. 
Footnotes are presented on the next page. 
 


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1 On Day 1 (Baseline), subjects will receive the last dose of assigned study drug (ACTIMMUNE or placebo) for HZNP-ACT-301, and undergo 
assessments; these assessments will serve as the Week 26 assessments for HZNP-ACT-301 and the Baseline assessments for HZNP-ACT-302. 
2 Height and weight will be measured at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), and Weeks 4, 13, and 26 to determine BSA; 
dosing will be based on BSA at Baseline/Day1, and Weeks 4 and 13. 
3 Study drug will be initiated at home following the Baseline/Day 1 visit  at 10 µg/m2 according to the subject’s TIW dosing schedule. The 
planned dose escalation consists of two doses of ACTIMMUNE 10 µg/m2 in the first week, followed by weekly escalation to 25, 50, and 
100 µg/m2 TIW on Days 8, 15, and 22, respectively; however, the dose may be reduced, interrupted, or held based on tolerability. All subjects 
are to be on a stable tolerated dose of study drug by Week 13 in order to continue study participation 
4 At the Baseline/Day 1 visit (Week 26 of Study HZNP-ACT-301), subjects will receive the last dose of study drug from the double-blind Study 
HZNP-ACT-301 (ACTIMMUNE or placebo). The first dose for this open-label extension study (ACTIMMUNE 10µg/m2) will be 
administered at home before bedtime according to the subject’s TIW dosing schedule. Dosing at Weeks 4, 13, and 26 will be performed at the 
clinic. All other doses will be administered at home before bedtime. 
5 Subjects will be given a 4-week supply of study drug prior to clinic discharge at the Baseline/Day 1 Visit (Week 26 of Study HZNP-ACT-
301). At the Week 4 and 13 Visits, subjects will be given a 6-week supply of study drug, and additional study drug will be directly shipped to 
the subjects’ homes as needed; if direct shipment is not feasible, subjects may receive a full supply at Weeks 4 and 13 (9-week supply at Week 
4 and 13-week supply at Week 13).  
6 Subjects and/or caregivers will be contacted by email or phone to monitor safety and dosing logistics on a weekly basis during the dose-
escalation period (from Day 1 through at least Week 4 [or later until a stable tolerated dose is reached]) and on a monthly basis after dose 
stabilization (from Week 4 or when dose is stabilized) through Week 26. 
7 Functional staging, FARS, T25W, and 9-HPT will be performed at approximately the same time of day at each visit and by the same examiner. 
8 The LiSN-S will only be performed for subjects who had a normal audiogram prior to enrollment in HZNP-ACT-301. The LiSN-S will be 
performed at the Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Week 26 visits. 
9 Muscle biopsies will be optional for each subject, and consent will be signed prior to biopsy collection. Biopsies will be the last efficacy 
assessment of the day at Weeks 13 and 26. 
10 The PedsQL (study subject and parent/caregiver assessments) will be administered throughout the study for subjects who received the PedsQL 
at their Baseline Visit of the HZNP-ACT-301 study (even if subjects turn 18 during their participation in either Study HZNP-ACT-301 or 
HZNP-ACT-302).  The SF-36 will continue to be administered throughout the study for subjects who completed the SF-36 during their 
HZNP-ACT-301 study participation. 
11 Adverse events occurring or worsening on or after the date of administration of the first dose of study drug at home through the end of the 
study will be considered treatment-emergent adverse events (TEAEs). All SAEs that occur on or after the date of administration of the first 
dose of study drug at home through two weeks after study discontinuation will be recorded. 
12 If a subject tests positive for anti-drug antibodies (ADA), he/she will be followed until ADA levels revert to baseline. 
13 Brief physical examinations will be performed at the Week 4 and Follow-Up Safety Visits; all other examinations will be complete physical 
examinations.  
14 Only for female subjects of childbearing potential. 
15 Collect blood samples for clinical safety laboratory testing (9.3 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, and 1.8 mL 
for PT/INR/aPTT) and a urine sample for urinalysis. 
 


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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE .......................................................................................................................... 2 
2. 
SYNOPSIS ............................................................................................................................ 11 
2.1 
Schedule of Assessments ............................................................................................... 15 
3. 
TABLE OF CONTENTS ...................................................................................................... 17 
4. 
LIST OF ABBREVIATIONS ............................................................................................... 21 
5. 
ETHICS ................................................................................................................................. 23 
5.1 
Institutional Review Board............................................................................................. 23 
5.2 
Ethical Conduct of the Study ......................................................................................... 23 
5.3 
Subject Information and Consent/Assent ....................................................................... 23 
6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................ 23 
7. 
INTRODUCTION ................................................................................................................ 25 
7.1 
Scientific Background .................................................................................................... 25 
7.2 
Rationale for the Study ................................................................................................... 26 
7.3 
Rationale for Dose Selection .......................................................................................... 27 
8. 
STUDY OBJECTIVES ......................................................................................................... 29 
8.1 
Primary Study Objective ................................................................................................ 29 
8.2 
Primary Efficacy Objective ............................................................................................ 29 
8.3 
Secondary Efficacy Objectives ...................................................................................... 29 
9. 
INVESTIGATIONAL PLAN ............................................................................................... 30 
9.1 
Overall Study Design and Plan ...................................................................................... 30 
9.2 
Discussion of Study Design ........................................................................................... 32 
9.3 
Selection of Study Population ........................................................................................ 33 
9.3.1 
Inclusion Criteria .................................................................................................... 33 
9.3.2 
Exclusion Criteria ................................................................................................... 33 
9.3.3 
Removal of Subjects from Therapy or Assessment ................................................ 33 
9.4 
Treatments ...................................................................................................................... 34 
9.4.1 
Treatments Administered ........................................................................................ 34 
9.4.1.1 Dose Adjustment Guidelines ............................................................................... 35 
9.4.2 
Identity of Investigational Products ........................................................................ 35 
9.4.2.1 ACTIMMUNE .................................................................................................... 35 


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9.4.3 
Labeling .................................................................................................................. 36 
9.4.4 
Storage .................................................................................................................... 36 
9.4.5 
Study Drug Quality Issues ...................................................................................... 36 
9.4.6 
Drug Accountability................................................................................................ 37 
9.4.7 
Study Drug Administration and Timing of Dose for each Subject ......................... 37 
9.4.7.1 Description of Clinical Supplies ......................................................................... 37 
9.4.7.2 Determination of Dose Volume .......................................................................... 37 
9.4.7.3 Details Concerning Timing and Dose Administration ........................................ 38 
9.4.8 
Method of Assigning Subjects to Treatment Group ............................................... 39 
9.4.9 
Blinding................................................................................................................... 39 
9.4.10 
Concomitant Therapy and Restricted Medications ................................................. 39 
9.4.11 
Treatment Compliance ............................................................................................ 39 
9.5 
Efficacy, Quality-of-Life, and Safety Variables ............................................................ 40 
9.5.1 
Efficacy Variables ................................................................................................... 40 
9.5.1.1 Functional Stage of Friedreich’s Ataxia.............................................................. 40 
9.5.1.2 Friedreich’s Ataxia Rating Scale (FARS) ........................................................... 40 
9.5.1.3 Activities of Daily Living ................................................................................... 41 
9.5.1.4 Timed 25-Foot Walk ........................................................................................... 41 
9.5.1.5 Nine-Hole Peg Test ............................................................................................. 41 
9.5.1.6 Low-Contrast Sloan Letter Chart (LCSLC) Vision Test .................................... 42 
9.5.1.7 Listening in Spatialized Noise – Sentences Test (LiSN-S) ................................. 42 
9.5.1.8 Frataxin................................................................................................................ 43 
9.5.1.9 Physician’s and Patient’s Global Assessments ................................................... 43 
9.5.2 
Quality-of-Life Assessments .................................................................................. 43 
9.5.2.1 Pediatric Quality of Life Inventory (PedsQL)..................................................... 43 
9.5.2.2 36-Item Short-Form Health Survey (SF-36) ....................................................... 44 
9.5.2.3 Modified Fatigue Impact Scale (MFIS) .............................................................. 44 
9.5.3 
Safety Variables ...................................................................................................... 44 
9.5.3.1 Adverse Events .................................................................................................... 44 
9.5.3.1.1 Definitions ..................................................................................................... 45 
9.5.3.1.2 Documentation of Adverse Events ................................................................ 46 


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9.5.3.1.3 Grading of Adverse Events............................................................................ 47 
9.5.3.1.4 Relationship to Study Drug ........................................................................... 47 
9.5.3.1.5 Reporting and Documenting SAEs................................................................ 48 
9.5.3.1.6 Follow-Up of Adverse Events ....................................................................... 49 
9.5.3.1.7 Medication Error and Overdose .................................................................... 49 
9.5.3.1.8 Review of Adverse Events and Emerging New Safety Information ............. 49 
9.5.3.1.9 Reporting of IND Safety Reports .................................................................. 50 
9.5.3.2 Pregnancy Reporting ........................................................................................... 50 
9.5.3.3 Vital Signs ........................................................................................................... 50 
9.5.3.4 Physical Examinations, Height, and Weight ....................................................... 50 
9.5.3.5 ECGs ................................................................................................................... 51 
9.5.3.6 Clinical Laboratory Tests .................................................................................... 51 
9.5.3.7 Immunogenicity Testing ..................................................................................... 51 
9.5.4 
Appropriateness of Measurements .......................................................................... 51 
9.5.5 
Study Procedures .................................................................................................... 52 
9.5.5.1 Baseline/Day 1 (Week 26 of study HZNP-ACT-301) ........................................ 52 
9.5.5.2 Week 4................................................................................................................. 53 
9.5.5.3 Week 13............................................................................................................... 54 
9.5.5.4 Week 26 (Termination Visit or Premature Withdrawal Visit) ............................ 55 
9.5.5.5 Follow-Up Safety Visit ....................................................................................... 56 
9.6 
Statistical Methods and Determination of Sample Size ................................................. 56 
9.6.1 
Endpoints ................................................................................................................ 56 
9.6.2 
Populations for Analysis ......................................................................................... 57 
9.6.3 
Baseline Characteristics .......................................................................................... 57 
9.6.4 
Sample Size and Power Considerations .................................................................. 57 
9.7 
Changes in the Conduct of the Study ............................................................................. 57 
10. 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES ................................... 57 
11. 
CASE REPORT FORMS ................................................................................................. 58 
12. 
STUDY MONITORING .................................................................................................. 59 
13. 
DATA MANAGEMENT.................................................................................................. 60 
14. 
RETENTION OF RECORDS .......................................................................................... 60 


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15. 
PUBLICATION ................................................................................................................ 60 
16. 
REFERENCES ................................................................................................................. 61 
17. 
APPENDICES .................................................................................................................. 64 
17.1 Administrative Appendix ............................................................................................... 64 
17.2 Approved US Labeling for ACTIMMUNE ................................................................... 65 
17.3 FARS Neurological Assessment .................................................................................... 76 
17.4 ADL Assessment ............................................................................................................ 83 
17.5 PedsQL Inventory (Child Report for Ages 8-12) ........................................................... 84 
17.6 SF-36 Assessment .......................................................................................................... 86 
17.7 MFIS Assessment ........................................................................................................... 93 
LIST OF TABLES 
Table 6.1 
Table of Non-Sponsor Study Responsibilities ........................................................... 24 
Table 7.1 
Approved Dosing for ACTIMMUNE versus Proposed Clinical Dosing in This 
Study .......................................................................................................................... 28 
Table 9.1 
Dosing Allowance for Acetaminophen, Ibuprofen, and Diphenhydramine .............. 39 
Table 9.2 
Functional Stage of Ataxia Scale ............................................................................... 40 
 
LIST OF FIGURES 
Figure 9.1 Schematic of Study Design ........................................................................................ 31 
 


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4. 
LIST OF ABBREVIATIONS 
ADA 
anti-drug antibody 
ADL 
activities of daily living 
AE 
adverse event 
aPTT 
activated partial thromboplastin time 
ARO 
Academic Research Organization 
ATP 
adenosine triphosphate 
BLA 
Biologics License Application 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CGD 
chronic granulomatous disease 
CHET 
Center for Human Experimental Therapeutics 
CPI 
coordinating principal investigator 
CSM 
Clinical Supplies Management, Inc 
CTCC 
Clinical Trials Coordination Center 
DNA 
deoxyribonucleic acid 
DRG 
dorsal root ganglion  
DSMB 
Data Safety Monitoring Board 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
FA 
Friedreich’s Ataxia 
FARA 
Friedreich’s Ataxia Research Alliance 
FARS 
Friedreich’s Ataxia Rating Scale 
FARS-mNeuro 
FARS excluding the peripheral nervous system subscale score and the facial 
and tongue atrophy and fasciculations from the bulbar subscale score 
FARStot 
FARS total score 
FDA 
Food and Drug Administration 
FLS 
flu-like symptoms 
FXN 
frataxin gene 
GAA 
guanine-adenine-adenine 
GCP 
Good Clinical Practice 
HDAC 
histone deacetylase 
HEENT 
head, eyes, ears, nose, throat 
HIPAA 
Health Insurance Portability and Accountability Act 
9-HPT 
9-Hole Peg Test 
ICH 
International Conference on Harmonization 
IIS 
Investigator-Initiated Study 
IFN-ɣ 
interferon gamma 
IM 
intramuscular 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IU 
international units 


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IV 
intravenous 
K2-EDTA 
potassium ethylene diamine tetraacetic acid 
LCSLC 
Low-contrast Sloan letter chart 
LiSN-S 
Listening in Spatialized Noise-Sentences 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFIS 
Modified Fatigue Impact Score 
mRNA 
messenger RNA 
PBMC 
peripheral blood mononuclear cells 
PedsQL 
Pediatric Quality of Life  
PW 
premature withdrawal 
PT 
prothrombin time 
QOL 
Quality of Life 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SF-36 
36-item short-form health survey 
SMO 
severe, malignant osteopetrosis 
SRT 
speech reception threshold 
T25FW 
Timed 25-foot walk 
TEAE 
treatment-emergent adverse event 
TIW 
three times per week 
URL 
uniform resource locator 
URMC 
University of Rochester Medical Center 
US 
United States 
VAS 
visual analog scale 
WHODrug 
World Health Organization Drug Dictionary 


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5. 
ETHICS 
5.1 
Institutional Review Board 
The Principal Investigator (Investigator) will submit this protocol, any protocol modifications, 
and the subject Consent/Assent Form to be used in this study to the appropriate Institutional 
Review Board (IRB) for review and approval. A letter confirming the IRB approval of the 
protocol and the subject Consent/Assent Form, as well as a statement that the IRB is organized 
and operates according to Good Clinical Practice (GCP) and the applicable laws and regulations, 
must be forwarded to the Sponsor or its designee prior to the enrollment of subjects into the 
study. A copy of the approved Consent/Assent Form will also be forwarded to the Sponsor or its 
designee. Appropriate reports on the progress of the study will be made to the IRB and the 
Sponsor or its designee by the Investigator in accordance with applicable governmental 
regulations and in agreement with the policy established by the Sponsor. 
5.2 
Ethical Conduct of the Study 
The Investigator will ensure that the study will be conducted in accordance with the Declaration 
of Helsinki and GCP in accordance to International Conference on Harmonisation (ICH) E6 
guidelines. Specifically, the study is based on adequately performed laboratory and animal 
experimentation; the study will be conducted under a protocol reviewed by an IRB; the study 
will be conducted by scientifically and medically qualified persons; the benefits of the study are 
in proportion to the risks; the rights and welfare of the subjects will be respected; and each 
subject and caregiver, if applicable, will give his/her informed consent/assent before any tests or 
evaluations are performed. 
5.3 
Subject Information and Consent/Assent 
The Investigator or his/her designee must explain to the subject and caregiver, if applicable, the 
purpose and nature of the study, the study procedures, the possible adverse effects, and all other 
elements of consent before enrolling that subject in the study. A properly executed, written 
Informed Consent and if necessary, Assent Form, in compliance with the Declaration of 
Helsinki, ICH GCP E6, and the United States (US) Code of Federal Regulations (CFR) for 
Protection of Human Subjects (21 CFR Parts 50 and 56), will be obtained from each subject and 
his/her caregiver as applicable prior to entering the study. The Investigator will provide a copy of 
the signed Consent and Assent Form to each subject and his/her caregiver, as applicable. The 
originals will be maintained at the study site. It is the Investigator’s (or designee’s) responsibility 
to obtain written Informed Consent and if required, Assent from each subject and his/her 
caregiver. 
6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The Sponsor of this study is Horizon Pharma Ireland Ltd (Horizon). Horizon personnel will 
serve as the Medical Monitor and the Sponsor’s regulatory representative (see Section 17.1 for 
details). The Sponsor’s regulatory representative will be responsible for timely reporting of 
serious adverse events (SAEs) to US regulatory authorities as required. The Sponsor will be 




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Study Responsibility 
Organization 
Clinical drug supply 
Clinical Supplies Management, Inc. 
342 42nd Street South 
Fargo, ND 58103 
Immunogenicity laboratory 
Intertek Pharmaceutical Services Immunochemistry 
10420 Wateridge Circle 
San Diego, CA  92121 
Central safety laboratory 
University of Rochester Medical Center (URMC) 
77 Ridgeland Road 
Rochester, NY  14623 USA 
Frataxin analysis 
CHOP Clinical and Translational Research Center  
502 Abramson Research Center 
Philadelphia, PA 19104 USA 
 
7. 
INTRODUCTION 
7.1 
Scientific Background 
ACTIMMUNE (interferon [IFN]-γ 1b) is an orphan drug product currently approved and 
indicated for reducing the frequency and severity of serious infections associated with chronic 
granulomatous disease (CGD) and for delaying the time to disease progression in patients with 
severe, malignant osteopetrosis (SMO); it is approved under Biologics License Application 
(BLA) 103836, and is now being studied by Horizon in the treatment of FA.  
FA is an autosomal recessive disorder associated with progressive ataxia, cardiomyopathy, 
scoliosis, diabetes, and loss of visual and sensorineural hearing function at later stages of the 
disease [Harding, 1981; Lynch et al, 2002a]. FA has a prevalence of about 1 in 50,000 persons in 
the US [Tsou et al, 2009]. Patients develop difficulty walking, loss of coordination, and 
dysarthria. Degeneration of the dorsal root ganglion (DRG) neurons, their axons in the dorsal 
columns, and the dorsal spinocerebellar pathways gives rise to loss of proprioception and 
associated ataxia. A few other nuclei (including the dentate of the cerebellum) within the central 
nervous system are affected and contribute to the ataxia [Simon et al, 2004]. The abnormal gene 
in FA and its product (frataxin) provide insight into pathophysiological mechanisms in this 
disease. In 98% of individuals, FA is caused by homozygous expanded guanine – adenine – 
adenine (GAA) repeats in the frataxin gene (FXN). This triplet repeat is located within an intron, 
leading to decreased ribonucleic acid (RNA) transcription and levels of the mitochondrial 
frataxin protein. Decreased frataxin expression is implicated in the assembly and repair of 
mitochondrial iron-sulfur-cluster containing enzymes and the ability to produce adenosine 
triphosphate (ATP) [Babcock et al, 1997; Koeppen, 2011; Rotig et al, 1997]. Frataxin deficiency 
leads to mitochondrial iron accumulation. This may initiate or propagate free radical reactions 
leading to cell death, consistent with mitochondrial dysfunction as a pathophysiological 
mechanism in FA.  


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Patients with FA have frataxin protein levels in peripheral tissues that range from 2-30% of 
control levels. The level of frataxin protein correlates with age of onset and inversely with the 
length of the GAA repeat. In carriers, who do not develop symptoms of FA, frataxin protein 
levels range from 30-80% of control levels [Deutsch et al, 2010]. The lack of symptoms 
observed in carriers suggests that restoration of frataxin levels in patients to those observed in 
carriers may lead to substantial improvement of symptoms. 
At present, no therapy is approved for use in FA [Corben et al, 2014; Delatycki et al, 2014]. 
Many of the therapies being developed are designed to increase levels of frataxin, either by 
reversal of its transcriptional depression or by other means [Arpa et al, 2014; Lynch et al, 2010; 
Lynch et al, 2012]. Frataxin-depleted cells have an increased sensitivity to oxidative stress. 
Subtype-selective histone deacetylase (HDAC) inhibition has been successful in vitro at 
increasing levels of transcription of frataxin, and is beginning early stage trials in humans [Rai et 
al, 2008; Sandi et al, 2011]. Erythropoietin and its derivatives raise frataxin levels in peripheral 
tissues by non-transcriptional means, but the effect has been too small to observe efficacy in 
human trials [Boesch et al, 2014; Mariotti et al, 2012]. 
IFN-γ, a protein produced by the immune system in response to infections, increases both 
frataxin messenger RNA (mRNA) and protein levels in a variety of different cell types, including 
cell lines derived from FA patients. In addition, an FA mouse model treated with subcutaneous 
(SC) injections of IFN-γ for 14 weeks showed improvements in motor coordination, an effect 
that was mirrored by accumulation of frataxin protein in the DRG tissue in these mice 
[Tomassini et al, 2012]. Its mechanism of action is as a transcriptional activator of multiple 
genes. From a therapeutic perspective, IFN-γ 1b (ACTIMMUNE®) is approved for use in the US 
in patients with CGD and SMO (see prescribing information in Section 17.2), and has been 
investigated in other conditions, including oncology, infectious diseases, and inflammatory 
disorders.  
7.2 
Rationale for the Study 
In an Investigator-Initiated Study (IIS) in FA conducted by 
, 12 subjects between 
the ages of 5 and 17 years (mean age of 12 years) with genetically-confirmed FA were treated 
with ACTIMMUNE by SC injection three times per week (TIW) over the course of a 12-week 
treatment period. The starting dose was 10 µg/m2 for the first two weeks of the study, then 
escalated to 25 µg/m2 for weeks three and four, and then escalated to 50 µg/m2 for the final eight 
weeks of treatment. All subjects followed the same dose-escalation schedule, with adjustments 
made in the event of clinically significant adverse events (AEs). Ten of the subjects completed 
12 weeks of treatment, with the remaining 2 subjects discontinuing prior to 8 weeks of treatment 
due to transportation issues. 
As reported by the authors, ACTIMMUNE was well-tolerated with no SAEs, with only two 
subjects reporting severe dose-related AEs and subsequent dose reductions. Efficacy results 
showed small changes in frataxin levels observed in red blood cells, peripheral blood 
mononuclear cells (PBMC), and platelets after 12 weeks of treatment; however, the results 


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varied between tissues. Frataxin tissue samples were not timed to drug administration, potentially 
contributing to the variability of the results [Seyer et al, 2014]. 
The mean improvement in FARS score was significant after 12 weeks of treatment (p = 0.008). 
The magnitude of improvement in FARS score when contrasted with the natural history of FA 
deterioration was equivalent to almost 18 months of disease progression prevention and the 
absolute improvement in FARS may suggest not only prevention of disease progression but 
potential subject salvage and absolute disease improvement. No statistically significant 
relationships were observed between frataxin protein levels, FARS scores, and in vivo IFN-γ 
levels [Seyer et al, 2014]. On withdrawal of ACTIMMUNE during the follow-up period, there 
was a trend for the FARS scores to worsen, suggesting a loss of therapy-related benefit. 
Other secondary endpoints included timed performance tests, such as the timed 25-foot walk 
(T25FW), failed to show any significant treatment-related changes, but this may reflect the small 
sample size in this IIS. 
Overall, the safety profile of ACTIMMUNE in FA subjects in this IIS mirrors the typical profile 
and frequency of AEs in the prescribing information for ACTIMMUNE. In two cases, the 
maintenance dose of ACTIMMUNE was lower than planned in response to either raised liver 
function tests and/or flu-like symptoms (FLS). Subjects were able to continue in the study 
following dose reduction. 
Based on the results of the IIS, Horizon is currently conducting a randomized, multicenter, 
double-blind, placebo-controlled study evaluating the efficacy and safety of ACTIMMUNE in 
children and young adults with FA (HZNP-ACT-301). This study (HZNP-ACT-302) is designed 
to be an open-label extension of HZNP-ACT-301, in which all subjects who complete 26 weeks 
of blinded treatment in HZNP-ACT-301 will be offered the opportunity to receive 
ACTIMMUNE for an additional 26 weeks.  
FA is a rare, debilitating, autosomal recessive deoxyribonucleic acid (DNA)-inherited, 
mitochondrial disease that causes progressive damage to the nervous system. The rationale for 
use of IFN-ɣ 1b for the treatment of FA is based on in vitro and animal data, and clinical 
experience in FA subjects. Currently, there is no FDA-approved therapy for FA. ACTIMMUNE 
was granted Orphan Drug Designation for the treatment of FA on October 1, 2014. 
7.3 
Rationale for Dose Selection 
In humans, ACTIMMUNE is rapidly cleared after intravenous (IV) administration and slowly 
absorbed after intramuscular (IM) or SC administration. After IM or SC injection, the apparent 
fraction of the dose absorbed was greater than 89%. Peak plasma concentrations occurred 
approximately 4 hours (1.5 ng/mL) after IM dosing and 7 hours (0.6 ng/mL) after SC dosing. In 
healthy male subjects, the mean elimination half-lives after IV, IM, and SC dosing with 
0.1 mg/m2 were 38 minutes, 2.9 hours, and 5.9 hours, respectively. ACTIMMUNE administered 
by the IV, IM, and SC routes (0.1 mg/m2) was not detected in the urine of healthy volunteers. 


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ACTIMMUNE is currently approved and indicated for reducing the frequency and severity of 
serious infections associated with CGD and for delaying the time to disease progression in 
subjects with SMO, both orphan indications (BLA 103836). The current recommended dosage of 
ACTIMMUNE for the treatment of subjects with CGD and SMO is 50 µg/m2 (1 million 
international units [IU]/m2) for subjects whose body surface area (BSA) is greater than 0.5 m2 
and 1.5 µg/kg/dose for subjects whose BSA is equal to or less than 0.5 m2, administered SC 
TIW. Please refer to the ACTIMMUNE prescribing information in Section 17.2 for the well-
established safety profile of ACTIMMUNE. This includes FLS upon initiation of ACTIMMUNE 
dosing that can be mitigated with medication, such as acetaminophen, and/or ibuprofen, and/or 
diphenhydramine, and dose titration [Devane et al, 2014]. FLS is defined as the presence of 
fever, chills, muscle aches, and tiredness. Transient elevation in liver transaminases can also 
occur; this was seen in the OLIGA-FA study, where one subject with severe FLS experienced 
elevated transaminases that returned to normal after dose reduction from 50 µg/m2 to 10 µg/m2, 
and has been reported in the literature in a trial administering recombinant interferon γ (rIFN-γ) 
to subjects with systemic sclerosis [Polisson et al, 1996]. 
In this clinical trial, FA subjects will be dose-escalated weekly (10, 25, 50, and 100 µg/m2 SC 
TIW). If severe reactions occur during dose escalation, the dosage will be reduced to the 
previous dose level or therapy will be interrupted until the adverse reaction resolves and then 
restarted at the previous or lower dose level. By Week 13 of the study, the dose will not be 
further adjusted and will be maintained for the remainder of the study (an additional 13 weeks of 
dosing), unless dose reductions are required for drug-related AE management. The dosing of 
ACTIMMUNE in this protocol is fairly consistent with that already approved for ACTIMMUNE 
(Table 7.1). The difference is that in this study, the dose will be titrated to a maximum of 100 
µg/m2 compared to the dose of 50 µg/m2 recommended in the current ACTIMMUNE prescribing 
information (Section 17.2). Although the pilot study showed promising results in the FARS 
assessment, the lack of clinically meaningful effects on other outcomes indicate a higher dose 
may be necessary in the treatment of FA. 
Table 7.1 
Approved Dosing for ACTIMMUNE versus Proposed Clinical Dosing in This 
Study  
 
Approved ACTIMMUNE  
Dosing Regimen 
Proposed ACTIMMUNE Dosing Regimen 
in Protocol HZNP-ACT-302 
Age 
All ages 
10 to 25 years of age 
at start of HZNP-ACT-301 
Route of administration 
SC 
SC 
Individual dose 
Per m2 (or /kg if <0.5 m2) 
Per m2 (or /kg if <0.5 m2) 
Maximum daily dose 
50 µg/m2 or 1.5 µg/kg 
100 µg/m2 or 3 µg/kg 
Initial dose 
No titration 
Titration weekly from 10 µg/m2 to 
25, 50, and 100 µg/m2 
Frequency 
TIW 
TIW 
 


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There are several well-documented Investigational New Drug (IND)-reported, randomized, 
controlled clinical trials providing experience in large, late-stage subject populations such as 
liver disease (fibrosis) and idiopathic pulmonary fibrosis (IPF) at doses, frequency, and duration 
equivalent to those proposed for this study (i.e., 200 µg SC or approximately 100 µg/m2; Sponsor 
data on file). There are also reports from Europe on the use of higher doses of IFN-ɣ 1b in the 
treatment of FA [https://fafysio.wordpress.com/]. The clinical safety and tolerability at the 200 
µg SC dose TIW appeared consistent with the safety described in the current package insert 
(Section 17.2). 
While the approved ACTIMMUNE dose regimen does not involve initial dose escalation or 
titration, a recently completed study in healthy volunteers demonstrated a potential reduction in 
the severity of acute FLS when dose escalation to the standard dose was utilized [Devane et al, 
2014]. This mirrors the clinical experience with other IFNs, particularly the interferon-betas 
(IFN-βs) used by multiple sclerosis patients where initial dose escalation using an acute titration 
regimen has been adopted. Natural tolerance to FLS develops relatively quickly in the majority 
of patients receiving IFNs and the dose escalation/titration minimizes the initial poor tolerability 
and treatment dropouts. It is expected that the use of the acute dose escalation as proposed in this 
protocol will facilitate subject retention during the early phase in the trial, particularly with dose 
escalation to 100 µg/m2. 
8. 
STUDY OBJECTIVES 
8.1 
Primary Study Objective 
The primary objective is to evaluate the long-term safety of ACTIMMUNE (IFN-γ 1b) in 
subjects with FA. 
8.2 
Primary Efficacy Objective 
To evaluate the effect of ACTIMMUNE (interferon [IFN]-γ 1b) on the change from Baseline to 
Week 26 for all subjects and from Baseline of HZNP-ACT-301 to Week 26 of HZNP-ACT-302 
(52-week treatment duration) for subjects receiving active treatment in both studies in 
neurological outcome as measured by Friedreich’s Ataxia Rating Scale (FARS) excluding the 
peripheral nervous system subscale score and the facial and tongue atrophy and fasciculations 
from the bulbar subscale score (FARS-mNeuro score). 
8.3 
Secondary Efficacy Objectives 
The secondary efficacy objectives are: 
To evaluate the effect of ACTIMMUNE (interferon [IFN]-γ 1b) on the change from Baseline to 
Week 26 for all subjects and from Baseline of HZNP-ACT-301 to Week 26 of HZNP-ACT-302 
(52-week treatment duration) for subjects receiving active treatment in both studies for the 
following: 


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• Activities of Daily Living (ADL) 
• The timed 25-foot-walk test (T25FW) 
• Responder rate (≥3 point improvement in the FARS mNeuro score) 
• Neurological outcome as measured by the total FARS score (FARStot) 
9. 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a multi-center, dose-escalation, open-label extension study of HZNP-ACT-301 examining 
the safety and efficacy of ACTIMMUNE in the treatment of FA in children and young adults. 
Subjects who complete 26 weeks of blinded treatment in HZNP-ACT-301 will be eligible to 
enter this 6-month study. All subjects who choose to participate will receive ACTIMMUNE 
three times a week (TIW) for 26 weeks. In order to maintain the study blind in HZNP-ACT-301, 
all subjects in this open-label extension study will undergo ACTIMMUNE titration, regardless if 
they received ACTIMMUNE or placebo in HZNP-ACT-301.  
The study drug dose is planned to be escalated on a weekly basis over the first four weeks of 
treatment (from 10 µg/m2 to 25, 50, and 100 µg/m2); however, the dose may be reduced, 
interrupted, or held based on tolerability. During the dose-escalation phase (i.e., through at least 
Week 4 or until the subject is receiving a stable tolerated dose), subjects will be contacted on a 
weekly basis either by email or telephone to monitor safety and dosing logistics. By Week 13, all 
subjects 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 subsequent drug-related AEs (e.g., elevated liver function tests). 
An overview of the study is provided in Figure 9.1. The Week 26 Visit from HZNP-ACT-301 
will serve as the Baseline Visit (Day 1) for this study. Subjects will receive the last dose of the 
randomized drug from HZNP-ACT-301 (ACTIMMUNE or placebo) in a double-blind fashion, 
and the first dose of study drug for the open-label extension study (10 µg/m2) will be distributed 
for administration at home according to the planned TIW dosing schedule. During the treatment 
period, additional clinic visits are scheduled at Weeks 4, 13, and 26; in between clinic visits, 
subjects (and/or caregivers) will be monitored via emails/phone calls on a weekly basis until 
subjects reach their maximum tolerated dose and on a monthly basis thereafter.  
Subjects will return to the clinic two weeks after the last dose of study drug for a Follow-Up 
Safety Visit.  


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Figure 9.1 
Schematic of Study Design 
 
 
 
<–––––––––– ACTIMMUNE (10 µg/m2 to 100 µg/m2) TIW SC –––––––––> 
(26 weeks) 
 
 
 
Baseline 1 
Visit 1 
Visit 2 
Visit 3 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1 
 
Week 4 
Week 13 
Week 26 
Week 28 
 
 
 
First dose 
 
 
 
 
 
 
 
at home 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<–– Dose escalation 2 ––> 
 
<––––– Stable dose 2 ––––––> 
 
 
 
 
 
 
<–– Weekly contact 3 ––> <–––––––––––– Monthly contact 3 –––––––––––––> 
 
 
 
 
1 Week 26 of HZNP-ACT-301 will serve as the Baseline Visit (Day 1) for this study. Subjects will receive the last dose of the randomized drug 
from HZNP-ACT-301in a double-blind fashion, and the first dose of study drug for the open-label extension study (10 µg/m2) will be distributed 
for administration at home according to the planned TIW dosing schedule. 
2 The planned dose escalation consists of two doses of ACTIMMUNE 10 µg/m2 in the first week, followed by weekly escalation to 25, 50, and 
100 µg/m2 TIW on Days 8, 15, and 22, respectively; however, the dose may be reduced, interrupted, or held based on tolerability. All subjects are 
to be on a stable tolerated dose of study drug by Week 13 in order to continue study participation. 
3 Subjects and/or caregivers will be contacted by email or phone to monitor safety and dosing logistics on a weekly basis from Day 1 through 
Week 4 (or until stable tolerated dose is achieved) and on a monthly basis after Week 4 (or after dose stabilization) through Week 26. 
 
The following assessments will be performed during the study: 
Safety Assessments 
• Adverse event (AE) monitoring, concomitant medication monitoring, and physical 
examinations throughout the study. 
• Immunogenicity testing pre-dose at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), 
and Weeks 4, 13, 26 (or premature withdrawal [PW]), and 28. 
• Vital signs, clinical safety laboratory evaluations (complete blood count, prothrombin time 
[PT], international normalized ratio [INR], activated partial thromboplastin time [aPTT], 
chemistry, and urinalysis), and pregnancy testing (if applicable) at all on-treatment clinic 
visits. 
• Echocardiogram at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Week 26 (or 
PW). 
• ECG at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), with additional ECGs at 
Weeks 13 and 26 (or PW). 
Efficacy Assessments 
• FARS, ADL assessment, T25FW, and 9-hole peg test (9-HPT) at Baseline/Day 1 (Week 26 
of Study HZNP-ACT-301) and 4 to 6 hours post-dose at Weeks 13 and 26 (or PW). 
• Low-contrast Sloan letter chart (LCSLC) Vision Test at Baseline/Day 1 (Week 26 of Study 
HZNP-ACT-301)and post-dose at Week 26 (or PW). 


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• For all subjects with a normal audiogram result at Screening in Study HZNP-ACT-301, 
Listening in Spatialized Noise-Sentences Auditory Test (LiSN-S) at Baseline/Day 1 (Week 
26 of Study HZNP-ACT-301) and post-dose at Week 26 (or PW). 
• Frataxin protein levels in whole blood, muscle biopsies (optional), and buccal cells at 
Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and post-dose at Weeks 13 and 26 (or 
PW).  
• Functional staging of ataxia at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), and 
post-dose at Weeks 13 and 26 (or PW). 
• Physician Global Assessment and Patient Global Assessment at Baseline/Day 1 (Week 26 of 
Study HZNP-ACT-301) and post-dose at Weeks 13 and 26 (or PW). 
Quality of Life Assessments 
Quality of life assessments (Modified Fatigue Impact Score [MFIS], and Pediatric Quality of 
Life [PedsQL] questionnaire or 36-item short-form health survey [SF-36]) will be completed at 
Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Weeks 13 and 26 (or PW). The MFIS 
will be completed for all subjects. Subjects who completed the PedsQL during Study HZNP-
ACT-301 will continue to complete the PedsQL in this study.  Subjects who completed the SF-
36 during Study HZNP-ACT-301 will continue to complete the SF-36 in this study. 
9.2 
Discussion of Study Design 
The study population consists of subjects who completed Study HZNP-ACT-301; this population 
was well-defined and consistent with the expected target population for whom ACTIMMUNE 
will be indicated (pediatric and young adult subjects with a FA functional stage of >1 to <5). 
The most common adverse experiences occurring with ACTIMMUNE therapy are FLS or 
constitutional symptoms such as fever, headache, chills, myalgia, or fatigue that may decrease in 
severity as treatment continues (see product prescribing information in Section 17.2). It is hoped 
that the weekly dose-escalation scheme and the allowable dose adjustments in this study will 
alleviate the severity of these symptoms. In addition, previous experience with this drug 
indicates these FLS may be minimized with bedtime administration of ACTIMMUNE and the 
use of acetaminophen, and/or ibuprofen, and/or diphenhydramine. Therefore, subjects in this 
study will be instructed to self-administer study drug at bedtime on days when they are not being 
seen in the clinic for neurological assessments, and the use of acetaminophen, and/or ibuprofen, 
and/or diphenhydramine (see Table 9.1 for allowable doses) will be allowed throughout the 
study. On clinic days when neurological assessments are being performed, study drug dosing 
will occur on site. 
The primary efficacy endpoint (change in FARS-mNeuro from Baseline to Week 26) has been 
agreed upon with the FDA as part of a pre-IND study submission. The measurements used in this 
study for the primary efficacy endpoint (FARS) are established and well-validated endpoints that 
have been shown to correlate significantly with functional disability in FA patients [Friedman et 
al, 2010; Lynch et al, 2006; Lynch et al, 2005]. 


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In order to maintain the study blind in HZNP-ACT-301, all subjects in this open-label extension 
study will undergo ACTIMMUNE titration, regardless if they received ACTIMMUNE or 
placebo in HZNP-ACT-301. The doses planned for dose escalation of ACTIMMUNE in this 
study are 10, 25, 50, and 100 µg/m2. The approved dosage of ACTIMMUNE for the treatment of 
CGD and SMO is 50 µg/m2 for patients whose BSA is greater than 0.5 m2 and the highest dose 
administered in the OLIGA-FA pilot study was also 50 µg/m2. Although the pilot study showed 
promising results in the FARS assessment, the lack of clinically meaningful effects on other 
outcomes indicate a higher dose may be necessary in the treatment of FA. During the 
ACTIMMUNE development program, the 100 µg/m2 dose was administered to healthy adult 
subjects in PK studies, and doses >100 µg/m2 were administered to subjects with disease states 
other than the approved indications. As expected, the AE profile of ACTIMMUNE at >100 
µg/m2 in other disease states was broader than that seen among patients with CGD at the 50 
µg/m2 dose. Since the safety profile of the 100 µg/m2 dose is unknown among pediatric subjects 
with FA, the study will be monitored by a DSMB, which will advise the Sponsor or its delegate 
regarding the continuing safety of study subjects and potential subjects as well as the continuing 
validity and scientific merit of the trial. The decision to modify or halt the study will be made 
collectively by the CPI, the Sponsor (Horizon), and FARA after review with the FDA. 
9.3 
Selection of Study Population 
9.3.1 Inclusion Criteria 
Eligible subjects must meet all of the following criteria: 
1. Written informed consent and child assent, if applicable.  
2. Completed 26 weeks of blinded treatment in Study HZNP-ACT-301. 
3. 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) and agree to use a reliable method of contraception 
throughout the study and for 30 days after the last dose of study drug. 
9.3.2 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.  
9.3.3 Removal of Subjects from Therapy or Assessment 
All subjects are free to withdraw from study participation at any time, for any reason, and 
without prejudice to their further medical care. In addition, the investigator may terminate a 
subject from the study at any time. The primary reason for discontinuation should be recorded on 
the case report form using one of the following categories: 


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• Adverse event. The subject experiences an AE that imposes an unacceptable risk to the 
subject’s health, or the subject is unwilling to continue because of an AE. 
• Lack of therapeutic effect. The investigator has determined that study drug administration 
is not benefitting the subject, and continued participation poses an unacceptable risk to 
the subject. 
• Inclusion/exclusion criteria violation. The investigator discovers that the subject did not 
meet all of the inclusion/exclusion criteria after study enrollment. 
• Protocol noncompliance. The subject has a significant protocol deviation, does not 
comply with study drug administration schedule, or fails to adhere to other study 
requirements as stated in the protocol. 
• Lost to follow-up. The subject does not return to the clinic for scheduled assessments, 
and does not respond to the site’s attempts to contact the subject. 
• Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes 
to withdraw from the study. The clinical site should attempt to determine the underlying 
reason for the voluntary withdrawal and document it on the eCRF; if the underlying 
reason is documented as an AE or lack of efficacy, the category of withdrawal should be 
marked in the corresponding category and not as voluntary withdrawal. 
• Study termination. The Sponsor, DSMB, IRB, or regulatory agency terminates the study. 
• Pregnancy. 
Following early discontinuation from the study, the subject or his/her legally acceptable 
representative will be informed regarding the additional study evaluations that are necessary to 
monitor his/her safety. These subjects or their representatives will be encouraged to complete the 
PW and Follow-Up Safety Visits. 
Discontinued or withdrawn subjects will not be replaced. Subject identification numbers are 
unique and will not be reassigned. 
9.4 
Treatments 
9.4.1 Treatments Administered 
In order to maintain the study blind in HZNP-ACT-301, all subjects in this open-label extension 
study will undergo ACTIMMUNE titration, regardless if they received ACTIMMUNE or 
placebo in HZNP-ACT-301. 
Subjects will receive SC doses of ACTIMMUNE TIW for 26 weeks. The planned dose 
escalation consists of two doses of ACTIMMUNE 10 µg/m2, followed by weekly-escalated 
doses of 25, 50, and 100 µg/m2 TIW on Days 8, 15, and 22, respectively. The first dose of study 
drug will be administered after the Baseline/Day 1 Visit at home before bedtime according to the 
subject’s TIW dosing schedule. 


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9.4.1.1 Dose Adjustment Guidelines 
The dose of ACTIMMUNE is based on the subject’s BSA; therefore, height and weight will be 
measured at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Weeks 4 and 13, and the 
dosing volume will be determined using the formula presented in Section 9.4.7.2.  
The planned 4-week dose escalation schedule will be implemented if it is tolerated by the 
subject. If, however, in the opinion of the investigator, the subject experiences severe reactions 
during dose escalation, the dose will be reduced to the previous dose level, or will be interrupted 
until the adverse reaction resolves and then restarted at the previous or a lower dose level. Once 
the previous/lower dose level is tolerated, the dose may then be titrated upwards again to the next 
dose level as tolerated. 
During the dose-escalation period, the clinical site will contact the subjects (or caregivers/legal 
representatives) via phone calls or email on a weekly basis to monitor AEs and dosing logistics. 
In addition, subjects may contact the clinical site at any time with dosing or possible drug 
reaction concerns throughout the study. Dose adjustments may be continued through Week 13, 
but at Week 13, all subjects should be on a stable tolerated dose and remain at that dose through 
Week 26. During the stable dosing period, subjects will be contacted by the site via phone calls 
or emails on a monthly basis to monitor AEs and dosing logistics. Although the dose may not be 
further increased after Week 13, it may be reduced on a case-by-case basis to manage subsequent 
drug-related AEs (e.g., elevated liver function tests). 
9.4.2 Identity of Investigational Products 
9.4.2.1 ACTIMMUNE 
ACTIMMUNE (IFN-γ 1b) is a single-chain polypeptide containing 140 amino acids with a 
molecular weight of approximately 16,465 Daltons. IFN-γ 1b differs from natural human IFN-γ 
by the substitution of an additional N-terminal methionine, deletion/loss of seven amino acids 
and lack of glycosylation. 
The commercial formulation of ACTIMMUNE is a sterile, clear, colorless solution filled in a 
single-use vial for SC injection. Each 0.5 mL of ACTIMMUNE contains: 100 µg (2 million IU) 
of IFN-γ 1b formulated in 20 mg mannitol, 0.37 mg disodium succinate hexahydrate, 0.14 mg 
succinic acid, 0.05 mg polysorbate 20, and sterile water for injection. 
The Sponsor will provide unlabeled, commercial ACTIMMUNE to CSM, Inc. The commercial 
formulation will be utilized, with each unlabeled vial containing ACTIMMUNE in a 
concentration of 200 µg/mL. Each vial permits the extraction of up to 0.5 mL of ACTIMMUNE 
with additional volume to facilitate solution withdrawal.  The study drug vials will be shipped to 
CSM, who will be responsible for labeling of the vials in accordance with regulatory guidelines 
(see Section 9.4.3). CSM will assemble kits containing three vials each, which will provide a 
sufficient quantity of study drug for one week of dosing until two vials per dose may be needed 
to deliver 100 µg/m2 depending on the BSA of the subject. When subjects reach the 100 µg/m2 
TIW dose level, and two vials per dose are required, the same volume should be removed from 


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each vial and delivered in individual syringes. For example, if the dose should be 0.8 mL, then 
0.4 mL should be withdrawn from each vial into separate syringes and two injections given.  
9.4.3 Labeling 
Subjects will maintain the unique 6-digit subject ID number assigned in Study HZNP-ACT-301; 
the first three digits are the site number and the last three digits are the sequential number 
assigned by the site to subjects who consented to the double-blind study beginning with 001. So 
for example, the first subject consented at site 222 in Study HZNP-ACT-301 would have been 
assigned subject ID 222001.  
CSM will label the ACTIMMUNE vials, assemble the study drug into kits containing three vials 
each, and ship kits to the study sites and directly to study subjects. Each kit will have a label that 
includes a unique 4-digit kit number. At the Baseline/Day 1 visit, study staff will contact the 
ARO at the University of Rochester in order to enroll eligible subjects and identify the kit 
number to dispense to the subject. Before dispensing study drug to the subject, study site staff 
will record the subject’s unique 6-digit subject ID number on the label. 
Labels on all vials of study drug and study drug kits will clearly indicate the study number, 
Sponsor’s name and location, storage conditions, and appropriate precautionary labeling required 
by US Federal law. Carton labels will also include the unique 4-digit kit number. Dosing 
instructions will be provided separately to the subject/caregiver. 
9.4.4 Storage 
Study drug kits are to be stored in a 2°C to 8°C (36°F to 46°F) refrigerator at the site, and 
subjects and their caregivers will be instructed to store all study drug in their home refrigerators.  
At the clinic, all study medications must be stored in a secure area with limited access, and a 
daily temperature log of the drug storage area will be maintained every working day; deviations 
from the specified temperature range will be reported as protocol deviations. 
Vials must be placed in a 2°C to 8°C (36°F to 46°F) refrigerator immediately upon receipt to 
ensure optimal retention of physical and biochemical integrity. The vials must not be frozen. 
Excessive or vigorous agitation should be avoided. Exposure of vials to temperatures greater 
than 25°C (77°F) should be strictly avoided. The sponsor should be contacted for disposition 
instructions for vials left at room temperature (>8°C) for a total time exceeding 8 hours. Vials 
should not be used beyond the expiration date. 
9.4.5 Study Drug Quality Issues 
ACTIMMUNE is a sterile, clear, colorless solution. If any vials of study drug are not colorless or 
contain particulate matter, study drug MUST NOT be administered. In the event that any of the 
vials stored at home are considered suspect by the subject/caregiver, the clinic is to be notified 
immediately for instructions regarding dosing and possible re-supply. 


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9.4.6 Drug Accountability 
The Principal Investigator at each site is responsible for the control of all study medication. The 
site must maintain adequate records of the receipt and disposition of all study medication shipped 
to the study center. Records will include receipt dates, quantities received, quantities dispensed, 
quantities returned or destroyed, and the ID numbers of the subjects who received study 
medication. 
All empty, partially empty, and full vials of study drug must be retained by the study center 
under locked storage, until drug accountability has been completed. Periodically throughout the 
study and at the conclusion of the study, inventory checks and accountability of study materials 
will be conducted by a representative of the Sponsor. Once accountability is completed, the 
Sponsor’s representative will authorize the return of study medication (all used, partially used, 
and unused vials) to CSM. The completed Drug Accountability and Drug Return/Destruction 
Record(s) will be returned to the Sponsor. The investigator’s copy of the Drug Accountability 
and Drug Return/Destruction Record(s) must document accurately the return of all study drug 
supplies. Records will also include disposition dates and quantities returned to the designated 
facility. 
In addition, subjects or their caregivers can return biohazard containers supplied by study staff 
with all used syringes and needles from the study to study staff at the follow-up visit(s). Study 
staff will dispose of these containers appropriately. 
9.4.7 Study Drug Administration and Timing of Dose for each Subject 
9.4.7.1 Description of Clinical Supplies 
CSM will supply study drug kits and packages containing ancillary supplies for dosing 
(i.e., syringes, alcohol swabs, gauze pads, bandages, and biohazard containers for safe storage of 
used needles and syringes) to the study sites. 
9.4.7.2 Determination of Dose Volume  
The volume of study drug to be administered will be determined by the site and will be based on 
the subject’s BSA. Height and weight will be measured at all clinic visits. The BSA will be 
calculated at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Weeks 4 and 13 using the 
Mosteller [Mosteller, 1987] formula: 
𝐵𝐵𝐵𝐵𝐵𝐵 (𝑚𝑚2) = ඨ𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻ℎ𝑡𝑡 (𝑖𝑖𝑖𝑖) ∗𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 (𝑙𝑙𝑙𝑙)
3131
 
Given that each 0.5 mL of study drug solution contains 100 µg IFN-γ 1b (0.005 mL/µg), the 
following calculation will be used to determine the volume of study drug to be administered.  


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Dose level (µg/m2)  × BSA  × 0.005 mL/µg = ___ mL to be dosed 
10 
25 
50 
100 
 
(m2) 
(drug  
concentration) 
 
For example, a subject who is 62 inches tall and weighs 100 pounds will have a BSA of 1.41 m2. 
At the 25 µg/m2 dose level, the subject will receive 0.18 mL of study drug. 
25 µg/m2 × 1.41 m2 × 0.005 mL/µg = 0.176 mL, rounded to 0.18 mL of study drug 
9.4.7.3 Details Concerning Timing and Dose Administration 
All doses of study drug will be administered by SC injection. Subjects and/or their caregivers 
will be instructed on their individualized dosing volume and proper dosing techniques; they will 
also be instructed to administer the study drug on the right and left deltoid, anterior thigh, and 
upper and lower abdomen and to rotate the injection sites.  
Subjects or their caregivers will also be instructed in safe handling and storage of used syringes 
and needles. The clinical staff will demonstrate proper technique for withdrawing the appropriate 
volume of study drug from the vial. When two vials are needed to achieve the dose, an equal 
volume should be removed from each vial. For example, if the dose should be 0.8 mL, then 
0.4 mL should be withdrawn from each vial into separate syringes and two injections given. The 
injection site will be cleaned with an alcohol swab and allowed to air dry. About an inch of skin 
and fat tissue will be pinched between the thumb and forefinger, the needle will be inserted all 
the way into the pinched skin, and the entire volume of study drug will be injected under the 
skin.  
The first dose of study drug is after the Baseline/Day 1 Visit and will be administered at home 
before bedtime according to the subject’s TIW dosing schedule. Subjects and their caregivers 
will be instructed to administer study drug on an outpatient basis TIW before bedtime; and to 
adhere to a dosing schedule of Monday, Wednesday and Friday or Tuesday, Thursday, and 
Saturday for the duration of the study as agreed to by the clinic staff. Subjects and their 
caregivers will also be instructed concerning the use of acetaminophen, and/or ibuprofen, and/or 
diphenhydramine to alleviate injection site and study drug reactions (see Table 9.1 for allowable 
doses).  
After Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), subjects are scheduled to return to 
the clinic at Weeks 4, 13, and 26 during the treatment period. Study drug will be administered in 
the morning at the clinic at each of these visits. If the subject’s next scheduled dose is the same 
day as the clinic visit, the dose will simply be given in the morning as opposed to bedtime for 
that particular day. If the subject is scheduled to dose the evening prior to the visit, the dose will 
be held and administered the next morning at the clinic. Bedtime dosing will be resumed after 
the clinic visit according to the subject’s regular dosing schedule. For the TIW schedule, dosing 
should be Monday, Wednesday and Friday or alternatively Tuesday, Thursday and Saturday. 


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At Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), subjects will be dispensed a 4-week 
supply of study drug for the dose-escalation period (up to 6 kits), and at Weeks 4 and 13, 
subjects and/or their caregivers will be dispensed a 6-week supply of study drug (up to 12 kits). 
Additional kits will be shipped to the subject’s house between Weeks 4 and 13, and between 
Weeks 13 and 26, as needed. Subjects/caregivers may be dispensed the full supply at Weeks 4 
and 13 if interim direct-to-subject shipments are not feasible. At Weeks 4, 13, and 26, subjects 
and/or their caregivers will return all unused kits and study drug vials. 
9.4.8 Method of Assigning Subjects to Treatment Group 
All subjects will receive ACTIMMUNE in this open-label extension study.     
9.4.9 Blinding 
This is an open-label extension study.  
9.4.10 Concomitant Therapy and Restricted Medications 
All concomitant medications (including over-the-counter medications) should be at stable doses 
beginning at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and for the duration of the 
study. Nicotinamide is limited to doses ≤1 g/day. Throughout the study, all possible efforts will 
be made to maintain stable doses of all concomitant medications, vitamins, and supplements. 
However, occasional use of acetaminophen, and/or ibuprofen, and/or diphenhydramine (per 
dosing label instructions, see Table 9.1) and other medications to treat AEs will be allowed 
throughout the study. The use of prednisone at a stable dose throughout the study will be 
allowed, but occasional use is not generally permitted. 
Table 9.1 
Dosing Allowance for Acetaminophen, Ibuprofen, and Diphenhydramine 
Age 
Acetaminophen 
Regular Strength 
Ibuprofen 
Diphenhydramine 
10 years 
325 mg every 4-6 hours 
≤1625 mg/24 hours 
200 mg every 6-8 hours 
≤800 mg/day 
25 mg every 4-6 hours 
≤150 mg/24 hours 
11 years 
325 mg every 4-6 hours 
≤1625 mg/24 hours 
300 mg every 6-8 hours 
≤1200 mg/day 
25 mg every 4-6 hours 
≤150 mg/24 hours 
≥12 years 
650 mg every 4-6 hours 
≤3250 mg/24 hours 
200 to 400 mg every 4-6 hours 
≤1200 mg/day 
25 to 50 mg every 4-6 hours 
≤300 mg/24 hours 
 
9.4.11 Treatment Compliance 
Study medication will be dispensed at clinic visits, and re-supplies of study drug may be shipped 
in temperature-controlled containers to the subject’s home. All unused study drug received by 
the subjects since the previous visit will be returned at the subsequent visit for drug 
accountability.  


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An inventory of the study medication supplies will be performed by the site or authorized study 
designee and recorded onto the Drug Accountability Log in the subject’s source document 
records or equivalent. 
9.5 
Efficacy, Quality-of-Life, and Safety Variables 
The Schedule of Assessments was previously provided in Section 2.1. 
9.5.1 Efficacy Variables 
Efficacy variables include the following: functional stage of FA, FARS, ADL, T25FW, 9-HPT, 
LCSLC vision test, LiSN-S auditory test, frataxin protein levels, and Physician’s and Patient’s 
Global Assessments. 
9.5.1.1 Functional Stage of Friedreich’s Ataxia 
The functional stage of FA will be assessed at Baseline/Day 1 (Week 26 of Study HZNP-ACT-
301), and Weeks 13 and 26 (or PW), and on each assessment day, it will be performed at 
approximately the same time of day and by the same examiner. The functional stage will be rated 
on a 7-point scale, with increments of 0.5 allowed if the status is about the middle between two 
stages (Table 9.2). 
Table 9.2 
Functional Stage of Ataxia Scale 
Stage 
Description 
0 
Normal. 
1.0 
Minimal signs detected by physician during screening. Can run or jump without loss of balance. 
No disability. 
2.0 
Symptoms present, recognized by patient, but still mild. Cannot run or jump without losing 
balance. The patient is physically capable of leading an independent life, but daily activities may 
be somewhat restricted. Minimal disability. 
3.0 
Symptoms are overt and significant. Requires regular or periodic holding onto wall/furniture or 
use of a cane for stability and walking. Mild disability. (Note: many patients postpone obtaining 
a cane by avoiding open spaces and walking with the aid of walls/ people etc. These patients are 
grades as stage 3.0.) 
4.0 
Walking requires a walker, Canadian crutches or two canes. Or other aids such as walking dogs. 
Can perform several activities of daily living. Moderate disability.  
5.0 
Confined but can navigate a wheelchair. Can perform some activities of daily living that do not 
require standing or walking. Severe disability. 
6.0 
Confined to wheelchair or bed with total dependency for all activities of daily living. Total 
disability. 
 
9.5.1.2 Friedreich’s Ataxia Rating Scale (FARS) 
The FARS will be performed at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), and 
Weeks 4, 13, and 26 (or PW), and on each assessment day, it will be performed at approximately 


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the same time of day and by the same examiner. The FARS 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 
[Friedman et al, 2010; Lynch et al, 2006; Subramony et al, 2005]. 
The FARStot score has a maximum of 125 points (see assessment in Section 17.3). The primary 
efficacy endpoint in this study is based on the FARS-mNeuro score, which excludes peripheral 
nervous system subscale score and the facial and tongue atrophy and fasciculations from the 
bulbar subscale score and has a maximum of 93 points.  
9.5.1.3 Activities of Daily Living 
The ADL assessment will be performed at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), 
and Weeks 4, 13, and 26 (or PW). Subjects and/or their caregivers will rate 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 subject or caregiver strongly 
feels that a task falls between two scores (Section 17.4). The maximum score for this assessment 
is 36 [Lynch et al, 2006; Subramony et al, 2005]. 
9.5.1.4 Timed 25-Foot Walk 
The T25FW, which is a quantitative measure of lower extremity function, has been shown to 
accurately reflect real-world ambulation in subjects with FA [Fahey et al, 2007] and has been 
established as a reliable outcome measure in clinical trials in FA [Friedman et al, 2010; Lynch et 
al, 2006; Lynch et al, 2005]. It will be performed at Baseline/Day 1 (Week 26 of Study HZNP-
ACT-301), and Weeks 4, 13, and 26 (or PW); on each assessment day, it will be performed at 
approximately the same time of day and whenever possible, by the same examiner. Subjects will 
be instructed to wear shoes suitable for walking at each study visit, and will be encouraged to 
wear the same shoes or the same style of shoes for the T25FW assessments on Day 1, and Weeks 
13 and 26. Subjects will be directed to one 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 subject walk back the same distance, and the score for the test is the average of the 
two walks (after reciprocal transformation). Subjects may use assistive devices when performing 
this task, with the same assistive device used at each assessment. 
9.5.1.5 Nine-Hole Peg Test 
The 9-HPT, which is a quantitative measure of upper extremity (arm and hand) function, has 
been established as a useful clinical outcome measure for subjects with FA [Friedman et al, 
2010; Lynch et al, 2006; Lynch et al, 2005]. It will be performed at Baseline/Day 1 (Week 26 of 
Study HZNP-ACT-301), and Weeks 4, 13, and 26 (or PW); and on each assessment day, it will 
be performed at approximately the same time of day and whenever possible, by the same 
examiner. At each assessment, two trials will be performed with each arm consecutively, starting 
with the dominant arm, and the average score of the two trials (after reciprocal transformation) 
will be reported for each arm separately. Using one hand only, the subject is instructed to take a 


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total of 9 pegs, one at a time, from a container and insert them into a pegboard, and then remove 
them from the pegboard, one at a time, and place them back in the container. 
The time of each test will be recorded in seconds, starting from the time the subject touches the 
first peg, and stopping when the last removed peg hits the container. If a peg drops on the floor, 
the examiner may retrieve it and put it back in the peg box; however, if a peg drops onto the 
table, the subject is instructed to retrieve it. 
9.5.1.6 Low-Contrast Sloan Letter Chart (LCSLC) Vision Test 
A quantitative binocular vision assessment will be performed using the LCSLC (100%, 2.5%, 
and 1.25% contrasts) at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Week 26 (or 
PW).  
Sloan letter charts contain 14 rows of letters (five letters per row for a total of 70 letters) with 
each successive row logarithmically decreasing in size. The letters are shaded gray on a 
white/retroilluminated background at different contrast levels; the 100%, 2.5%, and 1.25% 
contrast levels will be used in this study. The total score for each chart is the number of letters 
correctly read until five letters in succession are not identified (maximum score of 70) from a 
standard distance of six meters (approximately 20 feet). The LCSLC has been shown to be a 
useful clinical outcome measure for subjects with FA [Lynch et al, 2002b] and other 
neurological disorders [Balcer et al, 2003; Bodis-Wollner et al, 1976]. 
9.5.1.7 Listening in Spatialized Noise – Sentences Test (LiSN-S) 
The LiSN-S is only required for subjects who had normal audiogram results in Study HZNP-
ACT-301. The LiSN-S assesses the ability to understand speech when noise is arriving from 
different directions, and changes in this assessment have been shown to mirror disease 
progression in individuals with FA [Rance et al, 2012]. It will be performed at Baseline/Day 1 
(Week 26 of Study HZNP-ACT-301) and Week 26 (or PW). The subject will listen to a 
computer program with specialized headphones that creates a three-dimensional acoustic space. 
The computer program will have a target speaker saying sentences in the presence of competing 
noises. Scores are obtained under four conditions: 
Condition 
Type of voice for competing noise 
Direction of 
competing noise 
Direction of 
target speaker 
1: Different voices ± 90 degrees 
Different from target speaker 
Left and right 
Front 
2: Same voice ± 90 degrees 
Same as target speaker 
Left and right  
Front 
3: Different voices 0 degrees 
Different from target speaker 
Front 
Front 
4: Same voice 0 degrees 
Same as target speaker 
Front 
Front 
 
The spatial advantage score is the difference in scores between conditions 2 and 4, the talker 
advantage score is the difference in scores between conditions 3 and 4, and the total advantage 
score is the difference in scores between conditions 1 and 4. 


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9.5.1.8 Frataxin 
Individual whole blood (1 mL) and buccal cells, and optionally muscle biopsies, will be collected 
at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and post-dose at Weeks 13 and 26 (or 
PW) for analysis of frataxin protein levels. When performed, muscle biopsies should be the last 
efficacy assessment at Weeks 13 and 26 (or PW) and the last procedure prior to dosing at 
Baseline.  
Samples will be shipped to the central safety laboratory (URMC), which will batch samples and 
then ship them to CHOP for analysis. 
9.5.1.9 Physician’s and Patient’s Global Assessments  
The Physician’s Global Assessment of disease status and the Patient’s Global Assessment of 
overall well-being will be performed at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and 
Weeks 13 and 26 (or PW). 
The Physician’s Global Assessment of disease status is independent of the patient’s self-
assessment, and will be measured using a visual analog scale (VAS) from 0 to 100 where 
0 = very good and 100 = very poor.  
The Patient’s Global Assessment of overall well-being will also be measured using a 100 mm 
VAS by responding to the question “Considering all the ways in which your FA affects you, how 
are you doing?” with 0 = doing very well and 100 = doing very poorly.  
9.5.2 Quality-of-Life Assessments 
The MFIS will be completed for all subjects. For subjects <18 years of age at Baseline (Day 1) 
of Study HZNP-ACT-301, the PedsQL (study subject and parent/caregiver assessments) will be 
completed throughout the study, regardless if the subject turns 18 during the HZNP-ACT-301 
study or the HZNP-ACT-302 extension study. For subjects ≥18 years of age at Baseline (Day 1) 
of study HZNP-ACT-301, the SF-36 will be completed throughout the HZNP-ACT-301 and 
HZNP-ACT-302 studies. 
9.5.2.1 Pediatric Quality of Life Inventory (PedsQL) 
For subjects <18 years of age at Baseline (Day 1) of Study HZNP-ACT-301, the PedsQL will be 
completed by the subjects and their caregivers at Baseline/Day 1 (Week 26 of Study HZNP-
ACT-301) and at Weeks 13 and 26 (or PW). The PedsQL is a 23-item assessment including 
scales for physical functioning (8 items), emotional functioning (5 items), social functioning (5 
items), and school functioning (5 items) [Friedman et al, 2010; Paulsen et al, 2010; Varni et al, 
1999]. Each item is rated as to how much of a problem the item has been over the past month on 
a 5-point scale (0=it is never a problem → 4=it is almost always a problem) (see Section 17.5). 
The total score is the sum of all items, the physical health score is the sum of the Physical 
Functioning items, and the psychosocial score is the summary of the Emotional Functioning, 
Social Functioning, and School Functioning scores.  


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9.5.2.2 36-Item Short-Form Health Survey (SF-36) 
The SF-36 is one of the most widely-accepted generic health status measures [Ware et al, 1992] 
and has been shown a to be a useful clinical outcome measure for subjects with FA [Epstein et 
al, 2008]. For study subjects ≥18 years of age at Baseline of Study HZNP-ACT-301, the SF-36 
will be completed by the subjects at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and at 
Weeks 13 and 26 (or PW) in this study (HZNP-ACT-302). 
The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their 
section (Section 17.6). Each scale is directly transformed into a 0-100 scale on the assumption 
that each question carries equal weight. The lower the score, the more disability. The higher the 
score, the less disability (i.e., a score of zero is equivalent to maximum disability and a score of 
100 is equivalent to no disability).  
9.5.2.3 Modified Fatigue Impact Scale (MFIS) 
The MFIS, which has been shown to be a useful clinical outcome measure for subjects with FA 
[Epstein et al, 2008; Friedman et al, 2010], will be completed by all subjects or their caregivers 
at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and at Weeks 13 and 26 (or PW). The 
MFIS is a 21-item assessment, with each item rated on a 5-point scale (0=never → 4=almost 
always) (Section 17.7). It can be aggregated into three subscales (physical, cognitive, and 
psychosocial), as well as into a total MFIS score. All items are scaled so that higher scores 
indicate a greater impact of fatigue on a subject’s activities (i.e., no items are reverse scored). 
9.5.3 Safety Variables 
Safety will be assessed via AE and concomitant medication use monitoring, immunogenicity 
testing, physical examinations, vital signs, clinical safety laboratory evaluations (complete blood 
count, PT, INR, aPTT, chemistry, and urinalysis), pregnancy testing (if applicable), 
echocardiograms, and ECGs. 
9.5.3.1 Adverse Events 
Comprehensive assessments of any apparent AE experienced by the subject will be performed 
throughout the course of this study. Study center personnel will record all AEs, whether observed 
by the Investigator/designee or reported by the subject/caregiver, in the source document and on 
the eCRF. A physician (either the Principal Investigator or a physician/nurse 
practitioner/physician’s assistant designated by the Principal Investigator) will manage and treat 
any treatment-emergent AE (TEAE). 
AE information will be elicited from each subject/caregiver by indirect questioning using a non-
leading question, such as “Has anything bothered you since your last visit or is anything 
bothering you now?” AE data also may be volunteered by the parent/caregiver to the Investigator 
(or designee). A physician (either the Principal Investigator or a physician/nurse 
practitioner/physician’s assistant designated by the Principal Investigator) will assess the 
seriousness, severity, and causality of each AE based on the following definitions and 
documentation requirements. 


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9.5.3.1.1 
Definitions 
Adverse Event:  An AE is defined in 21 CFR 312.32(a) as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug-related. 
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 AE is considered related to the treatment or not. Adverse events 
include the following types of occurrences: 
• Adverse reaction:  an adverse reaction means any AE caused by a drug. Adverse 
reactions are a subset of all suspected adverse events for which there is reason to 
conclude that the drug caused the event. 
• Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the drug caused the AE. Reasonable possibility means there is evidence to suggest a 
causal relationship between the drug and the AE. A suspected adverse reaction implies a 
lesser degree of certainty about causality than adverse reaction, which means any AE 
caused by a drug. Suspected adverse reactions are the subset of all AEs for which there is 
a reasonable possibility that the drug caused the event.  
• Other medical experiences, regardless of their relationship to the study drug, such as 
injury, accidents, increased severity of pre-existing symptoms, apparently unrelated 
illness, and clinically significant abnormalities in clinical laboratory values, physiological 
testing, or physical examination findings. 
• Reactions from drug overdose, abuse, withdrawal, sensitivity, an interaction with another 
drug or substance, or toxicity. 
Serious Adverse Event (SAE):  An AE is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 
• Death. This includes any death that occurs during the conduct of a clinical study, 
including deaths that appear to be completely unrelated to the study drug (e.g., car 
accidents). 
• Life-threatening adverse experience. An AE or suspected adverse reaction is considered 
life-threatening if, in the view of either the Investigator or the Sponsor, its occurrence 
places the subject at immediate risk of death. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
• Persistent or significant disability or incapacity. 
• Inpatient hospitalization or prolongation of an existing hospitalization. 


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• Congenital anomaly or birth defect. 
• Other medically important event which, according to appropriate medical judgment, may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Of note: Surgical procedures or other therapeutic interventions themselves are not adverse 
events, but the condition for which the surgery/intervention is required is an adverse event and 
should be documented accordingly.  
Elective surgeries and/or treatments requiring hospitalization (e.g., cosmetic surgery), and 
treatment received at an emergency room or similar facility, will not be considered as SAEs 
unless one of the definitions of an SAE listed above is met. 
Non-Serious Adverse Event:  A non-serious AE includes any AE that is not described in the 
previous SAE category. 
Unexpected:  An AE or suspected adverse reaction is considered unexpected if it is not listed in 
the Investigator Brochure or is not listed with the specificity or severity that has been observed. 
Unexpected, as used in this definition, also refers to AEs or suspected adverse reactions that are 
mentioned in the Investigator Brochure as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation. 
9.5.3.1.2 
Documentation of Adverse Events 
Adverse events that are ongoing from Study HZNP-ACT-301 will be considered baseline 
signs/symptoms. The TEAE reporting period begins with the date of the first dose of study drug 
at home and continues until completion of the Follow-Up Safety Visit, performed two weeks 
after administration of the final dose of study medication. All baseline signs/symptoms and 
TEAEs must be recorded in the source documents and on the subject’s eCRF. 
If the Investigator observes an SAE after study completion that he/she believes was possibly 
caused by the study medication, the Investigator will report this SAE using the procedures 
described in Section 9.5.3.1.5. 
Unchanged, chronic conditions are NOT considered AEs and should not be recorded on the AE 
pages of the eCRF unless there is an exacerbation of a chronic condition.  
Disease progression can be considered as a worsening of a subject’s condition attributable to the 
disease for which the study drug is being studied (i.e., FA). It may be an increase in the severity 
of the disease under study and/or increases in the symptoms of the disease. The development of 
worsening ataxia may be considered as disease progression and not an AE. Events, which are 
unequivocally due to disease progression, should only be reported as AEs if they fulfill any of 
the SAE criteria or are the reason for discontinuation of treatment with the study drug. 


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In addition, hospitalizations for planned procedures are not considered an AE unless they are 
prolonged hospitalizations, and emergency room visits less than 24 hours in duration are not 
considered hospitalizations. 
Detailed information regarding all SAEs must also be recorded on the Serious Adverse Event 
Reporting Form. Whenever possible, the Investigator should group together into a single term 
the signs and symptoms that constitute a single diagnosis. For example, cough, rhinitis, and 
sneezing might be grouped together as “upper respiratory infection” if the Investigator is 
confident of the diagnosis. 
9.5.3.1.3 
Grading of Adverse Events 
The severity of all AEs, including all treatment-emergent clinically significant laboratory test 
results and all treatment-emergent clinically significant changes in laboratory test results, will be 
assessed in accordance with the following criteria: 
• Mild (Grade 1):  awareness of signs or symptoms that are easily tolerated, are of minor 
irritant type, cause no loss of time from usual activities, do not require medication or 
further medical evaluation, and/or are transient. 
• Moderate (Grade 2):  signs or symptoms sufficient to interfere with function but not 
activities of daily living. 
• Severe (Grade 3):  signs or symptoms sufficient to interfere with activities of daily living; 
signs and symptoms may be of a systemic nature or may require further medical 
evaluation and/or treatment. 
• Life-Threatening (Grade 4):  disabling or with life-threatening consequences. This 
definition does not include any event that might have caused death if it had occurred in a 
more severe form. 
• Fatal (Grade 5):  death related to an AE. 
9.5.3.1.4 
Relationship to Study Drug 
The relationship of the study drug to each AE will be determined by the Investigator based on 
the following definition: 
• No reasonable causal relationship (probably not related):  There is no plausible temporal 
relationship or there is another explanation that unequivocally provides a more plausible 
explanation for the event. 
• Yes, reasonable causal relationship (possibly related):  There is evidence in favor of a 
causal relationship; i.e., there is a plausible time course, and at least one of the following 
criteria apply: 


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 There is a reasonable pharmacological relationship (or known class effect) 
 There is no other more plausible explanation 
 There is a positive de-challenge (without active treatment of the event) 
 There is a positive re-challenge 
 There is a distinguishable dose effect 
Within the reporting requirement under 21 CFR 312.32(c)(1)(i), the FDA provides the following 
examples of types of evidence that would suggest a causal relationship between the drug and the 
adverse event. 
• A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome). 
• One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
rupture). 
• An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
9.5.3.1.5 
Reporting and Documenting SAEs 
All SAEs beginning with the time of signing IC and continuing until two weeks after 
administration of the final dose of study medication must be reported. The following steps will 
be taken to report promptly and document accurately any SAE, whether or not it appears to be 
related to the study medication: 
1) Report the SAE to Med Communications, Inc. by telephone or fax within 24 hours 
after becoming aware that a subject has experienced an SAE (see Appendix 17.1 for 
contact information). 
2) Record the SAE accurately in the source documents and on the AE page of the 
subject’s eCRF, as described in Section 9.5.3.1.2. Using the Serious Adverse Event 
Reporting Form, submit all known subject information to Med Communications, Inc. 
(as specified in separate instructions provided to the study center) on the SAE 
reporting form within 24 hours of learning of the SAE occurrence. 


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3) Perform appropriate diagnostic tests and therapeutic measures, and submit all follow-
up substantiating data, such as diagnostic test reports, hospital discharge summaries, 
and autopsy report to the Sponsor’s representative. 
4) Respond in a timely manner to any queries from Sponsor regarding the SAE. 
5) Conduct appropriate consultation and follow-up evaluation until the SAE is resolved, 
stabilized, or otherwise explained by the Investigator. 
6) Review each SAE report and evaluate the relationship of the SAE to study treatment. 
The Sponsor will determine whether the SAE is unexpected in nature. 
7) The Investigator must report all AEs or SAEs that meet the criteria for Unanticipated 
Problems Involving Risks to Human Subjects or Others to the IRB. 
9.5.3.1.6 Follow-Up of Adverse Events 
Any ongoing study drug-related AE present at the time of study termination, including a 
clinically significant laboratory test abnormality, will be followed until resolved or until the 
event stabilizes and the overall clinical outcome has been ascertained.  
In the event of unexplained, treatment-emergent, clinically significant abnormal laboratory test 
results or clinically significant changes in laboratory test results, the tests should be repeated 
immediately and followed until the values have returned to within the reference range or to 
baseline for that subject. 
9.5.3.1.7 Medication Error and Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to, or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 
If the subjects/caregivers accidently administer the wrong dose of study drug, they are to 
immediately contact the site to discuss possible safety concerns and receive instructions 
regarding future doses. All cases of medication errors and overdose (with or without associated 
AEs) will be documented on the eCRF in order to capture this important safety information 
consistently in the database. AEs associated with an overdose and SAEs of overdose are to be 
reported according to the procedures outlined in Sections 9.5.3.1.2 and 9.5.3.1.5, respectively. 
In the event of drug overdose, the subject is to be treated. 
9.5.3.1.8 Review of Adverse Events and Emerging New Safety Information 
The Sponsor’s Medical Monitor or designee in Pharmacovigilance will perform an ongoing 
review of all AEs and all other emerging new information relevant to the safety of the drug. 


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9.5.3.1.9 Reporting of IND Safety Reports 
The sponsor will notify the US FDA and all investigators on any new serious risks associated 
with the drug. 
9.5.3.2 Pregnancy Reporting 
All female subjects of childbearing potential will undergo urine pregnancy tests at Baseline/Day 
1 (Week 26 of Study HZNP-ACT-301), and Weeks 4, 13, and 26 (or PW) and will be instructed 
to use effective contraceptive measures in line with the inclusion and exclusion criteria. In case a 
female subject becomes pregnant during the study observation period (from Baseline to Week 
26) or pregnancy is confirmed within 30 days after the final study visit, the Investigator will 
immediately inform the Sponsor of the clinical trial using the Pregnancy Reporting Form. 
Pregnant subjects still ongoing in the trial will be withdrawn. Information regarding the outcome 
of the pregnancy must be provided shortly after the birth of the child or the termination of the 
pregnancy. Pregnancies will be followed whether or not an AE in the mother or the unborn child 
has been observed. 
Male subjects should refrain from fathering a child or donating sperm during the study and for 30 
days following the last dose of study drug. Pregnancy of the subject’s partner is not considered to 
be an AE; however, the outcome of all pregnancies should (if possible) be followed up and 
documented. 
9.5.3.3 Vital Signs 
Vital signs (resting systolic and diastolic blood pressure in the non-dominant arm, pulse, and 
temperature) will be assessed at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), and 
Weeks 4, 13, and 26 (or PW). Blood pressure and pulse measurements will be obtained with the 
subject’s arm unconstrained by clothing or other material and while the subject is sitting up. 
When possible, the same arm will be used for measurements in all study visits. Temperature will 
be obtained orally or via the ear. 
9.5.3.4 Physical Examinations, Height, and Weight 
Complete physical examinations (including evaluation of general appearance/mental status, 
HEENT [head, eyes, ears, nose, throat], and the following body systems:  skin, heart, lungs, 
abdomen, extremities) will be performed at Baseline/Day 1 (Week 26 of Study HZNP-ACT-
301), and Weeks 13 and 26 (or PW). Brief physical examinations will be performed at the Week 
4 and Follow-Up Safety Visits. 
Height and weight will be assessed at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), and 
Weeks 4, 13, and 26 (or PW); dosing will be based on the calculated BSA at Baseline/Day1, and 
Weeks 4 and 13. 
9.5.3.5 Echocardiograms  
Echocardiograms are scheduled for Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and 
Week 26 (or PW). 


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9.5.3.6 ECGs  
ECGs are scheduled for Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) and Weeks 13 and 
26 (or PW). 
9.5.3.7 Clinical Laboratory Tests 
Samples of blood (9.3 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, and 
1.8 mL for PT/INR/aPTT) and urine are scheduled for collection at Baseline/Day 1 (Week 26 of 
Study HZNP-ACT-301), and Weeks 4, 13, and 26 (or PW). Additional follow-up samples for 
clinical laboratory testing should be obtained as clinically indicated.  
All clinical laboratory testing, with the exception of on-site urine pregnancy tests during the 
treatment period for females of childbearing potential, will be performed by the central clinical 
safety laboratory (URMC). 
The following clinical laboratory tests will be performed:  
• Complete blood count  
• PT (and derivation of INR) and aPTT 
• Chemistry panel 
• Urinalysis 
9.5.3.8 Immunogenicity Testing 
Individual blood samples (2 mL) for immunogenicity testing will be collected from all subjects 
at Baseline/Day 1 (Week 26 of Study HZNP-ACT-301), and prior to dosing at Weeks 4, 13, 26 
(or PW), and 28. Samples will be collected in red top tubes, centrifuged, and serum will be 
collected and stored at ≥-70°C at the site until shipment to the central safety laboratory (URMC). 
URMC will store the samples at ≥-70°C until shipment to Intertek (San Diego, CA) for 
immunogenicity testing. 
If a subject tests positive for anti-drug antibodies (ADA), he/she will be followed until ADA 
levels revert to baseline.  
9.5.4 Appropriateness of Measurements 
The study population consists of subjects who completed Study HZNP-ACT-301; this population 
was well-defined and consistent with the expected target population for whom ACTIMMUNE 
will be indicated (pediatric and young adult subjects with a FA functional stage of >1 to <5). 
The primary efficacy endpoint (change in FARS-mNeuro from Baseline to Week 26) has been 
agreed upon with the FDA. The measurements used in this study for the primary and secondary 
endpoints (ADL, FARStot, and T25FW) are established and well-validated endpoints that have 
been shown to correlate significantly with functional disability in FA patients [Lynch et al, 
2006].  


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9.5.5 Study Procedures 
Subjects who provide Informed Consent/Assent and who meet all the entry criteria for 
participation in this study will be enrolled in the open-label extension study. Subjects may 
participate in this study for up to 28 consecutive weeks in total. The order and timing of the 
assessments at each study visit should be followed so that assessments are performed at 
consistent times relative to dosing at each visit. 
9.5.5.1 Baseline/Day 1 (Week 26 of Study HZNP-ACT-301) 
The Week 26 Visit from HZNP-ACT-301 will serve as Baseline/Day 1 for this study. At the 
Baseline Visit, subjects will receive the last dose of the randomized drug from HZNP-ACT-
301(ACTIMMUNE or placebo) in a double-blind fashion, and the first dose of study drug for the 
open-label extension study (10 µg/m2) will be distributed for administration at home according to 
the planned TIW dosing schedule. Baseline assessments should be performed in the order 
presented below to ensure that the neurological tests are performed at approximately the same 
time on testing days.  
• Collect all used, partially used, and unused study medication kits and vials from Study 
HZNP-ACT-301. 
• Obtain signed, written Informed Consent/Assent and permission to use Protected Health 
Information (in accordance with the Health Insurance Portability and Accountability Act 
[HIPAA]) for Study HZNP-ACT-302. Refusal to provide this permission excludes an 
individual from eligibility for study participation. Record date Informed Consent/Assent 
was given and who conducted the process on the appropriate source documentation. 
• Perform review of inclusion/exclusion criteria. 
• Collect blood (9.3 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, 
and 1.8 mL for PT/INR/aPTT ) and urine samples from all subjects for safety clinical 
laboratory values (including urine pregnancy test [if applicable]). The pregnancy test 
must be negative for those subjects to be eligible for participation in this study. 
• Collect blood samples (2 mL) for immunogenicity testing. 
• Collect blood samples (1 mL) for frataxin analyses. 
• Measure height and weight to calculate dose volume. 
• Educate subjects and caregivers on dosing technique and schedule. 
• Between approximately 7 to 10 AM, administer the last dose of double-blind study drug 
for Study HZNP-ACT-301 or supervise administration of the study drug by either the 
subject or the subject’s caregiver and record date/time of dosing. 
• Perform physical examination, including vital signs. 


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• Enquire about AEs and concomitant medications. 
• Perform ADL, and Physician’s and Patient’s Global Assessments. 
• Perform echocardiogram. 
• Perform ECG. 
• Perform vision testing (LCSLC) and auditory testing (LiSN-S) if normal audiogram 
results at Screening Visit of Study HZNP-ACT-301. 
• Perform QOL assessments (PedsQL, SF-36, MFIS). 
• Perform functional staging of FA and neurological assessments (FARS, T25FW, 9-HPT) 
at approximately 4 to 6 hours post-dose. 
• Collect buccal samples and muscle biopsies (optional) for frataxin analysis (muscle 
biopsies, if performed, will be the last activity prior to dosing activities). 
• Use CTCC’s electronic system to obtain the enrollment number and study drug kit 
assignment. 
• Dispense a 4-week supply of study drug. 
Subjects will be discharged from the study center after all of the Study Day 1 procedures have 
been completed. 
9.5.5.2 Week 4 
• Collect all used, partially used, and unused study medication kits and vials. 
• Collect blood (9.3 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, 
and 1.8 mL for PT/INR/aPTT) and urine samples from all subjects for safety clinical 
laboratory values (including urine pregnancy test [if applicable]). The pregnancy test 
must be negative for those subjects to continue participation in this study. 
• Collect blood samples (2 mL) for immunogenicity testing. 
• Measure height and weight to calculate dose volume. 
• Educate subjects and caregivers on dosing technique and schedule. 
• Between approximately 7 to 10 AM, administer study drug or supervise administration of 
the study drug by either the subject or the subject’s caregiver and record date/time of 
dosing. 


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• Perform brief physical examination, including vital signs. 
• Enquire about AEs and concomitant medication use. 
• Dispense a 6- or 9-week supply of study drug, as applicable. 
Subjects will be released from the study center after all of the visit procedures have been 
completed and instructed to return to the clinic at Week 13. 
9.5.5.3 Week 13 
• Collect all used, partially used, and unused study medication kits and vials. 
• Collect blood (9.3 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, 
and 1.8 mL for PT/INR/aPTT) and urine samples from all subjects for safety clinical 
laboratory values (including urine pregnancy test [if applicable]). The pregnancy test 
must be negative for those subjects to continue participation in this study. 
• Collect blood samples (2 mL) for immunogenicity testing. 
• Collect blood samples (1 mL) for frataxin analyses. 
• Measure height and weight to calculate dose volume. 
• Educate subjects and caregivers on dosing technique and schedule. 
• Between approximately 7 to 10 AM, administer study drug or supervise administration of 
the study drug by either the subject or the subject’s caregiver and record date/time of 
dosing. 
• Perform physical examination, including vital signs. 
• Enquire about AEs and concomitant medications. 
• Perform ADL and Physician’s and Patient’s Global Assessments. 
• Perform ECG. 
• Perform QOL assessments (PedsQL, SF-36, MFIS). 
• Perform functional staging of FA and neurological assessments (FARS, T25FW, 9-HPT) 
at approximately 4 to 6 hours post-dose. 
• Collect buccal samples and muscle biopsies (optional) for frataxin analysis. 
• Dispense a 6- or 13-week supply of study drug, as applicable. 


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Subjects will be released from the study center after all of the visit procedures have been 
completed and instructed to return to the clinic at Week 26. 
9.5.5.4 Week 26 (Termination Visit or Premature Withdrawal Visit) 
• Collect all used, partially used, and unused study medication kits and vials. 
• Collect blood (9.3 mL; 1.0 mL for hematology, 3.5 mL for chemistry, 3.0 mL discard, 
and 1.8 mL for PT/INR/aPTT) and urine samples from all subjects for safety clinical 
laboratory values (including urine pregnancy test [if applicable]). 
• Collect blood samples (2 mL) for immunogenicity testing. 
• Collect blood samples (1 mL) for frataxin analyses. 
• Measure height and weight. 
• Between approximately 7 to 10 AM, administer study drug or supervise administration of 
the study drug by either the subject or the subject’s caregiver and record date/time of 
dosing. 
• Perform physical examination, including vital signs. 
• Enquire about AEs and concomitant medications. 
• Perform ADL and Physician’s and Patient’s Global Assessments. 
• Perform echocardiogram. 
• Perform ECG. 
• Perform Vision testing (LCSLC) and auditory testing (LiSN-S) if audiogram results were 
normal at Screening Visit of Study HZNP-ACT-301. 
• Perform QOL assessments (PedsQL, SF-36, MFIS). 
• Perform functional staging of FA and neurological assessments (FARS, T25FW, 9-HPT) 
at approximately 4 to 6 hours post-dose. 
• Collect buccal samples and muscle biopsies (optional) for frataxin analysis. 
Subjects will be released from the study center after all of the visit procedures have been 
completed and instructed to return in approximately two weeks for the Follow-Up Safety Visit. 


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9.5.5.5 Follow-Up Safety Visit 
Subjects will return to the clinic approximately two weeks after administration of their final dose 
of study medication. They will undergo a brief physical examination and report any changes in 
concomitant medication and AEs. Any ongoing study drug-related AE present at the time of 
study termination, including a clinically significant laboratory test abnormality, will be followed 
until resolved or until the event stabilizes and the overall clinical outcome has been ascertained. 
In addition, individual blood samples (2 mL) will be collected for immunogenicity testing; if 
subjects test positive for ADA, they will be followed until the ADA levels revert to baseline. 
9.6 
Statistical Methods and Determination of Sample Size  
Detailed statistical analyses will be presented in a separate statistical analysis plan. Some key 
points identified for statistical analyses are outlined below. 
9.6.1 Endpoints 
Safety Endpoints  
Adverse event and concomitant medication data will be summarized. Clinical laboratory safety 
data, vital sign data, echocardiogram data, and ECG interval data will be summarized with 
descriptive statistics for Baseline, post-dose, and change from Baseline to post-dose values. Shift 
tables will be presented for clinical laboratory values and ECG categorical results from Baseline 
to each post-dose visit. Physical examination findings will be listed by subject. Results of 
immunogenicity testing will be presented in tabular format. 
Efficacy Endpoints 
The primary efficacy endpoint is the observed change from Baseline to Week 26 for all subjects 
and from Baseline of HZNP-ACT-301 to Week 26 of HZNP-ACT-302 (52-week treatment 
duration) for subjects receiving active treatment in both studies in the FARS-mNeuro score. 
Results will be summarized descriptively.  
Secondary Efficacy Endpoints 
The observed mean change from Baseline to Week 26 for all subjects and from Baseline of 
HZNP-ACT-301 to Week 26 of HZNP-ACT-302 (52-week treatment duration) for subjects 
receiving active treatment in both studies in ADL, T25FW, FARS-mNeuro responder rate, and 
FARStot scores will be summarized descriptively. 
Exploratory Efficacy/Quality of Life Endpoints 
The observed mean changes from Baseline will be summarized descriptively for the following 
endpoints: 
• Change from Baseline to Week 13 in the FARS-mNeuro, ADL, T25FW, and FARStot 
scores. 
• Change from Baseline to Weeks 13 and 26 for all subjects, and from Baseline of HZNP-
ACT-301 to Week 26 of HZNP-ACT-302 (52-week treatment duration) for subjects 
receiving active treatment in both studies in 9-HPT, remaining FARS subscale scores, FA 


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stage, frataxin protein levels, MFIS, SF-36, PedsQL, and Physician and Patient Global 
Assessments. 
• Change from Baseline to Week 26 for all subjects and from Baseline of HZNP-ACT-301 
to Week 26 of HZNP-ACT-302 (52-week treatment duration) for subjects receiving 
active treatment in both studies in LCSLC and LiSN-S. 
9.6.2 Populations for Analysis 
All analyses will be based on the Safety Population. The safety population will be all subjects 
who receive at least one dose of open-label study drug after the Baseline Visit for HZNP-ACT-
302).  
9.6.3 Baseline Characteristics 
Baseline and demographic characteristics will be summarized by standard descriptive summaries 
(e.g., means and standard deviations for continuous variables such as age and percentages for 
categorical variables such as gender). 
9.6.4 Sample Size and Power Considerations 
Subjects who complete 26 weeks of blinded treatment in Study HZNP-ACT-301 will be eligible 
for enrollment. The sample size is not based on statistical considerations. 
9.7 
Changes in the Conduct of the Study 
If any modifications in the experimental design, dosages, parameters, subject selection, or any 
other sections of the protocol are indicated or required, the Investigator will consult with the 
Sponsor before any such changes are instituted. Modifications will be accomplished through 
formal amendments to this protocol by the Sponsor and approved from the appropriate IRB. 
The Sponsor’s Medical Monitor will consider any requests for exceptions to protocol entry 
criteria on a case-by-case basis. The Investigator or other health professional in attendance must 
contact CTCC as soon as possible to discuss the associated circumstances; CTCC in turn, will 
notify the Sponsor. All protocol deviations and the reasons for such deviations must be 
documented in eClinical. In the event of a protocol deviation, the Investigator and Sponsor’s 
Medical Monitor will determine whether the subject should continue to participate in the study. 
The Sponsor has a legal responsibility to report fully to regulatory authorities all results of 
administration of investigational drugs to humans. No investigational procedures other than those 
described in this protocol will be undertaken on the enrolled subjects without the agreement of 
the IRB and Sponsor. 
10. 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES 
The Investigator must maintain adequate and accurate records to document fully the conduct of 
the study and to ensure that study data can be subsequently verified. These documents should be 
classified in two separate categories:  (1) Investigator study file and (2) subject clinical source 


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documents that corroborate data collected in the eCRFs. Subject clinical source documents 
would include, as applicable, original hospital/clinic subject records; physicians’ and nurses’ 
notes; appointment book; original laboratory, ECG, electroencephalogram, radiology, pathology, 
and special assessment reports; dispensing records; signed Informed Consent/Assent Forms; 
consultant letters; and subject screening and enrollment logs. 
In order to comply with regulatory requirements, it is the policy of the Sponsor that, at a 
minimum, the following be documented in source documents at the study center: 
• Medical history/physical condition and diagnosis of the subject before involvement in the 
study sufficient to verify that the subject meets protocol entry criteria, including genetic 
testing results. 
• Study number, assigned subject number, and verification that written Informed 
Consent/Assent was obtained (each recorded in dated and signed progress notes). 
• Progress notes for each subject visit (each dated and signed). 
• Records of each study visit including each study assessment and the identity of the staff 
member performing the assessment. 
• Study drug dispensing and return. 
• Review by the Investigator or qualified personnel on the 1572 of laboratory test results. 
• Adverse events (start and stop date, description, action taken, and resolution). 
• Investigator or sub-investigator’s signed assessment of each AE. 
• Concomitant medications (start and stop dates, reason for use). 
• Condition of subject upon completion of, or PW from, the study. 
11. 
CASE REPORT FORMS 
An electronic case report form (eCRF) is required for every subject who signs the informed 
consent/assent or for whom the caregiver has signed informed consent. Required data must be 
entered on the eCRF within three days after data collection or the availability of test results. 
Separate source records are required to support all eCRF entries. Data captured on the eCRF, and 
requested anonymized copies of supporting documents, will be transferred to the Sponsor at 
study completion. 
The Investigator will ensure that the eCRFs are accurate, complete, legible, and timely, and will 
review and provide an electronic signature for the eCRF according to the standard operating 
procedure of the ARO Data Management System. Final eCRFs will be provided to the 
Investigator and Sponsor by ARO Data Management. 


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12. 
STUDY MONITORING 
The Investigator will ensure that the study is conducted in accordance with all regulations 
governing the protection of human subjects. The Investigator will adhere to the basic principles 
of GCP as outlined in Title 21 of the CFR, Part 312, Subpart D, “Responsibilities of Sponsors 
and Investigators”; 21 CFR, Part 50, “Protection of Human Subjects”; 21 CFR, Part 56, 
“Institutional Review Boards”; 21 CFR, Part 54 “Financial Disclosure by Clinical Investigators”; 
and the ICH guideline entitled “Good Clinical Practice: Consolidated Guidance”. Additionally, 
this study will be conducted in compliance with the Declaration of Helsinki and with all local 
laws and regulations. 
The Investigator will ensure that all work and services described in or associated with this 
protocol are conducted in accordance with the investigational plan, applicable regulations, and 
the highest standards of medical and clinical research practice. The Investigator will provide 
copies of the study protocol and Investigator Brochure to all Sub-Investigators, pharmacists, and 
other staff responsible for study conduct. 
All aspects of the study will be monitored by qualified individuals designated by the Sponsor. 
The Sponsor will ensure that the study is monitored adequately in accordance with GCP 
guidelines. 
Prior to initiation of the study, the Sponsor’s representatives will review with study center 
personnel information regarding the investigational drug, protocol requirements, monitoring 
requirements, and reporting of SAEs. 
At intervals during the study, as well as after the completion of subject enrollment, the study 
center will be monitored by the ARO for compliance. During these visits, the monitor will 
discuss study progress, verify adherence to the protocol and the completeness, consistency, and 
accuracy of the data being entered on the eCRF (source data verification); oversee the resolution 
of outstanding data discrepancies, and check on various aspects of study conduct (e.g., drug 
accountability, sample storage). The Investigator agrees to allow these monitors access to the 
clinical supplies, dispensing and storage areas, and clinical records of the study subjects, and, if 
requested, agrees to assist the monitors. The Investigator must cooperate with the monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
A secondary audit may be conducted by Quality Assurance designated by the Sponsor. The 
Investigator will be informed if this is to take place and advised as to the nature of the audit. 
Representatives of the US FDA and/or representatives of other regulatory authorities may also 
conduct an inspection of the study at the investigative site. If informed of such an inspection, the 
Investigator should notify the Sponsor immediately. 
Every effort will be made to maintain the anonymity and confidentiality of subjects participating 
in this clinical study. However, because of the investigational nature of this treatment, the 
Investigator agrees to allow representatives of the Sponsor, its designated agents, and authorized 
employees of the appropriate regulatory agencies to inspect the facilities used in this study and to 
have direct access to inspect, for purposes of verification, the hospital or clinical records of all 


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subjects enrolled in this study. A statement to this effect should be included in the Informed 
Consent/Assent Form. 
13. 
DATA MANAGEMENT 
Data will be entered into a clinical database as specified in the ARO’s Data Management Plan. 
Quality control and data validation procedures will be applied to ensure the validity and accuracy 
of the clinical database. Data will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures. Data queries 
requiring clarification will be communicated to the investigational site for resolution. Only 
authorized personnel will make corrections to the clinical database, and all corrections will be 
documented in an audit trail. 
The coding of an adverse event, medical history and concomitant medication terms will be 
performed by the ARO and reviewed and approved by the Sponsor. Concomitant medications 
will be coded using the World Health Organization Drug Dictionary (WHODrug) and adverse 
event/medical history/surgery/non drug therapy terms will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
14. 
RETENTION OF RECORDS 
No study documents at the study site should be destroyed without prior written agreement 
between the Sponsor and the Investigator. All subjects’ medical records, the Investigator’s copy 
of the eCRF, other supporting data, records of drug dispensing and accountability, signed 
Informed Consent Forms, IRB correspondence, and correspondence with the Sponsor must be 
kept by the Investigator for at least two years following the date of the last approval of a 
marketing application in an ICH region (including the US) and until there are no pending or 
contemplated marketing applications in any other ICH region. If an application is not filed or not 
approved for the indication under study, all study-related files must be retained for at least two 
years following the date of discontinuation of the clinical development program for 
ACTIMMUNE and for a period in compliance with all federal, state and local regulations. The 
Sponsor must be notified prior to the disposal of any study-related files. If the Investigator leaves 
the practice or institution during the required retention period, it is important that arrangements 
be made for continued record retention. In that event, the records generally will be retained at the 
institution at which the study was conducted. 
15. 
PUBLICATION 
 
To avoid disclosures that could jeopardize proprietary rights, the institution and/or the 
Investigator agree to certain restrictions on publications (e.g., abstracts, speeches, posters, 
manuscripts, and electronic communications) as detailed in the Clinical Trial Agreement. 


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16. 
REFERENCES  
Arpa J, Sanz-Gallego I, Rodriguez-de-Rivera FJ, et al. Triple therapy with deferiprone, 
idebenone and riboflavin in Friedreich's ataxia - open-label trial. Acta Neurol Scand. 2014; 
129(1): 32-40. 
Babcock M, de Silva D, Oaks R, et al. Regulation of mitochondrial iron accumulation by Yfh1p, 
a putative homolog of frataxin. Science. 1997; 276(5319): 1709-12. 
Balcer LJ, Baier ML, Cohen JA, et al. Contrast letter acuity as a visual component for the 
Multiple Sclerosis Functional Composite. Neurology. 2003; 61(10): 1367-73. 
Bodis-Wollner I, Diamond SP. The measurement of spatial contrast sensitivity in cases of 
blurred vision associated with cerebral lesions. Brain. 1976; 99(4): 695-710. 
Boesch S, Nachbauer W, Mariotti C, et al. Safety and tolerability of carbamylated erythropoietin 
in Friedreich's ataxia. Mov Disord. 2014; 29(7): 935-9. 
Corben LA, Lynch D, Pandolfo M, et al. Consensus clinical management guidelines for 
Friedreich ataxia. Orphanet J Rare Dis. 2014; 9: 184. 
Delatycki MB, Tai G, Corben L, et al. HFE p.C282Y heterozygosity is associated with earlier 
disease onset in Friedreich ataxia. Mov Disord. 2014; 29(7): 940-3. 
Deutsch EC, Santani AB, Perlman SL, et al. A rapid, noninvasive immunoassay for frataxin: 
utility in assessment of Friedreich ataxia. Mol Genet Metab. 2010; 101(2-3): 238-45. 
Devane JG, Martin ML, Matson MA. A short 2 week dose titration regimen reduces the severity 
of flu-like symptoms with initial interferon gamma-1b treatment. Curr Med Res Opin. 2014; 
30(6): 1179-87. 
Epstein E, Farmer JM, Tsou A, et al. Health related quality of life measures in Friedreich Ataxia. 
J Neurol Sci. 2008; 272(1-2): 123-8. 
Fahey MC, Corben LA, Collins V, et al. The 25-foot walk velocity accurately measures real 
world ambulation in Friedreich ataxia. Neurology. 2007; 68(9): 705-6. 
Friedman LS, Farmer JM, Perlman S, et al. Measuring the rate of progression in Friedreich 
ataxia: implications for clinical trial design. Mov Disord. 2010; 25(4): 426-32. 
Harding AE. Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of 
early diagnostic criteria and intrafamilial clustering of clinical features. Brain. 1981; 104(3): 589-
620. 
https://fafysio.wordpress.com/. Extreme Living. How I live with ataxia. From 
https://fafysio.wordpress.com/. 


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Koeppen AH. Friedreich's ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci. 
2011; 303(1-2): 1-12. 
Lynch DR, Farmer JM, Balcer LJ, et al. Friedreich ataxia: effects of genetic understanding on 
clinical evaluation and therapy. Arch Neurol. 2002a; 59(5): 743-7. 
Lynch DR, Farmer JM, Rochestie D, et al. Contrast letter acuity as a measure of visual 
dysfunction in patients with Friedreich ataxia. J Neuroophthalmol. 2002b; 22(4): 270-4. 
Lynch DR, Farmer JM, Tsou AY, et al. Measuring Friedreich ataxia: complementary features of 
examination and performance measures. Neurology. 2006; 66(11): 1711-6. 
Lynch DR, Farmer JM, Wilson RL, et al. Performance measures in Friedreich ataxia: potential 
utility as clinical outcome tools. Mov Disord. 2005; 20(7): 777-82. 
Lynch DR, Perlman SL, Meier T. A phase 3, double-blind, placebo-controlled trial of idebenone 
in Friedreich ataxia. Arch Neurol. 2010; 67(8): 941-7. 
Lynch DR, Willi SM, Wilson RB, et al. A0001 in Friedreich ataxia: biochemical characterization 
and effects in a clinical trial. Mov Disord. 2012; 27(8): 1026-33. 
Mariotti C, Fancellu R, Caldarazzo S, et al. Erythropoietin in Friedreich ataxia: no effect on 
frataxin in a randomized controlled trial. Mov Disord. 2012; 27(3): 446-9. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987; 317(17): 1098. 
Paulsen EK, Friedman LS, Myers LM, et al. Health-related quality of life in children with 
Friedreich ataxia. Pediatr Neurol. 2010; 42(5): 335-7. 
Polisson RP, Gilkeson GS, Pyun EH, et al. A multicenter trial of recombinant human interferon 
gamma in patients with systemic sclerosis: effects on cutaneous fibrosis and interleukin 2 
receptor levels. J Rheumatol. 1996; 23(4): 654-8. 
Rai M, Soragni E, Jenssen K, et al. HDAC inhibitors correct frataxin deficiency in a Friedreich 
ataxia mouse model. PLoS One. 2008; 3(4): e1958. 
Rance G, Corben LA, Delatycki MB. Auditory pathway changes mirror overall disease progress 
in individuals with Friedreich ataxia. J Neurol. 2012; 259(12): 2746-8. 
Rotig A, de Lonlay P, Chretien D, et al. Aconitase and mitochondrial iron-sulphur protein 
deficiency in Friedreich ataxia. Nat Genet. 1997; 17(2): 215-7. 
Sandi C, Pinto RM, Al-Mahdawi S, et al. Prolonged treatment with pimelic o-aminobenzamide 
HDAC inhibitors ameliorates the disease phenotype of a Friedreich ataxia mouse model. 
Neurobiol Dis. 2011; 42(3): 496-505. 


Horizon Pharma Ireland Ltd. 
 
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Seyer L, Greeley N, Foerster D, et al. Open-label pilot study of interferon gamma-1b in 
Friedreich ataxia. Acta Neurol Scand. 2014; published online 21 Oct. 
Simon D, Seznec H, Gansmuller A, et al. Friedreich ataxia mouse models with progressive 
cerebellar and sensory ataxia reveal autophagic neurodegeneration in dorsal root ganglia. J 
Neurosci. 2004; 24(8): 1987-95. 
Subramony SH, May W, Lynch D, et al. Measuring Friedreich ataxia: Interrater reliability of a 
neurologic rating scale. Neurology. 2005; 64(7): 1261-2. 
Tomassini B, Arcuri G, Fortuni S, et al. Interferon gamma upregulates frataxin and corrects the 
functional deficits in a Friedreich ataxia model. Hum Mol Genet. 2012; 21(13): 2855-61. 
Tsou AY, Friedman LS, Wilson RB, et al. Pharmacotherapy for Friedreich ataxia. CNS Drugs. 
2009; 23(3): 213-23. 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
inventory. Med Care. 1999; 37(2): 126-39. 
Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
framework and item selection. Med Care. 1992; 30(6): 473-83. 
Weidemann F, Stork S, Liu D, et al. Cardiomyopathy of Friedreich ataxia. J Neurochem. 2013; 
126 Suppl 1: 88-93. 
Wyller VB, Jacobsen K, Dahl MB, et al. Interferon gamma may improve cardiac function in 
Friedreich's ataxia cardiomyopathy. Int J Cardiol. 2016; 221: 376-8. 
 
 




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17.2 
Approved US Labeling for ACTIMMUNE  
Interferon γ-1b was approved in 1990 in the US under the trade name ACTIMMUNE as a 
treatment to reduce the frequency and severity of serious infections associated with CGD, an 
inherited disorder characterized by deficient phagocyte oxidative metabolism (BLA 103836, 
approved for orphan indication). In February 2000, approval was obtained to market the product 
in SMO, a rare (and often fatal) bone disorder (BLA 103836/1001, approved for orphan 
indication).  
The current version of the approved US labeling (02 June 2015) is included in this appendix; any 
subsequent updates to the labeling can be found at 
http://actimmune.com/pdf/10889_Actimmune-PI_8_5x11.pdf 
 


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17.3 
FARS Neurological Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
  
   
  
 
 
 
 


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17.4 
ADL Assessment 
Category 
Score1 
0 
1 
2 
3 
4 
Speech 
Normal. 
Mildly affected.  
No difficulty 
being understood. 
Moderately affected. 
Sometimes asked to 
repeat statements. 
Severely affected. 
Frequently asked 
to repeat statements. 
Unintelligible  
most of the time. 
Swallowing 
Normal. 
Rare choking 
(less than once a  
month). 
Frequent choking  
(less than once a week, 
greater than once a 
month). 
Requires modified food 
or chokes multiple 
times a week. Or subject 
avoids certain foods. 
Requires NG tube  
or gastrostomy  
feedings. 
Cutting Food and 
Handling Utensils 
Normal. 
Somewhat slow and 
clumsy, but no help 
needed. 
Clumsy and slow, but 
can cut most foods with 
some help needed. Or 
needs assistance when 
in a hurry. 
Food must be cut by 
someone, but can still 
feed self slowly. 
Needs to be fed. 
Dressing 
Normal. 
Somewhat slow, but no 
help needed. 
Occasional assistance 
with buttoning, getting 
arms in sleeves, etc or 
has to modify activity  
in some way 
(e.g., having to sit to get 
dressed, use velcro for 
shoes, stop wearing ties, 
etc). 
Considerable help 
required, but can do 
some things alone. 
Helpless. 
Personal Hygiene 
Normal. 
Somewhat slow, but no 
help needed. 
Very slow hygienic care 
or has need for devices 
such as special grab 
bars, tub bench, shower 
chair, etc. 
Requires personal help 
with washing, brushing 
teeth, combing hair or 
using toilet. 
Fully dependent  
(bed-bound). 
Falling2 
Normal. 
Rare falling (less than 
once a month). 
Occasional falls (once a 
week to once a month). 
 Falls multiple times a 
week or requires device 
to prevent falls. 
Unable to stand  
or walk. 
Walking2 
Normal. 
Mild difficulty, 
perception of 
imbalance. 
Moderate difficulty, but 
requires little or no 
assistance. 
Severe disturbance of 
walking, requires 
assistance or walking 
aids. 
Cannot walk at all even 
with assistance 
(wheelchair bound). 
Quality of 
Sitting Position 
Normal. 
Slight imbalance of the 
trunk, but needs no back 
support. 
Unable to sit without 
back support. 
Can sit only with 
extensive support 
(geriatric chair, posy, 
etc). 
Unable to sit. 
Bladder Function3 
Normal. 
Mild urinary hesitance, 
urgency or retention 
(less than once a 
month). 
Moderate hesitance, 
urgency, rare 
retention/incontinence 
(greater than once a 
month, but less than 
once a week). 
Frequent urinary 
incontinence (greater 
than once a week). 
Loss of bladder function 
requiring intermittent 
catheterization/ 
indwelling catheter. 
1 
Increments of 0.5 may be used if subject or caregiver strongly feels that a task falls between two scores. 
2 
If assistive device is used, score = 3. 
3 
If using drugs for bladder control, automatic score of 3. 
 
 
 


Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
Version 2.0, incorporating Amendment 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON PHARMA IRELAND LTD 
Page 84 of 93 
 
17.5 
PedsQL Inventory (Child Report for Ages 8-12) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
  
 
 
  
 
 
   
  
 
 
   
  
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 


Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
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Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
Version 2.0, incorporating Amendment 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON PHARMA IRELAND LTD 
Page 86 of 93 
 
17.6 
SF-36 Assessment 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
   
   
 
 
 
 
 
 


Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
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Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
Version 2.0, incorporating Amendment 1 
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Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
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ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
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Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
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Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
Version 2.0, incorporating Amendment 1 
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Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 28 September 2016 
 
Protocol: HZNP-ACT-302 
 
 
Version 2.0, incorporating Amendment 1 
PRIVATE AND CONFIDENTIAL INFORMATION OF HORIZON PHARMA IRELAND LTD 
Page 93 of 93 
 
17.7 
MFIS Assessment 
Because of my fatigue during the past 4 weeks… 
 
Never 
Rarely 
Some-
times 
Often 
Almost 
Always 
1. I have been less alert. 
0 
1 
2 
3 
4 
2. I have had difficulty paying attention for long periods 
of time. 
0 
1 
2 
3 
4 
3. I have been unable to think clearly. 
0 
1 
2 
3 
4 
4. I have been clumsy and uncoordinated. 
0 
1 
2 
3 
4 
5. I have been forgetful. 
0 
1 
2 
3 
4 
6. I have had to pace myself in my physical activities. 
0 
1 
2 
3 
4 
7. I have been less motivated to do anything that requires 
physical effort. 
0 
1 
2 
3 
4 
8. I have been less motivated to participate in social 
activities. 
0 
1 
2 
3 
4 
9. I have been limited in my ability to do things away 
from home. 
0 
1 
2 
3 
4 
10. I have had trouble maintaining physical effort for long 
periods. 
0 
1 
2 
3 
4 
11. I have had difficulty making decisions. 
0 
1 
2 
3 
4 
12. I have been less motivated to do anything that 
requires thinking. 
0 
1 
2 
3 
4 
13. My muscles have felt weak. 
0 
1 
2 
3 
4 
14. I have been physically uncomfortable. 
0 
1 
2 
3 
4 
15. I have had trouble finishing tasks that require 
thinking. 
0 
1 
2 
3 
4 
16. I have had difficulty organizing my thoughts when 
doing things at home or at work. 
0 
1 
2 
3 
4 
17. I have been less able to complete tasks that require 
physical effort. 
0 
1 
2 
3 
4 
18. My thinking has been slowed down. 
0 
1 
2 
3 
4 
19. I have had trouble concentrating. 
0 
1 
2 
3 
4 
20. I have limited my physical activities.  
0 
1 
2 
3 
4 
21. I have needed to rest more often or for longer periods. 
0 
1 
2 
3 
4 
 
Physical Subscale 
This scale can range from 0-36. It is computed by adding raw scores on the following 
items: 4+6+7+10+13+14+17+20+21. 
Cognitive Subscale 
This scale can range from 0-40. It is computed by adding raw scores on the following 
items: 1+2+3+5+11+12+15+16+18+19. 
Psychosocial Subscale 
This scale can range from 0-8. It is computed by adding raw scores on the following 
items: 8+9 
Total MFIS Score 
The total MFIS score can range from 0-84. It is computed by adding scores on the 
physical + cognitive + psychosocial subscales. 
 

SAP_001.pdf: 
CONFIDENTIAL 
 
22-MAY-2017 
 16 Mar 2012  
 
Statistical Analysis Plan 
 
Protocol Title: Multicenter, Safety and Efficacy, Open-Label Extension Study of 
ACTIMMUNE® (interferon γ-1b) in Children and Young Adults with 
Friedreich’s Ataxia 
Protocol Number: HZNP-ACT-302 Version 2.0 Amendment 1 (28-SEP-2016) 
Compound: ACTIMMUNE 
Phase: III 
Sponsor: Horizon Pharma Ireland Ltd. 
Connaught House, 1st Floor 
1 Burlington Road 
Dublin 4, Ireland 
SAP Author: 
 
Premier Research Group Limited 
387 Shuman Boulevard, STE 340W 
Naperville, IL, 60563 
SAP Version: Final Version 1.0 
SAP Date: 22-MAY-2017 
CONFIDENTIAL 


Protocol: HZNP-ACT-302 
 
Page 2 of 21 
Final Version 1.0 
 
CONFIDENTIAL 
 
22-MAY-2017 
 16 Mar 2012  
DOCUMENT HISTORY 
Version 
Date 
Author 
Description 
0.1 
14-OCT-2016 
 
Initial Draft 
0.2 
23-NOV-2016 
 
Updated sponsor comments 
from original draft 
0.3 
09-MAY-2017 
 
• Updated to keep only 
Safety population,  
• Tables will only have 
overall column,  
• Remove all efficacy 
analyses,  
• Analysis  from Baseline of 
HZNP-ACT-301 to Week 
26 of HZNP-ACT-302 
(52-week treatment 
duration) will not be 
performed 
• Updated TOC to reflect 
removed analyses,  
• added note that analyses is 
only for abbreviated CSR 
report  
1.0 
22-MAY-2017 
 
Updated for finalization of 
Document 
 
 
 




Protocol: HZNP-ACT-302 
 
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CONFIDENTIAL 
 
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TABLE OF CONTENTS 
DOCUMENT HISTORY ..................................................................................................2 
SIGNATURE PAGE AND APPROVALS ......................................................................3 
TABLE OF CONTENTS ..................................................................................................4 
ABBREVIATIONS ............................................................................................................6 
1. 
OVERVIEW ...........................................................................................................7 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................7 
2.1 
Study Objectives ..........................................................................................7 
2.1.1 Primary Objective ............................................................................7 
2.1.2 Secondary Objectives.......................................................................8 
2.2 
Study Endpoints ...........................................................................................8 
2.2.1 Safety Endpoints ..............................................................................8 
3. 
OVERALL STUDY DESIGN AND PLAN .........................................................8 
4. 
ANALYSIS AND REPORTING ........................................................................12 
4.1 
Interim Analysis .........................................................................................12 
4.2 
Final Analysis ............................................................................................12 
5. 
ANALYSIS POPULATIONS .............................................................................12 
5.1 
Sample Size ................................................................................................12 
6. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................12 
6.1 
Visit Windows ...........................................................................................13 
6.2 
Data Adjustments, Handling, Conventions ................................................13 
6.3 
Derived and Computed Variables ..............................................................13 
7. 
STUDY SUBJECTS AND DEMOGRAPHICS.................................................14 
7.1 
Disposition of Subjects and Withdrawals ..................................................14 
7.2 
Protocol Violations and Deviations ...........................................................14 
7.3 
Demographics and Other Baseline Characteristics ....................................14 
8. 
EFFICACY ANALYSIS ......................................................................................15 
9. 
SAFETY AND TOLERABILITY ANALYSIS .................................................15 
9.1 
Adverse Events ..........................................................................................16 
9.1.1 Deaths ............................................................................................16 
9.2 
Clinical Laboratory Evaluations ................................................................16 
9.2.1 Immunogenicity Testing ................................................................16 
9.3 
Vital Signs ..................................................................................................16 


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9.4 
Electrocardiogram (ECG) and Echocardiogram ........................................17 
9.5 
Concomitant Medication ............................................................................17 
9.6 
Exposure and Compliance .........................................................................17 
10. 
CHANGES FROM PLANNED ANALYSIS .....................................................17 
11. 
REFERENCES .....................................................................................................17 
12. 
TABLES, LISTINGS, AND FIGURES .............................................................18 
13. 
PLANNED TABLES ...........................................................................................20 
14. 
PLANNED LISTINGS ........................................................................................21 
 


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ABBREVIATIONS 
 
ABBREVIATION DEFINITION OR DESCRIPTION 
9-HPT 
9-hole peg test 
ADA 
Anti-Drug Antibody 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BSA 
Body Surface Area 
CI 
Confidence Interval 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FA 
Friedreich’s Ataxia 
FARS 
Friedreich’s Ataxia Rating Scale 
FARS-mNeuro 
Friedreich’s Ataxia Rating Scale excluding the peripheral nervous system 
subscale score and the facial and tongue atrophy and fasciculations from 
the bulbar subscale score 
FARStot 
Total FARS Score 
FDA 
Food and Drug Administration 
ICH 
International Conference on Harmonisation 
IFN 
interferon 
LCSLC 
Low-contrast sloan letter chart 
LLOQ 
Lower Limit of Quantitation 
LOD 
Limit of Detection 
LiSN-S 
Listening in Spatialized Noise-Sentences Auditory Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFIS 
Modified Fatigue Impact Score 
NAb 
Neutralizing Antibody 
PedsQL 
Pediatric Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF-36 
36-item short-form health survey 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
T25FW 
Timed 25-foot-walk 
TIW 
Three times a week 
TEAE 
Treatment-emergent Adverse Event 
ULOQ 
Upper Limit of Quantitation 
WHO-DD 
World Health Organization Drug Dictionary 
 


Protocol: HZNP-ACT-302 
 
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Final Version 1.0 
 
CONFIDENTIAL 
 
22-MAY-2017 
 16 Mar 2012  
1. OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Horizon 
Pharma Ireland, Ltd. protocol HZNP-ACT-302 (Multicenter, Safety and Efficacy, Open-Label 
Extension Study of ACTIMMUNE® (interferon γ-1b) in Children and Young Adults with 
Friedreich’s Ataxia), Final Version 2.0 incorporating Amendment 1, dated 28-SEP-2016. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials [1]. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association [2] and the Royal Statistical 
Society [3], for statistical practice. 
The planned analysis identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analysis not 
necessarily identified in this SAP may be performed to further examine study data. Any post-
hoc, or unplanned, exploratory analysis performed will be clearly identified as such in the final 
CSR. 
In addition to the study protocol, the following documents were reviewed in preparation of this 
SAP: 
• The electronic case report forms (eCRFs) for this Protocol 
• ICH Guidance on Statistical Principles for Clinical Trials (E9). 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified 
documents, for details on the planned conduct of this study. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objectives of this study are: 
 
• To evaluate the long-term safety of ACTIMMUNE in subjects with Friedreich’s Ataxia 
(FA). 
• To evaluate the effect of ACTIMMUNE (interferon [IFN]-γ 1b) on the change from 
Baseline of HZNP-ACT-302 to Week 26 for all subjects and from Baseline of HZNP-
ACT-301 to Week 26 of HZNP-ACT-302 (52-week treatment duration) for subjects 
receiving active treatment in both studies in neurological outcomes as measured by 
Friedreich’s Ataxia Rating Scale (FARS) excluding the peripheral nervous system 
subscale score and the facial and tongue atrophy and fasciculations from the bulbar 
subscale score (FARS-mNeuro score). 


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2.1.2 Secondary Objectives 
The secondary objectives of this study are to evaluate the effect of ACTIMMUNE (interferon 
[IFN]-γ 1b) on the change from Baseline(HZNP-ACT-302) to Week 26 for all subjects and from 
Baseline of HZNP-ACT-301 to Week 26 of HZNP-ACT-302 (52-week treatment duration) for 
subjects receiving active treatment in both studies for the following: 
• Activities of Daily Living (ADL) 
• The timed 25-foot-walk-test (T25FW) 
• Responder rate (≥3 point improvement in the FARS-mNeuro score) 
• Neurological outcome as measured by the total FARS score (FARStot) 
2.2 
Study Endpoints 
The analysis for this study is for an abbreviated safety Clinical Study Report (CSR).  All efficacy 
endpoints mentioned in the protocol have been removed and noted as changes to the planned 
analyses. 
2.2.1 Safety Endpoints 
Adverse event and concomitant medication data will be summarized. Clinical laboratory safety 
data, vital sign data, echocardiogram data, and ECG interval data will be summarized with 
descriptive statistics for Baseline of HZNP-ACT-302, post-dose, and change from Baseline of 
HZNP-ACT-302 to post-dose values. Shift tables will be presented for clinical laboratory values 
and ECG categorical results from Baseline of HZNP-ACT-302 to each post-dose visit. Physical 
examination findings will be listed by subject. Results of immunogenicity testing will be 
presented in tabular format. 
3. OVERALL STUDY DESIGN AND PLAN 
This is a multi-center, dose-escalation, open-label extension study of HZNP-ACT-301 examining 
the safety and efficacy of ACTIMMUNE in the treatment of FA in children and young adults. 
Subjects who complete 26 weeks of blinded treatment in HZNP-ACT-301 will be eligible for 
enrollment in this study. In order to maintain the study blind in HZNP-ACT-301, all subjects in 
the open-label extension study will undergo ACTIMMUNE titration, regardless of treatment 
received in HZNP-ACT-301. The sample size is not based on statistical considerations. 
The overall maximum treatment duration for an individual subject is expected to be 26 weeks, 
with a Follow-Up Safety Visit two weeks following last dose of study drug. As per the study 
design and schedule of events below (Table 1, Table 2), subjects will all be assigned to start on 
ACTIMMUNE 10 µg/m2 in the first week. This will be followed by weekly escalation to 25, 50, 
and 100 µg/m2three times a week (TIW) on Days 8, 15, and 22, respectively. The study drug 
dose is planned to be escalated on a weekly basis over the first 4 weeks of treatment (from 
10µg/m2to 100 µg/m2), however, the dose may be reduced, interrupted, or held based on 
tolerability. By Week 13, all subjects are to be on a stable tolerated dose of study drug in order to 
continue study participation. 
 
 


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Table 1. Study Design 
 


Protocol: HZNP-ACT-302                                                                                        Page 10 of 21 
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Table 2.Schedule of Events 
 
 
 
 
 
 


Protocol: HZNP-ACT-302                                                                                        Page 11 of 21 
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CONFIDENTIAL 
22-MAY-2017 
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Protocol: HZNP-ACT-302                                                                                        Page 12 of 21 
Final Version 1.0 
 
CONFIDENTIAL                                                                                               22-MAY-2017 
 16 Mar 2012  
4. ANALYSIS AND REPORTING 
4.1 Interim Analysis 
No formal interim analysis is planned for this study, but the study will be monitored by a Data 
Safety Monitoring Board (DSMB), which will advise the Sponsor regarding the continuing 
safety of study subjects and potential subjects as well as the continuing validity and scientific 
merit of the trial. 
4.2 Final Analysis 
All final, planned analysis identified in the protocol and in this SAP will be performed after the 
last subject has completed the Follow-up Safety Visit and all relevant study data have been 
processed and integrated into the analysis data base.  
Any post-hoc, exploratory analysis completed to support planned study analysis, which were not 
identified in this SAP, will be documented and reported in appendices to the CSR. Any results 
from these unplanned analyses (post-hoc) will also be clearly identified in the text of the CSR. 
5. ANALYSIS POPULATIONS 
The following analysis populations are planned for this study: 
• Safety Population (SAFETY): The Safety Population includes all subjects who receive 
at least one dose of open-label study drug after the Baseline Visit for HZNP-ACT-302.  
All analyses will be based on the Safety Population unless otherwise noted. 
5.1 Sample Size 
Subjects who complete 26 weeks of blinded treatment in Study HZNP-ACT-301 will be eligible 
for enrollment. The sample size is not based on statistical considerations; therefore no inference 
will be drawn from any statistical tests conducted. 
6. GENERAL ISSUES FOR STATISTICAL ANALYSIS 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed using SAS® Software (release 9.3 or higher) for 
Windows, unless otherwise specified. 
Continuous (quantitative) variables will be summarized using descriptive statistics including 
number of non-missing values, mean, standard deviation (SD), median, minimum, and 
maximum.  
Categorical (qualitative) variables will be summarized using the number and proportion of each 
possible value. In general, the denominator for the percentage calculation will be based upon the 
total number of subjects in the study population for the treatment group.  
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the raw data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the raw data and measures of spread (standard 
deviation) will be reported to two degrees of precision more than the raw data. 
Assessments done on unscheduled visits will not be summarized but will be listed. All analyses 
will be completed on the Safety Population unless otherwise specified. Additionally, all 
summaries will be presented by overall treatment. 


Protocol: HZNP-ACT-302                                                                                        Page 13 of 21 
Final Version 1.0 
 
CONFIDENTIAL                                                                                               22-MAY-2017 
16 Mar 2012  
All final, planned analyses identified in the protocol and in this SAP will be performed after all 
relevant study data have been processed and integrated into the analysis database, analysis 
populations have been finalized, and the database has been locked. Any post-hoc, exploratory 
analysis completed to support planned study analyses, which were not identified in this SAP, will 
be documented and reported in Section 9.8 of the CSR. Any results from these unplanned 
analyses (post-hoc) will also be clearly identified as subject in the text of the CSR. 
6.1 Visit Windows 
Subjects who withdraw from the study will have their data collected at the premature withdrawal 
(PW) visit assigned to the closest scheduled visit (either prior or post PW) where the data was 
scheduled to have been collected based on the protocol schedule of events. The data collected 
closest in time and date to protocol scheduled timing will be used for analysis. 
6.2 Data Adjustments, Handling, Conventions 
All collected data will be presented in listings. Data not subject to analyses according to this plan 
will not appear in any tables or graphics but will be included only in the data listings. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
(version 16.1). Concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHO-DD) (version March 1, 2013). 
If partial dates occur, the convention for replacing missing dates for the purposes of calculating 
derived variables is as follows: 
If an AE has a missing severity, it will be imputed as ‘Severe’; any missing relationship to study 
drug of an AE will be imputed as ‘Related’. No other missing data will be imputed unless 
otherwise specified. 
In general, for quantitative laboratory values reported as ‘<’ or ‘≤’, the lower limit of 
quantitation (LLOQ), or limit of detection (LOD), the reported value (i.e., LLOQ, LOD) will be 
used for analysis). 
For quantitative laboratory values reported as ‘>’ or ‘≥’, the upper limit of quantitation (ULOQ), 
the reported value (i.e., ULOQ) will be used for analysis. 
For analysis purposes, repeat laboratory test results will not be used unless the original 
laboratory value is missing or indicated as invalid, in which case the first non-missing repeat 
laboratory value will be used for data analysis. 
6.3 Derived and Computed Variables 
The following derived and computed variables have been initially identified as important for the 
analyses of Safety, Efficacy and Exploratory endpoints. It is expected that additional variables 
may be required. The SAP will not be amended for additional variables that are not related to the 
primary target or key secondary target variables. Any additional derived or computed variables 
will be identified and documented in the SAS programs that create the analysis files. If the SAP 
is not amended, further derivations related to primary and secondary target variables will be 
described in the CSR. 
• 302 Baseline = The last non-missing measurement/assessment on the date of Week 26 
Visit from HZNP-ACT-301.  If this measurement is missing or otherwise unavailable, it 
will be the last non-missing measurement/assessment on or prior to first dose in HZNP-


Protocol: HZNP-ACT-302                                                                                        Page 14 of 21 
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16 Mar 2012  
ACT-302. 
• 301 Baseline = The last non-missing measurement/assessment prior to first dose of Study 
in HZNP-ACT-301. 
• Study Day = Assessment Date – Date of Enrollment + 1 
• Change from Baseline = Value at Post-Baseline – Value at Baseline 
• Concomitant Medication is defined as any medication a subject has received concurrently 
with study treatment. 
• Prior Medication is defined as any medication or therapies initiated prior to date of first 
dose of study drug. Medications that are started prior to the date of first dose of study 
drug and continue after the first dose of drug are considered to be both prior and 
concomitant medications. 
• Treatment-Emergent Adverse Event (TEAE) – A TEAE is any adverse change from the 
subject’s baseline condition that occurs on or after the date of the first dose of study drug 
through the duration of the clinical study. 
• Related TEAE – Any TEAE with a reported relationship to study drug of ‘possibly 
related’. 
• Compliance = Calculated as the percentage of the number of vials used divided by the 
expected number of vials used, where the number of vials used is the number of used 
vials returned. 
7. STUDY SUBJECTS AND DEMOGRAPHICS 
7.1 Disposition of Subjects and Withdrawals 
All subjects who provide informed consent/assent will be accounted for in this study. The 
number of subjects enrolled, completing, and withdrawing from the study, as well as reason for 
withdrawal, will be summarized by overall treatment. All disposition information will be 
included in a listing. 
7.2 Protocol Violations and Deviations 
Protocol deviations will be collected by the clinical team and provided to Premier biostatistics 
prior to database lock. Deviations will be reviewed on a case-by-case basis to be classified as 
major or minor by the project team prior to database lock. Major and minor deviations will be 
included in a listing. 
7.3 Demographics and Other Baseline Characteristics 
Descriptive summaries and frequencies/percentages of demographic and other baseline 
characteristics will be completed for all enrolled subjects in the safety population for data 
collected in HZNP-ACT-301. These tabulations will include the following variables: 
• Demographics (age, age categories (10-16 inclusive, and 17 and above), gender, race, 
ethnicity, height, weight, and Body Surface Area (BSA)) 
Tabulations of baseline HZNP-ACT-301 efficacy assessments will include the following in a 
separate table: 


Protocol: HZNP-ACT-302                                                                                        Page 15 of 21 
Final Version 1.0 
 
CONFIDENTIAL                                                                                               22-MAY-2017 
16 Mar 2012  
• FA Functional Stage  
• FARS-mNeuro score 
• ADL 
• T25FW 
• FARStot 
Descriptive summaries and frequencies/percentages of demographic and other baseline 
conditions in separate tabulations will include the following: 
• Medical History 
• Prior Medications 
• Baseline Physical Examination 
Medical History: Incidences of findings in medical history will be summarized by System Organ 
Class and preferred term.  
Prior Medications: The frequency and percentage of all prior medications will be summarized by 
Anatomical Therapeutic Chemical (ATC) classifications level 3 and preferred term for all 
subjects. Subjects will only be counted once within ATC and preferred term. These data will be 
grouped by overall treatment. 
Baseline physical examination: Baseline physical examination will be summarized by body 
system and result by overall treatment. 
8. EFFICACY ANALYSIS 
All analyses are being conducted for an abbreviated safety CSR, and no efficacy analysis will be 
carried out. 
9. SAFETY AND TOLERABILITY ANALYSIS 
The analysis of safety assessments in this study will include summaries of the following 
categories of safety and tolerability data collected for each subject: 
• Adverse Events 
o Summary of all Adverse Events 
o TEAEs, and Serious Adverse Events (SAEs) 
o TEAEs by severity 
o TEAEs by relationship to study drug 
o TEAEs leading to premature withdrawal 
o Any deaths 
• Clinical Laboratory Investigations  
o Complete Blood Count 
o PT, INR, and aPTT 
o Chemistry panel 
o Urinalysis 
o Immunogenicity samples 
• Electrocardiograms (ECG) 
• Echocardiograms 
• Physical Examinations 
• Concomitant Medications 


Protocol: HZNP-ACT-302                                                                                        Page 16 of 21 
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• Study Drug Exposure and Treatment Compliance 
All tabulations and summaries for these categories will be performed on the safety population 
unless otherwise noted. 
9.1 Adverse Events 
Missing and partially missing AE start and/or stop dates will be imputed for the purpose of 
statistical analysis, according to the specifications described in Section 6.1. 
A summary of overall TEAEs, TEAEs, SAEs, TEAEs leading to PW, TEAEs by relationship to 
study drug, and severity of TEAEs will be presented by overall treatment. 
Summaries and incidence rates (frequencies and percentages) of individual TEAEs by MedDRA 
System Organ Class (SOC) and preferred term will be displayed by overall treatment received. 
Such summaries will be displayed for TEAEs, SAEs, TEAEs leading to early termination, 
TEAEs by relationship to study drug, and TEAEs by severity 
Each subject will be counted only once within each preferred term. If a subject experiences more 
than one TEAE within a preferred term only the TEAE with the strongest relationship or the 
maximum intensity, as appropriate, will be included in the summaries of relationship and 
intensity. No inferential statistical tests will be performed. 
In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent will be 
flagged. 
9.1.1 Deaths 
A summary and data listing of deaths that occurred will be provided, displaying details of the 
event(s) captured on the CRF. 
9.2 Clinical Laboratory Evaluations 
Descriptive summaries of actual (absolute) values and changes from baseline will be presented 
for Chemistry, Urinalysis, Complete Blood Count, PR, INR, and aPTT. These tables will be 
grouped by visit, and overall treatment. 
The number and proportion of subjects with clinical laboratory values below, within, or above 
normal ranges, at each study visit will be tabulated (shift tables) for each clinical laboratory 
analyte by treatment group. Normal ranges will be provided by the central laboratory (URMC) 
used in this study. 
Laboratory values will be displayed in data listings and those that are outside the normal range 
will be flagged, along with the corresponding normal ranges. 
9.2.1 Immunogenicity Testing 
Frequency and percentages of positive anti-drug antibodies (ADA) and neutralizing antibodies 
(NAb) will be summarized by scheduled visit, and overall treatment received. Additionally, 
immunogenicity data will be presented in a data listing. 
9.3 Vital Signs 
Descriptive summaries of actual (absolute) values and changes from baseline will be presented 
for all vital signs (temperature, systolic blood pressure, diastolic blood pressure, heart rate), 


Protocol: HZNP-ACT-302                                                                                        Page 17 of 21 
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weight, height, and BSA will be presented by visit and overall treatment. These data will be 
presented in a data listing by subject. 
9.4 Electrocardiogram (ECG) and Echocardiogram 
Descriptive summaries of actual (absolute) values and changes from baseline will be presented 
for ECG quantitative measures (heart rate, PR interval, QRS duration, QT interval and QTC 
interval). These data will be summarized by visit and overall treatment. 
Additionally, the frequency and percentage of subjects with normal, abnormal not clinically 
significant, and abnormal clinically significant ECGs will be summarized by visit. Shift tables 
will also be presented and display the number of subjects who had values that shifted from their 
baseline result. 
Echocardiogram data will be summarized for left ventricular hypertrophy, left ventricle dilated, 
ejection fraction (%), PWTd (cm), IVSTd (cm), LVOT peak velocity (m/sec), LVOT obstruction 
(y/n). 
Left centricular hypertrophy, left ventricle dilated and LVOT obstruction will be counted by the 
frequency and percentage of subjects with, without, and unknown within ventricular category. 
Ejection fraction, PWTd (cm), IVSTd (cm), and LVOT peak velocity (m/sec), will be 
summarized by descriptive statistics. 
ECG and Echocardiogram data will be presented by subject in separate data listings. 
9.5 Concomitant Medication 
Concomitant medications will be analyzed the same way as prior medications as noted in Section 
7.3.  The frequency and percentage of all concomitant medications will be summarized by ATC 
classification level 3 and preferred term for all subjects. Subjects will only be counted once 
within ATC and preferred term. These data will be grouped by overall treatment. A listing of 
prior and concomitant medications will be presented by subject. 
9.6 Exposure and Compliance 
For each subject, treatment compliance and exposure will be calculated and summarized for the 
entire study. Overall compliance and exposure will be summarized and grouped by overall 
treatment. Compliance is defined in Section 6.3. Drug accountability, exposure, and treatment 
compliance will also be provided in a subject listing. 
10. CHANGES FROM PLANNED ANALYSIS 
All efficacy analyses has been removed from the study as described in the protocol. 
11. REFERENCES 
US Federal Register. (1998) International Conference on Harmonization; Guidance on Statistical 
Principles for Clinical Trials. Department of Health and Human Services: Food and Drug 
Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179, pages 
49583-49598. September 16, 1998. 
ASA. (1999) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, August 7, 1999.http://www.amstat.org/about/ethicalguidelines.cfm 
RSS. (1993) The Royal Statistical Society: Code of Conduct, April 1993. 
http://www.rss.org.uk/main.asp?page=1875. 


Protocol: HZNP-ACT-302                                                                                        Page 18 of 21 
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12. TABLES, LISTINGS, AND FIGURES 
This section presents the list of shells for the planned Tables, Listings and Figures to be 
programmed in support of the planned analyses identified in the SAP. This section is intended to 
support the SAP and provides guidance on the programming specifications (shells) for the 
planned outputs and may be updated, independent of the SAP, with any updates appropriately 
documented, reviewed, and approved. 
The following reporting conventions will be adopted for the presentation of study data.  These 
conventions will enhance the review process and help to standardize the presentation with 
common notations. 
       General Reporting Conventions 
• All tables and data listings will be developed in landscape orientation. 
• Specialized text styles, such as bolding, italics, borders, shading, superscripted and 
subscripted text will not be used in tables and data listings unless they add significant 
value to the table, figure, or data listing.  
• Only standard keyboard characters should be used in tables and data listings. Special 
characters, such as nonprintable control characters, printer-specific characters, or font 
specific characters, will not be used on a table, figure, or data listing. Hexadecimal 
character representations are allowed (e.g., µ,α,β). 
• All titles will be centered on a page. The ICH numbering convention is to be used for all 
outputs. 
• All footnotes will be left justified and at the bottom of a page.   
• Missing values for both numeric and character variables will be presented as blanks in a 
table or data listing. A value of zero may be used if appropriate to identify when the 
frequency of a variable is not observed. 
• All date values will be presented as ddmmmyyyy (e.g., 29AUG2011) format.  A 4-digit 
year is preferred for all dates. 
• If applicable, all observed time values will be presented by using a 24-hour clock 
HH:MM:SS format (e.g., 01:35:45 or 11:26). Seconds should only be reported if they 
were measured as part of the study.  
• All tables and data listings will have the name of the program, the location, and a date 
stamp on the bottom of each output.  
Population Summary Conventions 
• Population sizes may be presented for each classification factor as totals in the column 
header as (N=xxxx), where appropriate.  
• Population sizes shown with summary statistics are the samples sizes (n) of subjects with 
non-missing values.  
• All population summaries for categorical variables will include all categories that were 
planned and for which the subjects may have had a response. Percentages corresponding 
to null categories (cells) will be suppressed; however counts and percentages of missing 
values may be needed. 


Protocol: HZNP-ACT-302                                                                                        Page 19 of 21 
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• All population summaries for continuous variables will include: N, mean, SD, minimum, 
and maximum. Other summaries (e.g., number missing, geometric mean, median, 
quartiles, 95% CIs, and coefficient of variation (CV) or % CV) may be used as 
appropriate.  
• All percentages are rounded and reported to a single decimal point (xx.x %). A 
percentage of 100% will be reported as 100%. 
• Population summaries that include P-values will report the P-value to 4 decimal places 
with a leading zero (0.0001). All P-values reported on default output from statistical 
software (i.e., SAS® Software) may be reported at the default level of precision. P-values 
<0.0001 should be reported as <0.0001 not 0.0000.