Conditions: Friedreich's Ataxia
Keywords: ACTIMMUNE interferon y-1b
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 38
Healthy volunteers: no

Brief summary:
The purpose of this long term extension study is to evaluate the long-term safety of ACTIMMUNE® (interferon-γ 1b) in participants with Friedreich's Ataxia (FA).

Detailed description:
This is a multi-center, open-label, long-term safety extension study of ACTIMMUNE® in the treatment of FA in children and young adults. Participants who complete 26 weeks of treatment and the Week 28 Follow-Up Visit in HZNP-ACT-302 (NCT02593773) will be eligible to enter this long-term safety extension protocol. The Day 1 Visit of this study (HZNP-ACT-303) occurs on the same day as the Week 28 Follow-Up Visit for HZNP-ACT-302 (NCT02593773). Participants will be required to return for clinic visits at least every 6 months. The treatment duration is open-ended, and treatment will continue until ACTIMMUNE® is commercially available for the treatment of FA in the United States or until the Sponsor decides not to continue development for the treatment of FA.

Arms:
arm 1: ACTIMMUNE® will be administered 3 times per week (TIW) by subcutaneous (SC) injection.

Interventions: intervention 1: interferon γ-1b
Intervention descriptions: intervention 1: ACTIMMUNE® will be administered three times per week by subcutaneous injection. The initial dose will be individualized for each participant and will be determined by the investigator, provided that the initial dose does not exceed the maximum tolerated dose in HZNP-ACT-302 (NCT02593773). The investigator may subsequently adjust the dose for any participant if deemed clinically appropriate, provided that the dose does not exceed 100 μg/m².

Protocol document:
Prot_000.pdf: 
Horizon Pharma Ireland Ltd. 
 
ACTIMMUNE IND: 123947 
Date: 05 April 2016 
 
Protocol: HZNP-ACT-303 
 
 
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CLINICAL STUDY PROTOCOL  
FOR ACTIMMUNE® 
IND: 123947 
Protocol Number: HZNP-ACT-303 
Version 1.0 
 
Long-Term Safety Extension Study of ACTIMMUNE® (interferon γ-1b) in 
Children and Young Adults with Friedreich’s Ataxia 
Short title: STEADFAST Long-Term Safety Extension 
Safety, Tolerability and Efficacy of ACTIMMUNE® Dose Escalation in 
Friedreich’s Ataxia Study 
Date: 05 April 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: 05 April 2016 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
HZNP-ACT-303 
Version: 
1.0 
Protocol Title: 
Long-Term Safety Extension Study of ACTIMMUNE® (interferon γ-1b) 
in Children and Young Adults with Friedreich’s Ataxia 
Version Date: 
05 April 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 
 
 
 
 


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2. 
SYNOPSIS 
Protocol Title: Long-Term Safety Extension Study of ACTIMMUNE® (interferon γ-1b) in Children and Young 
Adults with Friedreich’s Ataxia 
Protocol Number: HZNP-ACT-303 
Phase: 3 
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. 
Objective: 
Evaluate the long-term safety of ACTIMMUNE in subjects with FA. 
Study Design: 
This is a multi-center, open-label, long-term safety extension study of ACTIMMUNE in the treatment of FA in 
children and young adults. Subjects who complete 26 weeks of treatment and the Week 28 Follow-Up Visit in 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) will be eligible to enter this long-term safety extension protocol. 
The Day 1 Visit of this study (HZNP-ACT-303) occurs on the same day as the Week 28 Follow-Up Visit for HZNP-
ACT-302.  
The treatment duration is open-ended, and treatment will continue until ACTIMMUNE is commercially available for 
the treatment of FA in the United States (US) or until the Sponsor decides not to continue development for the 
treatment of FA. The initial dose of ACTIMMUNE will be individualized for each subject and will be determined by 
the investigator, provided that the initial dose does not exceed the maximum tolerated dose in HZNP-ACT-302. The 
investigator may subsequently adjust the dose for any subject if deemed clinically appropriate, provided that the dose 
does not exceed 100 µg/m2. Dose adjustments, including the reason for the change, will be recorded on the appropriate 
electronic case report form. All doses of ACTIMMUNE will be administered by subcutaneous injection three times a 
week (TIW) at home. 
Subjects will be required to return for clinic visits at least every six months. At each 6-month assessment clinic visit, 
subjects will be dispensed a 3-month supply of study drug, and an additional 3-month supply will be directly shipped 
to the subjects’ home in between the required 6-month clinic visits. Subjects who are not able to receive study drug 
shipments at their home will return to the clinic for interim clinic visits three months after the Baseline and 6-month 
assessment visits to obtain study drug; however, assessments (other than enquiries regarding adverse events and 
concomitant medications) will only be performed every six months. Subjects who are able to receive direct-to-home 
shipments will be contacted by telephone at the 3-month interim visits and queried regarding adverse events and 
concomitant medication use. 
At each 6-month assessment visit, subjects will be queried about any adverse events that occurred since the last visit, 
concomitant medication use, and undergo brief physical examinations (including vital sign monitoring) and blood 
sample collection for routine clinical laboratory safety tests. If applicable, urine samples will be collected for 
pregnancy testing.  
At the time ACTIMMUNE becomes commercially available or if development is ceased for the treatment of FA, 
subjects who are active on study will return to the clinic while still on study drug and undergo electrocardiogram 
(ECG) and Friedreich’s Ataxia Rating Scale (FARS) assessments in addition to the above 6-month safety assessments 
at an End-of-Study (EOS) Visit prior to transitioning to the commercial product or discontinuing study drug. Subjects 
who prematurely withdraw from the study will have EOS assessments completed within two weeks of study drug 
discontinuation.  
Details of study activities are provided in Section 2.1, Schedule of Assessments. 
Subject Population: 
Male and non-pregnant female subjects who completed 26 weeks of treatment and the Week 28 Follow-Up Visit in 
Study HZNP-ACT-302 will be eligible for enrollment. 


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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 treatment and the Week 28 Follow-Up Visit in Study HZNP-ACT-302. 
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 Week 26 of Study HZNP-ACT-302, 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 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: 
ACTIMMUNE will be administered TIW by subcutaneous injection. The initial dose will be individualized for each 
subject and will be determined by the investigator, provided that the initial dose does not exceed the maximum 
tolerated dose in HZNP-ACT-302. The investigator may subsequently adjust the dose for any subject if deemed 
clinically appropriate, provided that the dose does not exceed 100 µg/m2. 
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. 
Duration of Treatment and Follow-Up: 
The planned treatment duration is open-ended, and treatment will continue until ACTIMMUNE is commercially 
available for the treatment of FA in the US or until the Sponsor decides not to continue development for this 
indication. 
Criteria for Evaluation: 
Efficacy will be assessed using the FARS. 
Safety assessments will include adverse event monitoring, concomitant medication monitoring, physical examinations, 
vital signs, ECGs, clinical safety laboratory evaluations (complete blood count, chemistry, and urinalysis), and 
pregnancy testing (if applicable). 
Statistical Analyses: 
No formal statistical hypothesis testing will be performed.  
FARS results (FARS total score [FARStot] and the FARS score excluding the peripheral nervous system subscale 
score and the facial and tongue atrophy and fasciculations from the bulbar subscale score [FARS-mNeuro score]) will 
be summarized with descriptive statistics for the EOS Visit. For statistical purposes, the FARS results for the last on-
treatment visit in HZNP-ACT-302 (Week 26) and the change from the Week 26 HZNP-ACT-302 Visit to the EOS 
Visit in this study will also be summarized. 
Adverse event and concomitant medication data will be summarized. Vital sign and clinical safety laboratory data will 
be summarized with descriptive statistics for Baseline, post-dose, and change from Baseline to post-dose values, and 
shift tables will be presented for clinical laboratory values from Baseline to each post-dose visit. The ECG analysis 
will use the same approach as described above for the FARS analysis. 
Physical examination findings will be listed by subject. 
Sample Size Estimate: 
Subjects who complete 26 weeks of treatment and the Week 28 Safety Follow-Up Visit in Study HZNP-ACT-302 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 
End-of-Study 
or Premature 
Withdrawal10 
 
Baseline6 
3-Month 
Visits8 
6-Month 
Visits 
Study Days (± visit window) 
Day 1  
(Week 28 of  
Study HZNP-ACT-302) 
90 (± 7) 
Days after 
Last Visit 
Every 180  
(± 14) Days 
 
Informed consent/assent 
X 
 
 
 
Medical history1 
X 
 
 
 
Review of inclusion/exclusion criteria 
X 
 
 
 
Dispense study drug2 
X 
X9 
X 
 
Drug compliance3 
 
X9 
X 
X 
TEAE, SAE assessment4 
X7 
X 
X 
X 
Brief physical examination 
X7 
 
X 
X 
Vital Signs: blood pressure, pulse, 
temperature 
X 
 
X 
X 
Clinical laboratory evaluation  
(hematology, chemistry, urinalysis) 
X 
 
X 
X 
Electrocardiograms 
 
 
 
X11 
Urine pregnancy test5 
X 
 
X 
X 
FARS 
 
 
 
X11 
Prior/concomitant medications 
X7 
X 
X 
X 
SAE=serious adverse event, TEAE=treatment-emergent adverse event. 
1 Changes in medical history from the Baseline of HZNP-ACT-301 will be recorded on the electronic case report forms. The 
medical history from the HZNP-ACT-301 study will be available for reference. 
2 Subjects will be given a 3-month supply of study drug at each clinic visit and an additional 3-month supply will be directly 
shipped to the subjects’ home in between the required 6-month clinic visits. If direct shipments are not feasible, subjects will 
return to the clinic every three months to obtain study drug; however, assessments (other than adverse event queries) will only 
be performed every six months.  
3 Subjects will be instructed to return all used and unused study drug vials at each clinic visit. 
4 Adverse events occurring or worsening on or after the date of administration of the first dose of study drug through the end of 
the study will be considered treatment-emergent adverse events (TEAEs). All serious adverse events (SAEs) that occur on or 
after the date of administration of the first dose of study drug through two weeks after study discontinuation will be considered 
treatment-emergent SAEs (TESAEs) and will be recorded and reported to Horizon drug safety. 
5 Only for female subjects of childbearing potential. 
6 The Day 1 Visit of this study (HZNP-ACT-303) occurs on the same day as the EOS Visit (Week 28 Follow-Up Visit) for 
HZNP-ACT-302.  
7 Findings will be recorded for both the Day 1 (Baseline) Visit of this study and the Week 28 Follow-up Visit for HZNP-ACT-
302.  
8 Subjects who are not able to receive direct-to-home study drug shipments will return to the clinic for interim clinic visits three 
months after the Baseline and 6-month assessment visits; those who are able to receive direct-to-home shipments will be 
contacted by telephone. 
9 Perform at clinic visits only; those with telephone visits will receive/return study drug supplies at next clinic visit. 
10 Subjects who complete the study will undergo final assessments while still on study drug and will then be transitioned to 
commercial product. Subjects who prematurely withdraw from the study will have the EOS assessments completed within two 
weeks of study drug discontinuation. In the event the Sponsor decides to discontinue development for the treatment of FA, all 
subjects will be contacted and instructed to return to the clinic for final assessments while still on active drug. 
11 For statistical purposes, the last on-treatment visit from HZNP-ACT-302 (Visit 26) will be used to assess changes to the EOS 
assessment in this study.  
 


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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE .......................................................................................................................... 2 
2. 
SYNOPSIS .............................................................................................................................. 5 
2.1 
Schedule of Assessments ................................................................................................. 7 
3. 
TABLE OF CONTENTS ........................................................................................................ 8 
4. 
ETHICS ................................................................................................................................. 12 
4.1 
Institutional Review Board............................................................................................. 12 
4.2 
Ethical Conduct of the Study ......................................................................................... 12 
4.3 
Subject Information and Consent/Assent ....................................................................... 12 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE............................ 12 
6. 
INTRODUCTION ................................................................................................................ 13 
6.1 
Scientific Background .................................................................................................... 13 
6.2 
Rationale for the Study ................................................................................................... 15 
7. 
STUDY OBJECTIVES ......................................................................................................... 16 
7.1 
Study Objective .............................................................................................................. 16 
8. 
INVESTIGATIONAL PLAN ............................................................................................... 16 
8.1 
Overall Study Design and Plan ...................................................................................... 16 
8.2 
Discussion of Study Design ........................................................................................... 17 
8.3 
Selection of Study Population ........................................................................................ 17 
8.3.1 
Inclusion Criteria .................................................................................................... 17 
8.3.2 
Exclusion Criteria ................................................................................................... 18 
8.3.3 
Removal of Subjects from Therapy or Assessment ................................................ 18 
8.4 
Treatments ...................................................................................................................... 19 
8.4.1 
Treatments Administered ........................................................................................ 19 
8.4.1.1 Dose Adjustment Guidelines ............................................................................... 19 
8.4.2 
Identity of Investigational Products ........................................................................ 19 
8.4.2.1 ACTIMMUNE .................................................................................................... 19 
8.4.3 
Labeling .................................................................................................................. 19 
8.4.4 
Storage .................................................................................................................... 20 
8.4.5 
Study Drug Quality Issues ...................................................................................... 20 
8.4.6 
Drug Accountability................................................................................................ 20 


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8.4.7 
Study Drug Administration and Timing of Dose for each Subject ......................... 21 
8.4.7.1 Description of Clinical Supplies ......................................................................... 21 
8.4.7.2 Determination of Dose Volume .......................................................................... 21 
8.4.7.3 Details Concerning Timing and Dose Administration ........................................ 21 
8.4.8 
Method of Assigning Subjects to Treatment .......................................................... 22 
8.4.9 
Blinding................................................................................................................... 22 
8.4.10 
Concomitant Therapy and Restricted Medications ................................................. 22 
8.4.11 
Treatment Compliance ............................................................................................ 22 
8.5 
Efficacy and Safety Variables ........................................................................................ 22 
8.5.1 
Efficacy Variables ................................................................................................... 22 
8.5.1.1 Friedreich’s Ataxia Rating Scale (FARS) ........................................................... 23 
8.5.2 
Safety Variables ...................................................................................................... 23 
8.5.2.1 Adverse Events .................................................................................................... 23 
8.5.2.1.1 Definitions ..................................................................................................... 23 
8.5.2.1.2 Documentation of Adverse Events ................................................................ 25 
8.5.2.1.3 Grading of Adverse Events............................................................................ 26 
8.5.2.1.4 Relationship to Study Drug ........................................................................... 26 
8.5.2.1.5 Reporting and Documenting SAEs................................................................ 27 
8.5.2.1.6 Follow-Up of Adverse Events ....................................................................... 28 
8.5.2.1.7 Medication Error and Overdose .................................................................... 28 
8.5.2.1.8 Review of Adverse Events and Emerging New Safety Information ............. 29 
8.5.2.1.9 Reporting of Investigational New Drug (IND) Safety Reports ..................... 29 
8.5.2.2 Pregnancy Reporting ........................................................................................... 29 
8.5.2.3 Vital Signs ........................................................................................................... 29 
8.5.2.4 Brief Physical Examinations ............................................................................... 30 
8.5.2.5 Clinical Laboratory Tests .................................................................................... 30 
8.5.2.6 Electrocardiograms.............................................................................................. 30 
8.5.3 
Appropriateness of Measurements .......................................................................... 30 
8.5.4 
Study Procedures .................................................................................................... 30 
8.5.4.1 Baseline/Day 1 (Week 28 of Study HZNP-ACT-302)........................................ 30 
8.5.4.2 3-Month Visits..................................................................................................... 31 


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8.5.4.3 6-Month Assessment Clinic Visits ...................................................................... 32 
8.5.4.4 End-of-Study or Premature Withdrawal Visit ..................................................... 32 
8.6 
Statistical Methods and Determination of Sample Size ................................................. 32 
8.6.1 
Efficacy Variables ................................................................................................... 33 
8.6.2 
Safety Variables ...................................................................................................... 33 
8.6.3 
Populations for Analysis ......................................................................................... 33 
8.6.4 
Baseline Characteristics .......................................................................................... 33 
8.6.5 
Sample Size and Power Considerations .................................................................. 33 
8.7 
Changes in the Conduct of the Study ............................................................................. 33 
9. 
SOURCE DOCUMENTATION AND INVESTIGATOR FILES ....................................... 34 
10. 
CASE REPORT FORMS ................................................................................................. 34 
11. 
STUDY MONITORING .................................................................................................. 35 
12. 
DATA MANAGEMENT.................................................................................................. 36 
13. 
RETENTION OF RECORDS .......................................................................................... 36 
14. 
PUBLICATION ................................................................................................................ 36 
15. 
REFERENCES ................................................................................................................. 37 
16. 
APPENDICES .................................................................................................................. 40 
16.1 Administrative Appendix ............................................................................................... 40 
16.2 Approved US Labeling for ACTIMMUNE ................................................................... 41 
16.3 FARS Neurological Assessment .................................................................................... 51 
LIST OF TABLES 
Table 5.1 
Table of Non-Sponsor Study Responsibilities ........................................................... 13 
 


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LIST OF ABBREVIATIONS 
ATP 
adenosine triphosphate 
BLA 
Biologics License Application 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CGD 
chronic granulomatous disease 
CPI 
coordinating principal investigator 
CSM 
Clinical Supplies Management, Inc. 
DNA 
deoxyribonucleic acid 
DRG 
dorsal root ganglion  
eCRF 
electronic case report form 
EOS 
end-of-study 
FA 
Friedreich’s Ataxia 
FDA 
Food and Drug Administration 
FXN 
frataxin gene 
GAA 
guanine-adenine-adenine 
GCP 
Good Clinical Practice 
HDAC 
histone deacetylase 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
IIS 
Investigator-Initiated Study 
IFN-ɣ 
interferon gamma 
IFN- ɣ  1b 
ACTIMMUNE 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IU 
international units 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger RNA 
PBMC 
peripheral blood mononuclear cells 
PW 
premature withdrawal 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SC 
subcutaneous 
SMO 
severe, malignant osteopetrosis 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TIW 
three times per week 
URMC 
University of Rochester Medical Center 
US 
United States 
WHODrug 
World Health Organization Drug Dictionary 


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4. 
ETHICS 
4.1 
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. 
4.2 
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 for the treatment of FA; 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. 
4.3 
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. 
5. 
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 16.1 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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responsible for timely reporting of SAEs and any other new pertinent safety information to all 
investigators as required. 
The study will be conducted at approximately 4 study centers located in the US, with 
 
 at the Children’s Hospital of Philadelphia (CHOP) serving as the coordinating 
principal investigator (CPI) (Table 5.1). Prior to initiation of the study, each principal 
investigator will provide the Sponsor or its designee with a fully executed and signed Food and 
Drug Administration (FDA) Form 1572 and a Financial Disclosure Form. Financial Disclosure 
Forms will also be completed by all sub-investigators listed on the Form 1572. It is the 
responsibility of the investigators or sub-investigators to advise the Sponsor of any change in the 
relevant financial interests that occur during the study and the one year period following its 
completion. 
The Sponsor will perform the responsibilities of project management and study monitoring. Data 
management and safety summaries will be performed by Premier Research International, LLC 
(Durham, NC). Clinical Supplies Management, Inc. ([CSM] in Fargo, ND) will label the study 
drug, package the study drug into kits, and provide kits of study drug to the clinical sites as well 
as direct-to-subject shipments. SAE intake will be performed by Med Communications, Inc. 
(Memphis, TN). A central laboratory will be used for clinical safety laboratory tests (Table 5.1). 
Table 5.1 
Table of Non-Sponsor Study Responsibilities 
Study Responsibility 
Organization 
Coordinating Principal Investigator 
(CPI) 
 
Professor of Neurology 
The Children’s Hospital of Philadelphia (CHOP) 
SAE intake 
Med Communications, Inc. 
20 South Dudley, Ste. 700 
Memphis, TN 38103 
Data management and statistical 
analyses  
Premier Research International, LLC 
One Park Drive, Suite 150 
Durham, NC 27709 
Clinical drug supply 
Clinical Supplies Management, Inc. (CSM) 
342 42nd Street South 
Fargo, ND 58103 
Central safety laboratory 
University of Rochester Medical Center (URMC) 
77 Ridgeland Road 
Rochester, NY  14623 USA 
 
6. 
INTRODUCTION 
6.1 
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 


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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 Friedreich’s Ataxia 
(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.  
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 


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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, ACTIMMUNE is approved for use in the US in patients 
with CGD and SMO (see prescribing information in Section 16.2), and has been investigated in 
other conditions, including oncology, infectious diseases, and inflammatory disorders.  
6.2 
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. Ten of the subjects completed 12 
weeks of treatment, with the remaining two 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 adverse events 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 
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 adverse events 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. Subjects were able to continue in the study following 
dose reduction. 
Based on the results of the IIS, Horizon is currently conducting two studies with ACTIMMUNE. 
The first study (HZNP-ACT-301) is a randomized, multicenter, double-blind, placebo-controlled 


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26-week study evaluating the efficacy and safety of ACTIMMUNE administered to children and 
young adults with FA, and the second study (HZNP-ACT-302) is an open-label 26-week efficacy 
and safety extension of HZNP-ACT-301, in which all subjects who complete blinded treatment 
in HZNP-ACT-301 will be offered the opportunity to receive ACTIMMUNE for an additional 
26 weeks. As of 10 March 2016, 14 subjects had completed HZNP-ACT-301 and enrolled in 
HZNP-ACT-302, and it is projected that the first subject will complete HZNP-ACT-302 in June 
of 2016. Therefore, the Sponsor has designed this protocol to collect long-term safety data and to 
offer subjects who complete HZNP-ACT-302 the opportunity to continue receiving 
ACTIMMUNE until it is commercially available for the treatment of FA in the US or until the 
Sponsor decides to discontinue development for this indication. 
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 ACTIMMUNE 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. 
STUDY OBJECTIVES 
7.1 
Study Objective 
The objective is to evaluate the long-term safety of ACTIMMUNE in subjects with FA. 
8. 
INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan 
This is a multi-center, open-label, long-term safety extension study of ACTIMMUNE in the 
treatment of FA in children and young adults. Subjects who complete 26 weeks of treatment and 
the Week 28 Follow-Up Visit in 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) will be eligible to enter this long-term safety extension protocol. The Day 1 
Visit of this study (HZNP-ACT-303) occurs on the same day as the Week 28 Follow-Up Visit 
for HZNP-ACT-302. 
The treatment duration is open-ended, and treatment will continue until ACTIMMUNE is 
commercially available for the treatment of FA in the US or until the Sponsor decides to 
discontinue development for this indication. The initial dose of ACTIMMUNE will be 
individualized for each subject and will be determined by the investigator, provided that the 
initial dose does not exceed the maximum tolerated dose in HZNP-ACT-302. The investigator 
may subsequently adjust the dose for any subject if deemed clinically appropriate, provided that 
the dose does not exceed 100 µg/m2. Dose adjustments, including the reason for the change, will 
be recorded on the appropriate electronic case report form (eCRF). All doses of ACTIMMUNE 
will be administered by subcutaneous injection three times a week (TIW) at home. 


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Subjects will be required to return for clinic visits at least every six months. At each 6-month 
assessment clinic visit, subjects will be dispensed a 3-month supply of study drug, and an 
additional 3-month supply will be directly shipped to the subjects’ home in between the required 
6-month clinic visits. Subjects who are not able to receive study drug shipments at their home 
will return to the clinic for interim clinic visits three months after the Baseline and 6-month 
assessment visits to obtain study drug; however, assessments (other than queries regarding 
adverse events and concomitant medications) will only be performed every six months. Subjects 
who are able to receive direct-to-home shipments will be contacted by telephone at the 3-month 
interim visits and queried regarding adverse events and concomitant medication use. 
At each 6-month assessment visit, subjects will be queried about any adverse events that 
occurred since the last visit, concomitant medication use, and undergo brief physical 
examinations (including vital sign monitoring) and blood sample collection for routine clinical 
laboratory safety tests. If applicable, urine samples will be collected for pregnancy testing. 
At the time ACTIMMUNE becomes commercially available or if development is ceased for the 
treatment of FA, subjects will return to the clinic while still on active study drug and undergo 
electrocardiogram (ECG) and Friedreich’s Ataxia Rating Scale (FARS) assessments in addition 
to the above 6-month safety assessments at an End-of-Study (EOS) Visit prior to transitioning to 
the commercial product or discontinuing study drug. Subjects who prematurely withdraw from 
the study will have EOS assessments completed within two weeks of study drug discontinuation. 
8.2 
Discussion of Study Design 
The study population consists of subjects who completed Study HZNP-ACT-302; 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). 
8.3 
Selection of Study Population 
8.3.1 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 treatment and the Week 28 Follow-Up Visit in Study HZNP-
ACT-302. 
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 Week 26 of Study 
HZNP-ACT-302 and agree to use a reliable method of contraception throughout the study 
and for 30 days after the last dose of study drug. 


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8.3.2 Exclusion Criteria 
Subjects will be ineligible if, in the opinion of the Investigator, they have a concomitant disease 
or condition that could interfere with the conduct of the study or potentially put the subject at 
unacceptable risk.  
8.3.3 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 eCRF using one of the following categories: 
• Adverse event. The subject experiences an adverse event that imposes an unacceptable 
risk to the subject’s health, or the subject is unwilling to continue because of an adverse 
event. 
• 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. 
• 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 adverse event or lack of efficacy, the category of withdrawal 
should be marked in the corresponding category and not as voluntary withdrawal. 
• Study termination. The Sponsor, IRB, or regulatory agency terminates the study. 
• Pregnancy. 
Following premature withdrawal from the study, the subject or his/her legally acceptable 
representative will be contacted by telephone to enquire about any adverse events and 
concomitant medication use.  
Discontinued or withdrawn subjects will not be replaced. Subject identification numbers are 
unique and will not be reassigned. 


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8.4 
Treatments 
8.4.1 Treatments Administered 
All subjects will receive ACTIMMUNE. The planned treatment duration is open-ended, and 
treatment will continue until ACTIMMUNE is commercially available for the treatment of FA in 
the US or until the Sponsor discontinues development for this indication. 
8.4.1.1 Dose Adjustment Guidelines 
Subjects will receive SC doses of ACTIMMUNE TIW at home. The initial dose of 
ACTIMMUNE will be determined by the investigator for each subject, provided that the initial 
dose does not exceed the maximum tolerated dose in HZNP-ACT-302. The investigator may 
subsequently adjust the dose for any subject if deemed clinically appropriate, provided that the 
dose does not exceed 100 µg/m2.  
8.4.2 Identity of Investigational Products 
8.4.2.1 ACTIMMUNE 
ACTIMMUNE is a single-chain polypeptide containing 140 amino acids with a molecular 
weight of approximately 16,465 Daltons. ACTIMMUNE 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 
international units [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. 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 8.4.3) and assembling vials into kits. If a subject requires two vials per dose, the 
same volume should be removed from 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.  
8.4.3 Labeling 
CSM will label the ACTIMMUNE vials, assemble the study drug into kits, and ship kits to the 
study sites as well as provide direct-to-subject shipments.  
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 


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by US Federal law. Kit labels will also include the unique subject ID. Dosing instructions will be 
provided separately to the subject/caregiver. 
8.4.4 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; significant 
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. 
8.4.5 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. The clinic will notify the 
Sponsor and Med Communications, Inc. of any product complaints. 
8.4.6 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 the Sponsor or the Sponsor’s representative. Once accountability is 
completed, the Sponsor or it’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. 


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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. 
8.4.7 Study Drug Administration and Timing of Dose for each Subject 
8.4.7.1 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 as well as the direct-to-subject shipments. 
8.4.7.2 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 body surface area (BSA). The BSA will be calculated 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.  
Dose (µg/m2)  × BSA  × 0.005 mL/µg = ___ mL to be dosed 
For example, a subject who is 62 inches tall and weighs 100 pounds will have a BSA of 1.41 m2. 
If the dose is 100 µg/m2, the subject will receive 0.71 mL of study drug. 
100 µg/m2 × 1.41 m2 × 0.005 mL/µg = 0.705 mL, rounded to 0.71 mL of study drug 
8.4.7.3 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. If 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.  


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Subjects and their caregivers will be instructed to administer study drug on an outpatient basis 
TIW (e.g., a dosing schedule of Monday, Wednesday and Friday or Tuesday, Thursday, and 
Saturday) for the duration of the study.  
At each clinic visit, subjects and/or their caregivers will be dispensed a 3-month supply of study 
drug, and an additional 3-month supply will be directly shipped to the subjects’ home in between 
the required 6-month clinic visits. If direct shipments are not feasible, subjects will return to the 
clinic every three months to obtain study drug. At all post-Baseline clinic visits, subjects and/or 
their caregivers will return all unused kits and study drug vials. 
8.4.8 Method of Assigning Subjects to Treatment 
All subjects will receive ACTIMMUNE in this open-label extension study. 
Subjects will maintain the unique 6-digit subject ID number assigned in Study HZNP-ACT-301 
and carried through to Study HZNP-ACT-302; 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.  
8.4.9 Blinding 
This is an open-label safety extension study.  
8.4.10 Concomitant Therapy and Restricted Medications 
Concomitant medication use will be monitored throughout the study. No specific concomitant 
medications are restricted. 
8.4.11 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. 
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. 
8.5 
Efficacy and Safety Variables 
The Schedule of Assessments was previously provided in Section 2.1. 
8.5.1 Efficacy Variables 
Efficacy will be assessed using the Friedreich’s Ataxia Rating Scale (FARS) (total score 
[FARStot] and score 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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8.5.1.1 Friedreich’s Ataxia Rating Scale (FARS) 
The FARS will be performed at the EOS (or PW) Visit. 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 Section16.3), and the 
FARS-mNeuro score has a maximum of 93 points. 
8.5.2 Safety Variables 
Safety assessments will include adverse event monitoring, concomitant medication monitoring, 
physical examinations, vital signs, ECGs, clinical safety laboratory evaluations (complete blood 
count, chemistry, and urinalysis), and pregnancy testing (if applicable). 
8.5.2.1 Adverse Events 
Comprehensive assessments of any apparent adverse event experienced by the subject will be 
performed throughout the course of this study. Study center personnel will record all adverse 
events, whether observed by the Investigator/designee or reported by the subject/caregiver, in the 
source document and on the eCRF. A physician (the Principal Investigator or a physician/nurse 
practitioner/physician’s assistant designated by the Principal Investigator) will manage and treat 
any treatment-emergent adverse event (TEAE). 
Adverse event 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?” Adverse event 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 adverse event based on the following 
definitions and documentation requirements. 
8.5.2.1.1 
Definitions 
Adverse Event: As defined by the ICH, an adverse event is any untoward medical occurrence in 
a patient or clinical investigation subject administered an investigational product, whether or not 
the event is considered related to the investigational product. An AE is therefore any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of the investigational product. 
NOTE: The term “adverse event” includes both non-serious and serious adverse events unless 
otherwise specified 
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 


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clinical study, whether the adverse event is considered related to the treatment or not. Adverse 
events include the following types of occurrences: 
• Adverse reaction: an adverse reaction means any adverse event 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 adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. Reasonable possibility means there is 
evidence to suggest a causal relationship between the drug and the adverse event. A 
suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any adverse event caused by a drug. Suspected adverse 
reactions are the subset of all adverse events 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 adverse event 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 adverse event 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 adverse 
event 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. 
• 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. 


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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 adverse event includes any adverse event that is not 
described in the previous SAE category. 
Unexpected: An adverse event 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 adverse events 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. 
8.5.2.1.2 
Documentation of Adverse Events 
Adverse events that are ongoing from Study HZNP-ACT-302 will be considered baseline 
signs/symptoms. The TEAE reporting period begins with the date of the first dose of study drug 
in Study HZNP-ACT-303 and continues until completion of study participation (i.e., the patient 
is transitioned to the commercially available product, the Sponsor decides not to continue 
development for the treatment of FA, or the subject prematurely withdraws from the study). 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 8.5.2.1.5. 
Unchanged, chronic conditions are NOT considered adverse events and should not be recorded 
on the adverse event 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 adverse event. Events, 
which are unequivocally due to disease progression, should only be reported as adverse events if 
they fulfill any of the SAE criteria or are the reason for discontinuation of treatment with the 
study drug. 
In addition, hospitalizations for planned procedures are not considered an adverse event unless 
they are prolonged hospitalizations, and emergency room visits less than 24 hours in duration are 
not considered hospitalizations. 


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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. 
8.5.2.1.3 
Grading of Adverse Events 
The severity of all adverse events, 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 adverse event. 
8.5.2.1.4 
Relationship to Study Drug 
The relationship of the study drug to each adverse event 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: 
 There is a reasonable pharmacological relationship (or known class effect) 
 There is no other more plausible explanation 


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 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. 
8.5.2.1.5 
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 16.1 for 
contact information). 
2) Record the SAE accurately in the source documents and on the adverse event page of 
the subject’s eCRF, as described in Section 8.5.2.1.2. 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. 
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. 


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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 adverse events or SAEs that meet the criteria for 
Unanticipated Problems Involving Risks to Human Subjects or Others to the IRB. 
8.5.2.1.6 Follow-Up of Adverse Events 
Once the study-defined non-serious adverse event and SAE reporting periods have passed, 
reporting is required only if an Investigator becomes aware of an SAE that he or she considers 
related to the study treatment. 
After the initial recording of an adverse event, the Investigator should proactively follow the 
subject. Any ongoing study drug-related adverse event 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.  
The Investigator will document on the adverse event eCRF any/all ongoing non-serious adverse 
events that will not be followed further after the subject exits the study. If in doubt, the 
Investigator should consult the sponsor’s medical monitor. 
All SAEs should be followed until resolution, until the condition stabilizes, or until the subject is 
lost to follow-up. Once the SAE is resolved, the corresponding adverse event eCRF page should 
be updated. 
8.5.2.1.7 Medication Error and Overdose 
A medication error is any preventable event that may cause or lead to inappropriate medication 
use or patient harm.  
An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to, or by a study subject, at a dose above the target dose of 100 µg/m2 or above the stable 
tolerated dose for an individual subject.  
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 
adverse events) will be documented on the eCRF in order to capture this important safety 


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information consistently in the database. Adverse events associated with an overdose or 
medication error and SAEs of overdose or medication error are to be reported according to the 
procedures outlined in Sections 8.5.2.1.2 and 8.5.2.1.5, respectively. 
In the event of drug overdose, the subject is to be treated symptomatically with supportive 
measures instituted as required. 
8.5.2.1.8 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 adverse events and all other emerging new information relevant to the safety of the 
drug. 
8.5.2.1.9 Reporting of Investigational New Drug (IND) Safety Reports 
The sponsor will notify the US FDA and all investigators on any new serious risks associated 
with the drug. 
8.5.2.2 Pregnancy Reporting 
All female subjects of childbearing potential will undergo urine pregnancy tests at 
Baseline/Day 1, each 6-month assessment  clinic visit, and the EOS (or PW) Visit. Subjects 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 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 adverse event 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 adverse event; however, the outcome of all pregnancies should (if possible) be followed up 
and documented. 
8.5.2.3 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, each subsequent 6-month assessment clinic 
visit, and the EOS (or PW) Visit. 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. 


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8.5.2.4 Brief Physical Examinations 
Brief physical examinations will be performed at Baseline/Day 1, each subsequent 6-month 
assessment clinic visit, and the EOS (or PW) Visit; these exams will include evaluation of 
general appearance and the following body systems: skin, lungs, cardiovascular (including 
peripheral vascular), abdomen, and other. 
8.5.2.5 Clinical Laboratory Tests 
Samples of blood (4.5 mL) and urine are scheduled for collection at Baseline/Day 1, each 
6-month assessment clinic visit, and the EOS (or PW) Visit. 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  
• Chemistry panel 
• Urinalysis 
8.5.2.6 Electrocardiograms 
ECGs are scheduled for the EOS (or PW) Visit. 
8.5.3 Appropriateness of Measurements 
The efficacy and safety measurements in this study are widely used and generally recognized as 
reliable, accurate, and relevant. 
The study population consists of subjects who completed Studies HZNP-ACT-301 and HZNP-
ACT-302; 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). 
8.5.4 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 long-term safety extension study. The treatment 
duration is open-ended, and subjects will be seen at the clinic at least every six months. 
8.5.4.1 Baseline/Day 1 (Week 28 of Study HZNP-ACT-302) 
The Baseline/Day 1 Visit of this study (HZNP-ACT-303) occurs on the same day as the EOS 
Visit (Week 28 Follow-Up Visit) for HZNP-ACT-302. At the Baseline Visit, study drug will be 


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distributed for administration at home according to the planned TIW dosing schedule. Clinic 
staff will perform the following procedures:  
• 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-303. 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. 
• Record any changes in medical history since Baseline of HZNP-ACT-301. 
• Perform brief physical examination1, including vital signs. 
• Enquire about adverse events1 and concomitant medications1. 
• Collect blood (4.5 mL) and urine samples for safety clinical laboratory values (including 
urine pregnancy test [if applicable]). 
• Dispense a 3-month supply of study drug. 
1 Findings will be recorded for Day 1 (Baseline) of this study and for the EOS Visit (Week 28) of previous study 
(HZNP-ACT-302). 
Subjects will be discharged from the study center after all of the Study Day 1 procedures have 
been completed. Subjects who are able to receive study drug shipped directly to their home will 
be instructed to return to the clinic in six months, and those who are not able to receive study 
drug shipments at home will be instructed to return in three months.  
8.5.4.2 3-Month Visits 
Subjects who are able to receive direct-to-home shipments of study drug will be contacted by 
phone three months after the Baseline and 6-month assessment visits and queried regarding 
adverse events and concomitant medication use. 
Subjects who are not able to receive study drug shipments at their home will return to the clinic 
for interim clinic visits three months after the Baseline and 6-month assessment visits, and clinic 
staff will perform for the following assessments: 
• Collect all used, partially used, and unused study medication kits and vials from the 
previous clinic visit. 
• Enquire about adverse events and concomitant medication use 
• Dispense a 3-month supply of study drug. 


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8.5.4.3 6-Month Assessment Clinic Visits 
• Collect all used, partially used, and unused study medication kits and vials from previous 
clinic visit. 
• Perform brief physical examination, including vital signs. 
• Collect blood (4.5 mL) and urine samples for safety clinical laboratory values (including 
urine pregnancy test [if applicable]). 
• Enquire about adverse events and concomitant medication use. 
• Dispense a 3-month supply of study drug. 
Subjects will be released from the study center after all of the visit procedures have been 
completed and instructed to return to the clinic in three or six months, as applicable. 
8.5.4.4 End-of-Study or Premature Withdrawal Visit 
At the time ACTIMMUNE becomes commercially available or if development is ceased for the 
treatment of FA, subjects will return to the clinic while still on active study drug for an EOS 
Visit prior to transitioning to the commercial product or discontinuing study drug. Subjects who 
prematurely withdraw from the study will have EOS assessments completed within two weeks of 
study drug discontinuation. Clinic staff will perform the following procedures at the Final/EOS 
visit: 
• Collect all used, partially used, and unused study medication kits and vials from previous 
clinic visit. 
• Perform brief physical examination, including vital signs. 
• Collect blood (4.5 mL) and urine samples for safety clinical laboratory values (including 
urine pregnancy test [if applicable]). 
• Enquire about adverse events and concomitant medication use. 
• Perform FARS. 
• Perform ECG. 
8.6 
Statistical Methods and Determination of Sample Size  
No formal statistical hypothesis testing will be performed. Detailed statistical analyses will be 
presented in a separate statistical analysis plan. Some key points identified for statistical analyses 
are outlined below. 


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8.6.1 Efficacy Variables 
FARS results (FARStot and FARS-mNeuro) will be summarized with descriptive statistics for 
the EOS Visit. For statistical purposes, the FARS results for the last on-treatment visit in HZNP-
ACT-302 (Week 26) and the change from the Week 26 HZNP-ACT-302 Visit to the EOS Visit 
in this study will also be summarized. 
8.6.2 Safety Variables 
Adverse event and concomitant medication data will be summarized. Vital sign and clinical 
safety laboratory data will be summarized with descriptive statistics for Baseline, post-dose, and 
change from Baseline to post-dose values, and shift tables will be presented for clinical 
laboratory values from Baseline to each post-dose visit. The ECG statistical analysis will use the 
same approach as described above for the FARS analysis. 
Physical examination findings will be listed by subject. 
8.6.3 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 study drug on or after the Baseline/Day 1 Visit.  
8.6.4 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). 
8.6.5 Sample Size and Power Considerations 
Subjects who complete 26 weeks of treatment and the Week 28 Follow-Up Visit in Study 
HZNP-ACT-302 will be eligible for enrollment. The sample size is not based on statistical 
considerations. 
8.7 
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 the Sponsor as soon as possible to discuss the associated circumstances. All protocol 
deviations and the reasons for such deviations must be documented. 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. 


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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. 
9. 
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 
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: 
• 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 adverse event. 
• Concomitant medications (start and stop dates, reason for use). 
• Condition of subject upon completion of, or PW from, the study. 
10. 
CASE REPORT FORMS 
An 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. 


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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 Premier Research. Final eCRFs will be provided to the Investigator and Sponsor by 
Premier Research. 
11. 
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 and/or it’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 Sponsor 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. 


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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 
subjects enrolled in this study. A statement to this effect should be included in the Informed 
Consent/Assent Form. 
12. 
DATA MANAGEMENT 
Data will be entered into a clinical database as specified in Premier Research’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 Premier Research 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). 
13. 
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. 
14. 
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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15. 
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. 
NCT01965327. Interferon Gamma-1b in FRDA. Open-label Pilot Study of Interferon Gamma-1b 
(Actimmune™) for the Treatment of Friedreich Ataxia. From 
https://clinicaltrials.gov/ct2/show/NCT01965327. 
NCT02035020. A Phase IIa Trial to Test Safety and Efficacy Interferon Gamma Treatment in 
Elevating Frataxin Levels in FRDA Patients. From 
https://clinicaltrials.gov/ct2/show/NCT02035020. 
OLIGA-FA Clinical Study Report. Open-label pilot study of interferon gamma-1b 
(ACTIMMUNE®) for the treatment of Friedreich Ataxia, ClinicalTrials.gov # NCT01965327.    
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. 


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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. 
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. 
 




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16.2 
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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16.3 
FARS Neurological Assessment 
 


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SAP_001.pdf: 
CONFIDENTIAL 
 
14-Jun-2017 
16 Mar 2012  
 
Statistical Analysis Plan 
 
Protocol Title: Long-Term Safety Extension of ACTIMMUNE® (interferon γ-1b) in 
Children and Young Adults with Friedreich’s Ataxia 
Protocol Number: HZNP-ACT-303 Version 1.0 (05-Apr-2016) Administrative Change 1 (21-
Apr-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: 14-Jun-2017 
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 
2.2 
Study Endpoints ...........................................................................................7 
2.2.1 Safety Endpoints ..............................................................................7 
3. 
OVERALL STUDY DESIGN AND PLAN .........................................................8 
4. 
11 FOR STATISTICAL PURPOSES, THE LAST ON-TREATMENT VISIT 
FROM HZNP-ACT-302 (VISIT 26) WILL BE USED TO ASSESS CHANGES 
TO THE EOS ASSESSMENT IN THIS STUDY. ANALYSIS AND 
REPORTING .......................................................................................................10 
4.1 
Interim Analysis .........................................................................................10 
4.2 
Final Analysis ............................................................................................10 
5. 
ANALYSIS POPULATIONS .............................................................................10 
5.1 
Sample Size ................................................................................................10 
6. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................................10 
6.1 
Visit Windows ...........................................................................................11 
6.2 
Data Adjustments, Handling, Conventions ................................................11 
6.3 
Derived and Computed Variables ..............................................................12 
7. 
STUDY SUBJECTS AND DEMOGRAPHICS.................................................12 
7.1 
Disposition of Subjects and Withdrawals ..................................................12 
7.2 
Protocol Violations and Deviations ...........................................................12 
7.3 
Demographics and Other Baseline Characteristics ....................................13 
8. 
EFFICACY ANALYSIS ......................................................................................13 
9. 
SAFETY AND TOLERABILITY ANALYSIS .................................................13 
9.1 
Adverse Events ..........................................................................................14 
9.1.1 Deaths ............................................................................................14 
9.2 
Clinical Laboratory Evaluations ................................................................14 
9.3 
Vital Signs ..................................................................................................15 


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9.4 
Electrocardiogram (ECG) ..........................................................................15 
9.5 
Concomitant Medication ............................................................................15 
9.6 
Exposure and Compliance .........................................................................15 
10. 
CHANGES FROM PLANNED ANALYSIS .....................................................15 
11. 
REFERENCES .....................................................................................................15 
12. 
TABLES, LISTINGS, AND FIGURES .............................................................16 
13. 
PLANNED TABLES ...........................................................................................18 
14. 
PLANNED LISTINGS ........................................................................................19 
 


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ABBREVIATIONS 
 
ABBREVIATION DEFINITION OR DESCRIPTION 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BSA 
Body Surface Area 
CI 
Confidence Interval 
CRF 
Case Report Form 
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 
LLOQ 
Lower Limit of Quantitation 
LOD 
Limit of Detection 
MedDRA 
Medical Dictionary for Regulatory Activities 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TIW 
Three times a week 
TEAE 
Treatment-emergent Adverse Event 
ULOQ 
Upper Limit of Quantitation 
WHO-DD 
World Health Organization Drug Dictionary 
 


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CONFIDENTIAL 
 
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1. OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Horizon 
Pharma Ireland, Ltd. protocol HZNP-ACT-303 (Long-Term Safety Extension of 
ACTIMMUNE® (interferon γ-1b) in Children and Young Adults with Friedreich’s Ataxia), 
Final Version 1.0 and Administrative Change 1, dated 21-Apr-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). 
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, and ECG interval data will be summarized with descriptive statistics for 


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Baseline of HZNP-ACT-303, post-dose, and change from Baseline of HZNP-ACT-303 to post-
dose values. Shift tables will be presented for clinical laboratory values and ECG categorical 
results from Baseline of HZNP-ACT-303 to each post-dose visit. Physical examination findings 
will be listed by subject.  
3. OVERALL STUDY DESIGN AND PLAN 
This is a multi-center, open-label, long-term safety extension study of ACTIMMUNE in the 
treatment of FA in children and young adults. Subjects who complete 26 weeks of treatment in 
HZNP-ACT-302 will be eligible for enrollment in this study. The sample size is not based on 
statistical considerations. 
The overall maximum treatment duration for an individual subject is open-ended and treatment 
will continue until ACTIMMUNE is commercially available for the treatment of FA in the US or 
until the Sponsor decides to discontinue development for this indication. The initial dose of 
ACTIMMUNE will be individualized for each subject and will be determined by the 
investigator, provided that the initial dose does not exceed the maximum tolerated dose in 
HZNP-ACT-302. The investigator may subsequently adjust the dose for any subject if deemed 
clinically appropriate, provided that the dose does not exceed 100 μg/m2. All doses of 
ACTIMMUNE will be administered by subcutaneous injection three times a week (TIW) at 
home.  
 
 


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Table 1.Schedule of Events 
Study Phase 
Treatment Period 
End-of-Study 
or Premature 
Withdrawal10 
 
Baseline6 
3-Month 
Visits8 
6-Month 
Visits 
Study Days (± visit window) 
Day 1  
(Week 28 of  
Study HZNP-ACT-302) 
90 (± 7) 
Days after 
Last Visit 
Every 180  
(± 14) 
Days 
 
Informed consent/assent 
X 
 
 
 
Medical history1 
X 
 
 
 
Review of inclusion/exclusion criteria 
X 
 
 
 
Dispense study drug2 
X 
X9 
X 
 
Drug compliance3 
 
X9 
X 
X 
TEAE, SAE assessment4 
X7 
X 
X 
X 
Brief physical examination 
X7 
 
X 
X 
Vital Signs: blood pressure, pulse, 
temperature 
X 
 
X 
X 
Clinical laboratory evaluation  
(hematology, chemistry, urinalysis) 
X 
 
X 
X 
Electrocardiograms 
 
 
 
X11 
Urine pregnancy test5 
X 
 
X 
X 
FARS 
 
 
 
X11 
Prior/concomitant medications 
X7 
X 
X 
X 
SAE=serious adverse event, TEAE=treatment-emergent adverse event. 
1 Changes in medical history from the Baseline of HZNP-ACT-301 will be recorded on the electronic case report forms. The 
medical history from the HZNP-ACT-301 study will be available for reference. 
2 Subjects will be given a 3-month supply of study drug at each clinic visit and an additional 3-month supply will be directly 
shipped to the subjects’ home in between the required 6-month clinic visits. If direct shipments are not feasible, subjects will 
return to the clinic every three months to obtain study drug; however, assessments (other than adverse event queries) will only 
be performed every six months.  
3 Subjects will be instructed to return all used and unused study drug vials at each clinic visit. 
4 Adverse events occurring or worsening on or after the date of administration of the first dose of study drug through the end of 
the study will be considered treatment-emergent adverse events (TEAEs). All serious adverse events (SAEs) that occur on or 
after the date of administration of the first dose of study drug through two weeks after study discontinuation will be considered 
treatment-emergent SAEs (TESAEs) and will be recorded and reported to Horizon drug safety. 
5 Only for female subjects of childbearing potential. 
6 The Day 1 Visit of this study (HZNP-ACT-303) occurs on the same day as the EOS Visit (Week 28 Follow-Up Visit) for 
HZNP-ACT-302.  
7 Findings will be recorded for both the Day 1 (Baseline) Visit of this study and the Week 28 Follow-up Visit for HZNP-ACT-
302.  
8 Subjects who are not able to receive direct-to-home study drug shipments will return to the clinic for interim clinic visits three 
months after the Baseline and 6-month assessment visits; those who are able to receive direct-to-home shipments will be 
contacted by telephone. 
9 Perform at clinic visits only; those with telephone visits will receive/return study drug supplies at next clinic visit. 
10 Subjects who complete the study will undergo final assessments while still on study drug and will then be transitioned to 
commercial product. Subjects who prematurely withdraw from the study will have the EOS assessments completed within two 
weeks of study drug discontinuation. In the event the Sponsor decides to discontinue development for the treatment of FA, all 
subjects will be contacted and instructed to return to the clinic for final assessments while still on active drug. 
11 For statistical purposes, the last on-treatment visit from HZNP-ACT-302 (Visit 26) will be used to assess changes to the EOS 
assessment in this study. 


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4. ANALYSIS AND REPORTING 
4.1 Interim Analysis 
No formal interim analysis is planned for this study. 
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 End of Study 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-303.  
All analyses will be based on the Safety Population unless otherwise noted. 
5.1 Sample Size 
Subjects who complete 26 weeks of treatment in Study HZNP-ACT-302 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. 
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 


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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: 
For partial start dates: 
• If the year is unknown, then do not impute the date but assign a missing value. 
• If the month is unknown, then: 
o If the year matches the year of enrollment date, then impute the month and day of 
the randomization date. 
o Otherwise, assign 01 January 
• If the day is unknown, then: 
o If the month and year match the month and year of the enrollment date, then 
impute the day of the first dose date. 
o Otherwise, assign 01 
For partial end dates: 
• If the year is unknown, then do not impute the date but assign a missing value. 
• If the month is unknown, then assign the last day of the year, 31 December. 
If the day is unknown, then assign the last day of the month. 
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 


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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 and Efficacy 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. 
• 303 Baseline = The last non-missing measurement/assessment on the date of Week 26 
Visit from HZNP-ACT-302.  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-
ACT-303. 
• 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 


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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: 
• 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 


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o Any deaths 
• Clinical Laboratory Investigations  
o Complete Blood Count 
o Chemistry panel 
o Urinalysis 
• Electrocardiograms (ECG) 
• Echocardiograms 
• Physical Examinations 
• Concomitant Medications 
• 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 6.2. 
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.  
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, and Complete Blood Count. 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 (Eurofins 
Central Laboratory) 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. 


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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), 
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. 
 
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 as described in the protocol will not be summarized since the clinical study 
report is an abbreviated safety report. 
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. 


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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. 


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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.