Clinical trial NCT02351856
Conditions: LMNA-Related Dilated Cardiomyopathy
Keywords: laminopathy ARRY-797
Sponsor: Pfizer
Start date: 2015-02-02; Completion date: 2020-12-21
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a rollover study designed to investigate the safety and effectiveness of investigational study drug ARRY-371797 in patients who previously received ARRY-371797 in a study for patients with LMNA-related dilated cardiomyopathy sponsored by Array BioPharma and may, in the Investigator's opinion, derive benefit from continued treatment.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: ARRY-371797, p38 inhibitor, oral
Intervention descriptions: intervention 1: multiple dose, single schedule

Protocol documents:
Prot_000.pdf: 
Clinical Study ARRAY-797-001 
An Open-label Rollover Study of ARRY-371797 in Patients with Symptomatic Genetic 
Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation 
Protocol Version 1: 01 December 2014 
Array BioPharma Inc. 
3200 Walnut Street 
Boulder, CO 80301 
Phone: (303) 381-6600 
Fax: (303) 386-1240 
CONFIDENTIAL INFORMATION 
This document contains trade secrets and other confidential and proprietary information belonging to 
Array BioPharma Inc. Except as otherwise agreed to in writing, by accepting or reviewing this 
document you agree to hold this information in confidence and not to disclose it to others (except where 
required by applicable law) or to use it for unauthorized purposes. In the event of any actual or 
suspected breach of this obligation, Array BioPharma Inc. should be promptly notified. 


A R R Y- 3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or) 
Cli nical St u d y A R R A Y - 7 9 7- 0 0 I 
SI G N A T U R E P A G E ( S P O N S O R) 
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V e rsi o n 1 
0 1 D e c e m b er 2 0 1 4 
2 
Arra y Bi o P har ma I nc. 
C o nfi d e nti al 
P P D
P P D
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ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
Version 1 
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Confidential 
01 December 2014 
PRINCIPAL INVESTIGATOR AGREEMENT 
I have read and understand the contents of the clinical protocol for Clinical Study 
ARRAY-797-001 dated 01 December 2014 and will adhere to the study requirements as 
presented, including all statements regarding confidentiality. In addition, I will conduct the study 
in accordance with the requirements of this protocol and also protect the rights, safety, privacy 
and well-being of study patients in accordance with the following: 
•
International Conference on Harmonization (ICH) of Technical Requirements for
Registration of Pharmaceuticals for Human Use Harmonized Tripartite Guideline for
Good Clinical Practice E6(R1)
•
All applicable laws and regulations, including, without limitation, data privacy laws and
regulations
•
Requirements for reporting serious adverse events (SAEs) defined in Section 10.9 of this
protocol
•
Terms outlined in the Clinical Study Site Agreement
My signature also acknowledges that: 
•
Neither my subinvestigators nor I are members of the Institutional Review Board (IRB)
reviewing this protocol, or
•
I and/or my subinvestigators are members of the IRB, but I/we will not participate in the
initial review or continuing review of this study
Name of Principal Investigator 
Signature of Principal Investigator 
Date 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
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Confidential 
01 December 2014 
PROTOCOL SYNOPSIS 
Title 
An Open-label Rollover Study of ARRY-371797 in Patients 
with Symptomatic Genetic Dilated Cardiomyopathy Due to a 
Lamin A/C Gene Mutation 
Protocol Number 
ARRAY-797-001 
Study Center(s) 
All applicable study centers worldwide 
Objectives 
Primary: 
• Evaluate the safety of ARRY-371797 administered after 
completion of the parent study  
Secondary: 
• Evaluate measures of efficacy of ARRY-371797 
• Determine the exposure of ARRY-371797 and metabolites 
Endpoints 
Primary: 
• Incidence and severity of adverse events (AEs), clinical 
laboratory tests (hematology, chemistry), physical 
examination, vital signs (blood pressure [BP] and pulse 
rate [PR]) and 12-lead electrocardiogram (ECG) values 
Secondary: 
Assessed at 24, 48, 72 and 96 weeks and termination visit 
(if applicable): 
• 6-minute walk test (6MWT) 
• Left ventricular end systolic volume index (LVESVI) 
• Left ventricular (LV) end diastolic volume index 
• LV mass 
• LV ejection fraction 
• LV mass-to-volume ratio 
• 
Right ventricular (RV) end-diastolic diameter (RVEDD) 
and RV fractional area 
• Medical Outcomes Study 36-item Short-Form Health 
Survey (SF-36) and Quality of Life (QOL) by Kansas City 
Cardiomyopathy Questionnaire (KCCQ) 
In patients who previously participated in Clinical Study 
ARRAY-797-231: 
• 
Plasma concentrations of ARRY-371797 and metabolites 
pre-dose and at a single time point 1 to 2 hours post-dose at 
the Screening Visit and at 12 and 24 weeks 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
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Confidential 
01 December 2014 
Design 
This rollover study is designed to investigate the safety and 
efficacy of ARRY-371797 administration in patients who 
previously received ARRY-371797 in a lamin A/C gene (LMNA) 
mutation study sponsored by Array BioPharma (the “parent 
study”) and may, in the investigator’s opinion, derive benefit from 
continued treatment. 
Patients will be screened for eligibility at the last visit in the 
treatment period of the parent study. Eligible patients will be 
enrolled into the study immediately upon confirmation of 
eligibility so that ARRY-371797 administration is not interrupted. 
Clinic visits for safety assessments and study drug dispensing will 
be performed every 12 weeks (± 14 days) through 48 weeks, then 
every 24 weeks (± 14 days) until treatment discontinuation criteria 
are met. Efficacy assessments (6MWT, echocardiogram, SF-36 
and QOL KCCQ) will be performed at 24, 48, 72 and 96 weeks 
and termination visit (if applicable). Patients will undergo a 
termination visit as soon as possible after study drug 
discontinuation and a safety follow-up visit 30 days (± 14 days) 
after the last dose of study drug. 
Treatment Regimens 
Patients will receive ARRY-371797 at the same dose and schedule 
they were administered at the conclusion of the parent study. 
Study Population 
Patients with genetic dilated cardiomyopathy secondary to LMNA 
mutations who received ARRY-371797 in a LMNA mutation study 
sponsored by Array BioPharma, and may, in the investigator’s 
opinion, derive benefit from continued treatment. 
Duration of Study 
Participation 
Patients may continue receiving ARRY-371797 as long as no 
treatment discontinuation criteria are met. 
Treatment 
Discontinuation Criteria 
ARRY-371797 administration must be discontinued for patients 
meeting any of the following criteria: 
• Withdrawal of consent 
• Unacceptable AE(s) or failure to tolerate ARRY-371797 
• Pregnancy or initiation of breastfeeding 
• Lost to follow-up 
In addition, the Investigator may discontinue study treatment if, in 
the opinion of the Investigator, it is not in the best medical interest 
of the patient to continue treatment. 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
6 
Confidential 
01 December 2014 
Eligibility Criteria 
Patients must meet all of the following criteria to be eligible for 
enrollment in the study. 
1. Provide a personally signed and dated informed consent 
document prior to initiation of any study-related procedures 
that are not considered standard of care. 
2. Received ARRY-371797 as treatment for genetic dilated 
cardiomyopathy secondary to LMNA mutations in a clinical 
study sponsored by Array BioPharma. 
3. May, in the opinion of the Investigator, benefit from continued 
ARRY-371797 treatment. 
4. Male patients and female patients of childbearing potential 
must agree to use a highly effective method of contraception. 
5. Willingness and ability to comply with scheduled visits, 
treatment plan, laboratory tests and other study procedures. 
Patients meeting any of the following criteria are ineligible for 
enrollment in the study. 
1. Discontinued treatment in the parent study for any reason other 
than study completion or Sponsor termination of the study. 
2. Pregnant or breastfeeding women. 
3. Local access to commercially available ARRY-371797. 
Statistical 
Considerations 
Safety, efficacy and plasma concentration data will be summarized 
using descriptive statistics. Formal statistical comparisons will not 
be performed.  
Sponsor 
Array BioPharma Inc. 


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
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Versi o n 1 
7 
C o nf i de ntial 
0 1 Dece m ber  2 0 1 4  
T A B L E O F C O N T E N T S  
1. 0  
I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E ................... 1 5 
2. 0  
I N T R O D U C TI O N............................................................................................................ 1 6 
2. 1  
Bac k gr o u n d T hera pe utic I nf or mati o n .................................................................... 1 6  
2. 2  
I n vesti gati o nal Me dici nal Pr o d uct ......................................................................... 1 7 
2. 2. 1  N o ncli nical St u dies wit h A R R Y - 3 7 1 7 9 7 ............................................................... 1 7 
2. 2. 2  Cli nical E x perie nce wit h A R R Y - 3 7 1 7 9 7 .............................................................. 2 0 
2. 3  
Rati o nale f or t he St u d y .......................................................................................... 2 3  
2. 4  
D ose Selecti o n  ....................................................................................................... 2 4 
3. 0  
S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  .................................................................. 2 5 
3. 1  
St u d y O bjecti ves .................................................................................................... 2 5  
3. 1. 1  Pri mar y O bjecti ve  .................................................................................................. 2 5 
3. 1. 2  Sec o n dar y O bjecti ves  ............................................................................................. 2 5 
3. 2  
St u d y E n d p oi nts ..................................................................................................... 2 5  
3. 2. 1  Pri mar y E n d p oi nt ................................................................................................... 2 5  
3. 2. 2  Sec o n dar y E n d p oi nts ............................................................................................. 2 5  
4. 0  
S T U D Y D E SI G N  .............................................................................................................. 2 6 
4. 1  
St u d y Desi g n O ver vie w ......................................................................................... 2 6  
4. 2  
D oses a n d Sc he d ule of A d mi nistrati o n .................................................................. 2 6  
4. 3  
Bli n di n g.................................................................................................................. 2 6  
4. 4  
Esti mate d St u d y D urati o n  ...................................................................................... 2 6 
4. 5  
Data M o nit ori n g C o m mittee  .................................................................................. 2 6 
5. 0  
P A TI E N T P O P U L A TI O N  .............................................................................................. 2 7 
5. 1  
I ncl usi o n Criteria ................................................................................................... 2 7 
5. 2  
E xcl usi o n Criteria  .................................................................................................. 2 7 
5. 3  
Lifest yle G ui deli nes  ............................................................................................... 2 8 
5. 3. 1  Re q uire me nts f or C o ntrace pti o n ............................................................................ 2 8  
5. 3. 2  Restricti o ns o n P h ysical Acti vit y a n d Ot her Acti vities  ......................................... 2 9 
5. 4  
Pri or a n d C o nc o mita nt Me dicati o ns ...................................................................... 2 9  
6. 0  
S T U D Y T R E A T M E N T  ................................................................................................... 3 0 
6. 1  
St u d y Dr u g S u p pl y ................................................................................................. 3 0  
6. 1. 1  Ma n ufact uri n g a n d F or m ulati o n ............................................................................ 3 0  
6. 1. 2  Pac ka gi n g a n d La beli n g ......................................................................................... 3 0  
6. 1. 3  S hi p pi n g, St ora ge a n d Ha n dli n g ............................................................................ 3 0  


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6.1.4 Accountability and Return of Study Drug Supply .................................................31 
6.2 
Study Drug Dispensing and Administration ..........................................................31 
6.3 
Dose Modification .................................................................................................31 
6.4 
Treatment Compliance ...........................................................................................32 
7.0 
STUDY PROCEDURES AND ASSESSMENTS ..........................................................33 
7.1 
Screening Assessments ..........................................................................................33 
7.2 
Safety Assessments ................................................................................................33 
7.2.1 Adverse Events ......................................................................................................33 
7.2.2 Medical History .....................................................................................................33 
7.2.3 Physical Examination.............................................................................................33 
7.2.4 Vital Signs ..............................................................................................................33 
7.2.5 Electrocardiogram ..................................................................................................34 
7.2.6 Pregnancy Test .......................................................................................................34 
7.2.7 Clinical Laboratory Tests .......................................................................................35 
7.3 
Efficacy Assessments .............................................................................................36 
7.3.1 6-Minute Walk Test ...............................................................................................36 
7.3.2 Echocardiogram Complete with Contrast ..............................................................36 
7.3.3 SF-36 ......................................................................................................................36 
7.3.4 QOL KCCQ ...........................................................................................................37 
7.4 
Pharmacokinetic Assessments ...............................................................................37 
8.0 
SCHEDULE OF PROCEDURES AND ASSESSMENTS ...........................................38 
8.1 
Screening Visit (Final Visit in Parent Study) ........................................................38 
8.2 
Study Period ...........................................................................................................39 
8.2.1 Weeks 12 and 36 ....................................................................................................39 
8.2.2 Weeks 24, 48, 72, 96 ..............................................................................................39 
8.2.3 Every 24 Weeks After Week 96 ............................................................................40 
8.3 
Termination Visit ...................................................................................................40 
8.4 
Follow-Up Visit 30 Days After Last Dose ............................................................41 
9.0 
TREATMENT DISCONTINUATION ..........................................................................43 
9.1 
Treatment Discontinuation for Individual Patients ................................................43 
9.2 
Sponsor Discontinuation Criteria ...........................................................................44 
10.0 
ADVERSE EVENTS .......................................................................................................45 
10.1 
Adverse Event ........................................................................................................45 
10.2 
Serious Adverse Event ...........................................................................................45 
10.3 
Clarifications to Serious Adverse Event Reporting ...............................................45 


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
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C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
1 0. 4  
Assess me nt of Se verit y  .......................................................................................... 4 6 
1 0. 5  
Assess me nt of Ca usalit y  ........................................................................................ 4 6 
1 0. 6  
O ver d ose ................................................................................................................ 4 7  
1 0. 7  
Pre g na nc y or Dr u g E x p os ure D uri n g Pre g na nc y ................................................... 4 7  
1 0. 8  
Cli nical La b orat or y A b n or malities  ........................................................................ 4 7 
1 0. 9  
Re p orti n g of Seri o us a n d N o nseri o us A d verse E ve nts .......................................... 4 7  
1 0. 1 0  Re vie w of Safet y Data  ........................................................................................... 4 8 
1 1. 0  
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F  S A M P L E SI Z E  ........... 4 9 
1 1. 1. 1  Ge neral C o nsi derati o ns  .......................................................................................... 4 9 
1 1. 1. 2  Safet y A nal ysis  ...................................................................................................... 4 9 
1 1. 1. 3  Efficac y A nal ysis  ................................................................................................... 4 9 
1 1. 1. 4  P har mac o ki netic A nal ysis  ...................................................................................... 4 9 
1 2. 0  
D A T A R E C O R DI N G, R E T E N TI O N A N D M O NI T O RI N G  ...................................... 5 0 
1 2. 1  
Case Re p ort F or ms  ................................................................................................. 5 0 
1 2. 2  
Data M o nit ori n g  ..................................................................................................... 5 0 
1 2. 3  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  ................................................................. 5 1 
1 3. 0  
R E G U L A T O R Y, E T HI C A L A N D L E G A L O B LI G A TI O N S  .................................... 5 2 
1 3. 1  
G o o d Cli nical Practice  ........................................................................................... 5 2 
1 3. 2  
I nstit uti o nal Re vie w B oar d A p pr o val .................................................................... 5 2 
1 3. 3  
Re g ulat or y A ut h orit y A p pr o val  ............................................................................. 5 2 
1 3. 4  
Ot her Re q uire d A p pr o vals ..................................................................................... 5 2  
1 3. 5  
I nf or me d C o nse nt................................................................................................... 5 3 
1 3. 6  
Patie nt C o nfi de ntialit y  ........................................................................................... 5 3 
1 3. 7  
Discl os ure of I nf or mati o n ...................................................................................... 5 3  
1 3. 8  
P u blicati o n of St u d y Data ...................................................................................... 5 4  
1 4. 0  
A D H E R E N C E T O T H E P R O T O C O L  .......................................................................... 5 5 
1 4. 1  
A me n d me nts t o t he Pr ot oc ol .................................................................................. 5 5  
1 5. 0  
R E F E R E N C E S  ................................................................................................................. 5 6 
A P P E N DI X 1: T O XI CI T Y  G R A DI N G S C A L E F O R H E A L T H Y A D U L T A N D 
A D O L E S C E N T V O L U N T E E R S E N R O L L E D I N P R E V E N TI V E 
V A C CI N E C LI NI C A L T RI A L S  ...................................................................... 5 8 
A P P E N DI X 2: N Y H A C L A S SI FI C A TI O N S  ............................................................................ 6 9 
A P P E N DI X 3: 6 -MI N U T E W A L KI N G T E S T  ......................................................................... 7 0 
A P P E N DI X 4: S F - 3 6.................................................................................................................... 7 7 
 
C CI


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
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LIST OF TABLES 
Table 1: 
Summary of Clinical Laboratory Tests ............................................................35 
Table 2: 
Schedule of Events ...........................................................................................42 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
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Confidential 
01 December 2014 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study protocol. 
Abbreviation or special term Explanation 
2D 
2 dimensional 
6MWT 
6-minute walk test 
AE 
Adverse event 
ALT  
Alanine aminotransferase  
AS 
Ankylosing spondylitis 
AST  
Aspartate aminotransferase  
AUC 
Area under the plasma concentration-time curve 
BID 
Twice daily 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C 
Celsius 
CK 
Creatine kinase 
Cmax 
Maximum concentration 
COMP 
Cartilage oligomeric matrix protein 
CPK 
Creatine phosphokinase 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CSD 
Conduction system disease 
CTX-I 
C-terminal cross-linking telopeptide of type I collagen 
CV 
Curriculum vitae 
CYP 
Cytochrome P450 
DCM 
Dilated cardiomyopathy 
dL 
Deciliter(s) 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
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01 December 2014 
Abbreviation or special term Explanation 
EDC 
Electronic data capture 
EDMD 
Emery-Dreifuss muscular dystrophy 
ERK 
Extracellular signal-regulated kinase 
F 
Fahrenheit 
FDA 
U.S. Food and Drug Administration 
FMO 
Flavin-containing monoooxygenase 
FSH 
Follicle-stimulating hormone 
g 
Gram(s) 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
GI 
Gastrointestinal 
HEENT 
Head, eyes, ears, nose, throat 
HSP27 
Heat shock protein 27 
IC50 
Half-maximal inhibitory concentration 
ICD 
Implantable cardioverter defibrillator 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IL 
Interleukin 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
JNK 
c-Jun N-terminal kinase 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
kg 
Kilogram(s) 
L 
Liter(s) 
LMNA 
Gene encoding the Lamin A/C protein 
LPS 
Lipopolysaccharide 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
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Confidential 
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Abbreviation or special term Explanation 
LS 
Least squares 
LV 
Left ventricular 
LVEDD 
Left ventricular end diastolic diameter 
LVEDVI 
Left ventricular end diastolic volume index 
LVEF 
Left ventricular ejection fraction 
LVESD 
Left ventricular end systolic diameter 
LVESVI 
Left ventricular end systolic volume index 
µg 
Microgram(s) 
µL 
Microliter(s) 
m 
Meter(s) 
MAO 
Monoamine oxidase 
MAP3K 
Mitogen-activated protein kinase kinase kinase 
MAPK 
Mitogen-activated protein kinase 
MAPKK 
Mitogen-activated protein kinase kinase 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mL 
Milliliter(s) 
mRNA 
Messenger ribonucleic acid 
MTX 
Methotrexate 
nM 
Nanomolar 
NSAID 
Nonsteroidal anti-inflammatory drug 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
OA 
Osteoarthritis 
PD 
Pharmacodynamic 
PDF 
Portable document format 
PGE2 
Prostaglandin E2 
PK 
Pharmacokinetic(s) 
PR 
Pulse rate 


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Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
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Abbreviation or special term Explanation 
QD 
Once daily 
QOL 
Quality of life 
QT 
QT interval: a measurement of the time between the start of the 
Q wave and the end of the T wave in an ECG 
QTc 
Corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RA 
Rheumatoid arthritis 
RBC 
Red blood cell(s) 
RV 
Right ventricular 
RV-FS 
Right ventricular fractional shortening 
RVEDD 
Right ventricular end-diastolic diameter 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
SF-36 
Medical Outcomes Study 36-item Short-Form Health Survey 
SOP 
Standard operating procedure 
t1/2 
Terminal half-life 
TNF 
Tumor necrosis factor 
TNFα 
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 
US 
United States (of America) 
WBC 
White blood cell(s) 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 


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Clinical Study ARRAY-797-001 
 
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1.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The Principal Investigator is the person responsible for the conduct of the study at the 
investigational site. A subinvestigator is any member of the clinical study team designated and 
supervised by the Principal Investigator to perform critical study-related procedures and/or to 
make important study-related decisions. 
Prior to study initiation, the Principal Investigator at each site must provide to Array BioPharma 
Inc. (Array BioPharma/Sponsor) a signed protocol signature page, a fully executed and signed 
United States (US) Food and Drug Administration (FDA) Form 1572, a current curriculum vitae 
(CV), medical license and a financial disclosure form. Financial disclosure forms, current CVs 
and medical licenses must also be provided for all subinvestigators listed on Form 1572 who will 
be directly involved in the treatment or evaluation of patients in this study. 
The study will be administered and monitored by employees or representatives of Array 
BioPharma and/or a contract research organization (CRO) in accordance with all applicable 
regulations. Clinical research associates (CRAs) will monitor each site on a periodic basis and 
perform verification of source documentation for each patient. The Array BioPharma Drug 
Safety Department (and/or the CRO, if applicable) will be responsible for ensuring timely 
reporting of expedited serious adverse event (SAE) reports to regulatory authorities and 
Investigators. 


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2.0 
INTRODUCTION 
2.1 
Background Therapeutic Information 
LMNA-RELATED DILATED CARDIOMYOPATHY 
Lamins are critical components of the nuclear lamina, which lie between the inner nuclear 
membrane and the chromatin, and provide structural support for the cell nucleus, participate in 
many different nuclear processes, including chromatin organization, connecting the nucleus to 
the cytoplasm, gene transcription, and mitosis. Mutations in LMNA (gene encoding the lamin 
A/C protein) cause a variety of human diseases, known collectively as laminopathies. Dilated 
cardiomyopathy (DCM) is one of the more common phenotypes associated with LMNA 
mutations, and LMNA-related DCM appears to be one of the more common causes of familial 
dilated cardiomyopathy, accounting for up to 8% of all cases.1,2,3 LMNA-related DCM is 
typically autosomal dominant in inheritance, and is usually accompanied by atrial arrhythmias 
and/or conduction system disease (CSD). To date, ~100 LMNA mutations have been reported 
that were associated with cardiac disease (DCM and/or CSD).4 Differential response to treatment 
based on the specific mutation identified has not been observed. The prevalence of familial DCM 
is approximately 1 in 2,500 persons in the US.4,5 Of these individuals, it has been estimated that 
5% to 8% carry disease-causing LMNA mutations.5,6 Thus, the population of patients in the US 
(based on a US population estimate of ~316 million in September 2013)7 with LMNA-related 
DCM is in the range of 6,000 to 10,000 patients. 
The majority of patients with LMNA-related DCM follow a clinical course starting with CSD 
and/or arrhythmias in early to mid-adulthood, with some early mortality due to sudden cardiac 
arrest from a fatal arrhythmia or embolus. Over time, most patients progress to DCM, which can 
lead to rapidly progressive heart failure. Although the age of presentation in LMNA-related DCM 
varies, the age of onset typically appears to be in the third and fourth decades.6,8 Furthermore, 
LMNA-related DCM patients have a more malignant clinical course than other familial DCM 
types, due to high rates of progressive heart failure and sudden cardiac death from ventricular 
tachyarrhythmia, despite conventional heart failure therapies, unless prevented by an implantable 
cardioverter defibrillator (ICD).9,10,11 Spontaneous improvement is not seen in LMNA-related 
DCM, and while the response to conventional heart failure therapies has not been fully 
characterized in this specific form of DCM, the relentless progression of disease despite 
conventional medical therapies suggests that it is poor. 
Currently, there is no effective, disease-specific treatment available or known to be in clinical 
development for LMNA-related DCM. To date, treatment is limited to conventional therapies for 
DCM (angiotensin-converting-enzyme inhibitors or angiotensin 2 receptor blockers, beta 
blockers, aldosterone receptor antagonists and diuretics) which are largely symptomatic and 
supportive. Progressive deterioration in left ventricular (LV) function and refractory heart failure 
symptoms are often treated with resynchronization therapy (bi-ventricular pacing/ICD). In 


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patients whose disease continues to progress in spite of aggressive cardiovascular management, 
cardiac transplantation may be considered. 
2.2 
Investigational Medicinal Product 
ARRY-371797 is a selective oral inhibitor of the α-isoform of p38 mitogen-activated protein 
kinase (MAPK), a key enzyme of the MAPK family that regulates the production of the enzymes 
that are responsible for prostaglandin synthesis and for the production of pro-inflammatory 
cytokines, including tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β and IL-6. 
ARRY-371797 has demonstrated potent activity against p38 MAPK, possesses broad 
anti-inflammatory activity ex vivo and in vivo, and has undergone investigation for a number of 
indications including inflammatory conditions and the treatment of cardiac dysfunction in 
patients with LMNA-related DCM. 
2.2.1 Nonclinical Studies with ARRY-371797 
Detailed information regarding nonclinical studies of ARRY-371797 is presented in the 
Investigator’s Brochure. 
2.2.1.1 
Nonclinical Pharmacology 
Numerous in vitro and in vivo studies were performed to evaluate and confirm the ability of 
ARRY-371797 to interact with its intended target, p38 MAPK. In enzyme studies, 
ARRY-371797 inhibits the α-isoform of p38 with an IC50 of 8.2 nM. In cellular studies, 
ARRY-371797 is a potent inhibitor of p38-mediated downstream phosphorylation of heat shock 
protein 27 (HSP27) in HeLa cells with an IC50 of 17 nM. Also, in the well-accepted ex vivo 
assay of p38 activity, lipopolysaccharide (LPS)-induced TNFα in human whole blood, 
ARRY-371797 demonstrated extraordinary potency with an IC50 of 0.3 nM. This compound has 
demonstrated little to no activity against over 210 enzymes, receptors, channels and transporters.   
In vivo studies have been conducted to evaluate the activity of ARRY-371797 with respect to 
inhibiting cytokine production and inflammation in vivo. ARRY-371797 has been evaluated in 
inflammatory disease models and has proven to be a potent anti-TNF/anti-inflammatory 
compound in vivo with bone protective effects in animal models of arthritis. Several murine 
models of LMNA-related DCM have allowed exploration of pathophysiologic mechanisms of 
disease progression and novel therapies for these conditions. In vivo studies have demonstrated 
that the p38 MAPK is activated in murine models of LMNA-related DCM and that this activation 
of p38 MAPK precedes the development of cardiac dysfunction. ARRY-371797 has been tested 
in the homozygous LMNA H222P model of Emery-Dreifuss muscular dystrophy (EDMD) with 
cardiomyopathy (EDMD2, MIM:181350) and in the homozygous LMNA N195K model of 
LMNA-related DCM, one of the original LMNA mutations linked to familial DCM with 
conduction defects (CMD1A, OMIM:150330.0006). These two nonclinical models bracket the 
spectrum of phenotypes (EDMD2: cardiac and skeletal muscle disease and DCM: cardiac disease 


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only). Results from these studies confirm that treatment with ARRY-371797 improves cardiac 
structure and function and reduces myocardial apoptosis. In these mouse studies, the LV 
functional measures of left ventricular end diastolic diameter (LVEDD)/body weight and left 
ventricular end systolic diameter (LVESD)/body weight are indices that correlate with the human 
clinical study endpoints of left ventricular end diastolic volume index (LVEDVI) and left 
ventricular end systolic volume index (LVESVI), respectively. The measure of left ventricular 
ejection fraction (LVEF) is common to both mouse and human echocardiography. In addition, 
ARRY-371797 improves survival in the murine LMNA-related DCM model (LMNA N195K). 
2.2.1.2 
Nonclinical Pharmacokinetics and Absorption, Distribution, Metabolism and 
Excretion 
Pharmacokinetic (PK) studies were conducted with single doses of ARRY-371797 in mice, rats 
and monkeys. The mean observed systemic plasma clearance values were high (range, 67.1 to 
135 mL/min/kg) where monkey > mouse > rat, and mean plasma terminal half-life (t1/2) values 
were on the order of monkey ≈ mouse < rat (range, ~0.6-5.9 hours). The mean steady-state 
volume of distribution values ranged from 0.609 L/kg (mouse) to 10.2 L/kg (rat). The area under 
the plasma concentration-time curve (AUC) and maximum concentration (Cmax) values increased 
in a greater than dose-proportional manner in mice, rats and monkeys following intravenous (IV) 
or oral administration. The mean absolute oral bioavailability was similar in mice, rats and 
monkeys, generally increasing with increases in dose (range, 1.3% to 32%); AR00333953 was 
the principal metabolite in mice, rats and monkeys. In monkeys, the metabolite (AR00333953) 
exposure was greater than that of the parent (3.1-fold greater exposure), whereas, in mice and 
rats, the ARRY-371797 exposure was greater than that of the metabolite (1.4- to 2-fold greater 
exposure). ARRY-371797 is approximately 27 times more potent than AR00333953 at inhibiting 
LPS-induced tumor necrosis factor (TNF) in an ex vivo human whole blood assay. Formation of 
the major in vivo circulating metabolite, AR00333953, was not mediated by cytochrome P450 
(CYP)s. Multiple Phase I enzymes (CYPs, flavin-containing monoooxygenases [FMOs], 
amidases and esterases) are involved in the metabolism of ARRY-371797. 
In vitro experiments indicated that ARRY-371797 has moderate membrane permeability and 
may be a substrate for active efflux. ARRY-371797 was moderately, but reversibly, bound to 
plasma proteins in vitro across mouse, monkey and human plasma, as was AR00333953. 
ARRY-371797 was predicted to have moderate-to-good stability in humans with respect to 
hepatic metabolism and was metabolized in vitro primarily by CYP3A4 and CYP2D6. Other 
Phase I enzymes (FMOs, amidases, and esterases) were involved in the metabolism of 
ARRY-371797. ARRY-371797 was a weak inhibitor of 5 major CYP isoforms in vitro. 
ARRY-371797 was not a time-dependent inhibitor of CYP3A4, nor did it induce in vitro 
enzymatic activity or messenger ribonucleic acid (mRNA) expression of CYP3A4 or CYP1A2 in 
hepatocytes. ARRY-371797 was not a substrate or inhibitor of recombinant monoamine oxidase 
(MAO)-A or MAO-B. AR00333953 was a principal metabolite from in vitro incubations with 
liver microsomes, hepatocytes, plasma or blood and was also a principal metabolite in vivo. 


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Other, less abundant, metabolites that were found in vitro or in vivo were a result of oxidative 
metabolism. No glucuronide conjugates were detected in hepatocyte incubations. 
2.2.1.3 
Nonclinical Toxicity and Safety 
Preclinical toxicological studies have indicated that ARRY-371797 was well tolerated at 
multiple doses of up to 100 mg/kg twice daily (BID) in rats and monkeys, with gastrointestinal 
(GI) side effects and minimal clinical pathology changes. Associated histopathology changes 
were reversible in monkeys treated with doses of up to 100 mg/kg BID for 28 days. 
Histopathology findings in rats receiving ARRY-371797 for 28 days were partially reversible 
with respect to severity and incidence at the 100 mg/kg BID (200 mg/kg/day) dose level. In the 
chronic dosing studies for up to 6 months in the rat and 9 months in the monkey at doses up to 
30 mg/kg BID, there were no significant adverse histopathology findings. In general, 
administration of ARRY-371797 at doses of up to 30 mg/kg BID was tolerated in-life in rats and 
monkeys in chronic safety studies.  
Administration of ARRY-371797 to rats was associated with microscopic findings of skeletal 
muscle fiber changes, with no effects on clinical chemistry. Evidence of gastric irritation and 
increased gastric fluid secretion was observed in rats after a single oral dose of 100 mg/kg of 
ARRY-371797. After treatment with ARRY-371797 for multiple days, evidence of changes in 
stool consistency, ranging from loose stools to diarrhea was observed in monkeys. The GI 
disturbances were mild to moderate in the lower dose groups. In most dose groups, these GI 
effects resolved within 28 days after discontinuation of treatment with ARRY-371797. 
In all of the studies that were conducted, ARRY-371797 had no significant effect on vital signs, 
ophthalmologic examinations, coagulation parameters, troponins or urinalysis parameters after 
administration of doses of up to 100 mg/kg BID in rats and monkeys for 28 consecutive days and 
up to 30 mg/kg BID for chronic dosing in rats and monkeys. Occasional increases in liver 
enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), total bilirubin, 
blood urea nitrogen (BUN), glucose levels and decreases in potassium levels were observed in 
rats after BID administration of ARRY-371797 at doses of up to 100 mg/kg. Mild increases in 
liver enzymes (ALT and AST) were observed in monkeys. Mild increases in lymphocytes and 
neutrophils were observed in both rats and monkeys, but these changes did not appear to have 
any functional or pathological consequences. No electrocardiogram (ECG) abnormalities related 
to ARRY-371797 administration were observed in monkeys.  
There was no evidence of genotoxicity from the 2 in vitro assays (bacterial reverse mutation or 
mouse lymphoma), nor from the 1 in vivo assay (mouse micronucleus). The genotoxicity tests 
were conducted at concentrations of the standard limits for these test systems. The embryo-fetal 
developmental toxicity studies support the exclusion of pregnant women from clinical studies of 
ARRY-371797 and the continued requirement that women of childbearing potential use 
appropriate contraception. 


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2.2.2 Clinical Experience with ARRY-371797 
ARRY-371797 has been investigated in 10 completed placebo-controlled clinical studies, 
including 5 Phase 1 studies in healthy subjects and 5 five studies (one Phase 1b and four Phase 2) 
in patients with inflammatory disorders. ARRY-371797 is currently undergoing evaluation in a 
Phase 2 study in stable patients with genetic DCM secondary to LMNA mutations, and is also 
being studied in a single-patient study under a named-patient Investigational New Drug 
Application (IND) for the treatment of progressive DCM and congestive heart failure. 
Detailed information regarding clinical studies of ARRY-371797 is presented in the 
Investigator’s Brochure. 
2.2.2.1 
Clinical Pharmacokinetics 
The clinical PK of ARRY-371797 and AR00333953 have been evaluated in healthy subjects 
following single- and repeat-dose administration. Following single doses of ARRY-371797, 
exposure of ARRY-371797 increased in a dose-proportional manner up to the highest dose 
evaluated (2000 mg total daily dose). After repeat-dose administration, exposure increased in a 
nearly dose-proportional manner. The maximal plasma concentrations were generally observed 
~1 to 2 hours following dose administration with consistent plasma concentration-time profile 
shapes at all doses evaluated. The t1/2 was ~1.5 to 5 hours and was dose-dependent, with longer 
half-lives at higher doses. Less than 2-fold accumulation was observed (1.3 to 1.8). The 
metabolite (AR00333953)-to-parent ratio ranged from ~9 to 22. In general, low-to-moderate 
inter-subject variability was observed for exposure-related PK parameters. 
Exposure was also assessed in the rheumatoid arthritis (RA), ankylosing spondylitis (AS), 
osteoarthritis (OA) and post-surgical pain patient populations. Analysis in the RA population 
could neither detect nor rule out a significant drug-drug interaction of ARRY-371797 with 
methotrexate (MTX). In addition, greater exposure of ARRY-371797 and AR00333953 was 
observed following administration of ARRY-371797 under fasted conditions as compared to fed 
conditions; however, the clinical significance of this difference is unclear due to the study design 
and limited data. In patients with OA, AS and postsurgical pain, exposure was evaluated with 
sparse sampling. Although formal PK analyses were not performed, evaluation of plasma 
concentration data indicated that exposure to ARRY-371797 was comparable to that in healthy 
subjects. 
2.2.2.2 
Clinical Pharmacodynamics 
After both single-day and 14-day repeat-dose administration of ARRY-371797 in healthy 
subjects, inhibition of ex vivo, LPS-induced IL-1β, TNF and prostaglandin E2 (PGE2) production 
was observed, with the greatest degree of inhibition generally observed following the highest 
doses. IL-6 was also inhibited by ARRY-371797 but to a much lesser extent than IL-1β and 
TNF. 


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The observed inhibitory effects of ARRY-371797 on ex vivo LPS-induced cytokine production 
and prostaglandin levels were generally sustained for at least 4 to 6 hours after single- or 
repeat-dose oral administration. ARRY-371797 did not appear to have an effect on PGE2 
metabolite or creatinine levels in urine. 
2.2.2.3 
Clinical Efficacy 
In a 29-day Phase 1 study of ARRY-371797 in RA (Clinical Study ARRAY-797-103), an 
analysis of patient’s assessment of arthritis pain suggested that perceived pain was lower in the 
ARRY-371797 groups than in the placebo group. Decreases from Baseline in the patient 
assessment of arthritis pain were observed at Day 29 in the 100 mg group (decreases of 30% to 
35%) and the 200 mg group (decreases of 29% to 41%). In comparison, decreases of ~5% were 
observed in the placebo group, although that group had substantially higher Baseline values than 
either active treatment group. 
In two Phase 2 studies (Clinical Study ARRAY-797-221 and Clinical Study ARRAY-797-222) 
evaluating ARRY-371797 in the treatment of moderate to severe postsurgical dental pain, results 
demonstrated that ARRY-371797 administered at single doses of 200, 400 and 600 mg was an 
effective anti-inflammatory agent, clearly superior to placebo in a variety of measures of 
analgesic efficacy for the treatment of patients with moderate to severe acute postsurgical dental 
pain. Non-inferiority to celecoxib was not established (Clinical Study ARRAY-797-222). 
A Phase 2, randomized, double-blind, double-dummy, active- and placebo-controlled 
parallel-group study evaluated 4 weeks of treatment with ARRY-371797 in patients with 
moderate to severe pain due to OA of the knee, despite chronic use of a single nonsteroidal 
anti-inflammatory drug (NSAIDs). ARRY-371797 demonstrated a statistically significant 
treatment effect on the primary endpoint, with a least squares (LS)-mean decrease in Western 
Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score from 
Baseline to Week 4 of -2.65 for the ARRY-371797 group compared with -1.84 for the placebo 
group (LS-mean difference = -0.80; p = 0.049 [90% CI: -1.47 to -0.13]). A statistically 
significant and clinically meaningful reduction in WOMAC pain subscale scores was observed 
after 1 week of treatment, and the reduction in pain continued to improve numerically through 
4 weeks of treatment as compared to placebo. Nearly all secondary endpoints favored the 
ARRY-371797 treatment group; however, none reached statistical significance. Treatment with 
ARRY-371797 was also associated with significant reductions in C-terminal cross-linking 
telopeptide of type I collagen (CTX-I) and cartilage oligomeric matrix protein (COMP), markers 
of bone resorption and cartilage degradation, suggesting a possibility for disease-modifying 
activity, which warrants further investigation. 
The efficacy and safety of ARRY-371797 is being investigated in a single named-patient IND. 
A male patient with progressive DCM and congestive heart failure is being treated with 400 mg 
BID for an indefinite duration. After 6 months the patient had an improvement in his clinical 


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symptoms from New York Heart Association (NYHA) class II to class I and an improved LVEF 
and right ventricular fractional shortening (RV-FS) from Baseline. 
To further evaluate the activity of ARRY-371797, a Phase 2 study in stable patients with genetic 
DCM secondary to LMNA mutations has been initiated. 
2.2.2.4 
Clinical Safety 
Five Phase 1 safety, PK and pharmacodynamics (PD) studies of ARRY-371797 in healthy 
subjects have been completed (Clinical Study ARRAY-797-101, Clinical Study 
ARRAY-797-102, Clinical Study ARRAY-797-104, Clinical Study ARRAY-797-107 and 
Clinical Study ARRAY-797-108). ARRY-371797 demonstrated an acceptable safety profile 
when administered at single doses up to 900 mg once daily (QD), up to 400 mg/day for 14 days 
and up to 2000 mg/day for 7 days. In these studies, the most commonly reported adverse events 
(AEs) in subjects receiving ARRY-371797 were dizziness, headache, diarrhea, nausea and acne; 
the incidence of these AEs was not clearly related to the ARRY-371797 dose nor to the duration 
of exposure. 
In patients with RA receiving stable doses of MTX who received doses of 100 or 200 mg BID of 
ARRY-371797 or placebo for 29 days, the primary AEs reported by patients receiving 
ARRY-371797 were diarrhea and nausea (Clinical Study ARRAY-797-103). In a 12-week study 
of patients with AS (Clinical Study ARRAY-797-201), events reported most commonly by 
patients receiving doses of 100 or 200 mg BID or 400 mg QD of ARRY-371797 were stomach 
discomfort, pharyngeal erythema, peripheral edema and dizziness. In studies of postsurgical 
dental pain (Clinical Study ARRAY-797-221 and Clinical Study ARRAY-797-222), events 
reported most commonly by patients receiving doses of 200, 400 or 600 mg ARRY-371797 were 
nausea, vomiting, dizziness and headache. In patients with knee pain due to OA despite chronic 
use of an NSAID who received 400 mg BID of ARRY-371797 for 4 weeks (ARRAY-797-223), 
the most common AEs were dizziness, diarrhea, nausea, somnolence, constipation, headache, 
insomnia and stomatitis. 
No clinically meaningful association has been observed between treatment with ARRY-371797 
and abnormalities in hematology or urinalysis parameters. Mild elevations in creatine 
phosphokinase (CPK) and AST have been noted in 1 study (ARRAY-797-223). In the same 
study, mild reduction in mean arterial pressure was also noted. No other association between 
treatment with ARRY-371797 and changes in vital signs in any of the clinical studies has been 
observed. While there is no nonclinical evidence for corrected QT interval (QTc) prolongation, 
in a pooled analysis across clinical studies, there is some evidence for dose-related prolongation 
of the QT interval corrected for heart rate using Fridericia’s formula (QTcF), compared with 
placebo in patients receiving ARRY-371797. The magnitude of mean placebo-adjusted QTcF 
prolongation at the projected therapeutic dose of 400 mg BID or lower is about 8 ms or less 
while at supra-therapeutic doses of up to 500 mg q6h, the magnitude is about 20 to 25 ms. 


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2.3 
Rationale for the Study 
The p38 MAPK family is involved in the regulation of a number of diverse cellular functions in 
a variety of cell types in all eukaryotes from yeast to humans. Classical MAPK signaling occurs 
in cascades, involving MAPKs that are activated by MAPK kinases (MAPKK), which are in turn 
activated by MAPK kinase kinases (MAP3K). These latter kinases are activated by multiple 
extracellular stimuli, particularly cell stressors such as bacterial endotoxins, osmotic shock, 
cytotoxic agents and pro inflammatory cytokines. Subsequent downstream activation of p38 
MAPK leads to a multiplicity of responses such as the activation of transcription factors and 
other kinases, resulting in prostaglandin and cytokine production, cell cycle arrest, cell 
differentiation and/or apoptosis.12,13 Since p38 MAPK and p38α, in particular, appear to play a 
central role in the cellular response to stress, inhibitors of this pathway have been evaluated 
predominantly in the context of treating inflammatory diseases.14,6 
In addition to its role in inflammation, activation of the p38 MAPK pathway has been linked to 
aberrant cardiovascular function in patients with DCM due to LMNA gene mutations. 
Nonclinical studies using genetically modified mouse models have identified important 
molecular mechanisms of disease in LMNA-related DCM. For example, homozygote knock-in 
mice expressing a human LMNA mutation associated with cardiomyopathy, 
(LMNAH222P/H222P mice) develop LV dilatation and depressed contractile function starting at 
8 to 10 weeks of age. This phenotype is associated with abnormal activation of the extracellular 
signal-regulated kinase (ERK), the c-Jun N-terminal kinase (JNK), and the p38α branches of the 
MAPK signaling cascade in cardiomyocytes.8,15,16 When mice with LMNA-related DCM were 
treated with p38 MAPK inhibitors, such as ARRY-371797, they demonstrated improved cardiac 
function and survival.17 Upregulation of p38 MAPK has also been reported in the hearts from 
human patients with LMNA-related DCM.15 
Progress reports that include echocardiographic findings are being obtained in an ongoing 
single-patient IND (Sponsor: Meriter Medical Group; IND 117,699) in which a male patient with 
DCM and CSD due to LMNA mutation (LMNA-related DCM with CSD) is receiving the p38α 
MAPK inhibitor, ARRY-371797. After 3 months of BID oral treatment, this patient has 
demonstrated improvements that appear similar to the cardiac functional improvements observed 
in the mutant mouse model studies.  
Based on these nonclinical and single-patient data, Array BioPharma considers that inhibition of 
p38 MAPK with the selective p38 α inhibitor ARRY-371797 may provide a novel therapeutic 
approach and has the potential to fill an unmet medical need for the treatment of cardiovascular 
dysfunction in patients with progressive LMNA-related DCM. 
The current open-label rollover study (Clinical Study ARRAY-797-001) is designed to 
investigate the safety and efficacy of ARRY-371797 administration in patients who previously 
received ARRY-371797 in a LMNA mutation study sponsored by Array BioPharma (the “parent 


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study”) and may, in the investigator’s opinion, derive benefit from continued treatment. 
In addition, to allow evaluation of plasma concentrations associated with the original capsule 
formulation as well as a new tablet formulation, patients enrolling in the current study from 
Clinical Study ARRAY-797-231 will undergo plasma concentration measurements at the 
Screening Visit (i.e., following an extended treatment period with the capsule formulation) and at 
12 and 24 weeks (i.e., after transition to the tablet formulation). 
2.4 
Dose Selection 
Patients will receive the same ARRY-371797 dose they were receiving at the conclusion of the 
parent study. 


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3.0 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 Primary Objective 
• Evaluate the safety of ARRY-371797 administered after completion of the parent study 
3.1.2 Secondary Objectives 
• Evaluate measures of efficacy of ARRY-371797 
• Determine the exposure of ARRY-371797 and metabolites 
3.2 
Study Endpoints 
3.2.1 Primary Endpoint 
• Incidence and severity of adverse events (AEs), clinical laboratory tests (hematology, 
chemistry), physical examination, vital signs (blood pressure [BP] and pulse rate [PR]) 
and 12-lead electrocardiogram (ECG) values 
3.2.2 Secondary Endpoints 
Assessed at 24, 48, 72 and 96 weeks and termination visit (if applicable): 
• 6-minute walk test (6MWT) 
• Left ventricular end systolic volume index (LVESVI) 
• Left ventricular (LV) end diastolic volume index 
• LV mass 
• LV ejection fraction 
• LV mass-to-volume ratio 
• Right ventricular (RV) end-diastolic diameter (RVEDD) and RV fractional area 
• Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and Quality of Life 
(QOL) by Kansas City Cardiomyopathy Questionnaire (KCCQ) 
In patients previously receiving ARRY-371797 capsules in Clinical Study ARRAY-797-231: 
• Plasma concentrations of ARRY-371797 and metabolites pre-dose and at a single time 
point 1 to 2 hours post-dose at the Screening Visit and at 12 and 24 weeks 


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4.0 
STUDY DESIGN 
4.1 
Study Design Overview 
This rollover study is designed to investigate the safety and efficacy of ARRY-371797 
administration in patients who previously received ARRY-371797 in a LMNA mutation study 
sponsored by Array BioPharma and may, in the investigator’s opinion, derive benefit from 
continued treatment. 
Patients will be screened for eligibility at the last visit in the treatment period of the parent study. 
Eligible patients will be enrolled into the study immediately upon confirmation of eligibility so 
that ARRY-371797 administration is not interrupted. 
Clinic visits for safety assessments and study drug dispensing will be performed every 12 weeks 
(± 14 days) through 48 weeks, then every 24 weeks (± 14 days) until treatment discontinuation 
criteria are met. Efficacy assessments (6MWT, echocardiogram, SF-36 and QOL KCCQ) will be 
performed at 24, 48, 72 and 96 weeks and termination visit (if applicable). Patients will undergo 
a termination visit as soon as possible after study drug discontinuation and a safety follow-up 
visit 30 days (± 14 days) after the last dose of study drug. 
4.2 
Doses and Schedule of Administration 
Patients will receive ARRY-371797 at the same dose and schedule they were administered at the 
conclusion of the parent study. 
If a patient has tolerability concerns at 400 mg BID, they may be down-titrated to 200 mg BID 
(400 mg total daily dose). If a patient has tolerability concerns at 200 mg BID, they may be 
down-titrated to 100 mg BID (200 mg total daily dose). 
4.3 
Blinding 
Not applicable. 
4.4 
Estimated Study Duration 
Patients may continue receiving ARRY-371797 as long as no treatment discontinuation criteria 
are met. 
4.5 
Data Monitoring Committee 
This study will not have a data monitoring committee (DMC). However, data from this study 
may be made available to a DMC associated with another study(ies) evaluating ARRY-371797. 


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5.0 
PATIENT POPULATION 
The eligibility criteria described in this study protocol are designed to identify patients for whom 
treatment is considered appropriate. All relevant medical and nonmedical conditions should be 
considered when deciding whether a patient is suitable for enrollment in the study. 
Questions regarding patient eligibility should be addressed to the Sponsor prior to enrollment. 
Patients must fulfill all of the following inclusion criteria and none of the exclusion criteria to be 
eligible for admission to the study. 
5.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for enrollment in the study. 
1. Provide a personally signed and dated informed consent document prior to initiation of 
any study-related procedures that are not considered standard of care. 
2. Received ARRY-371797 as treatment for genetic dilated cardiomyopathy secondary to 
LMNA mutations in a clinical study sponsored by Array BioPharma. 
3. May, in the opinion of the Investigator, benefit from continued ARRY-371797 treatment. 
4. Male patients and female patients of childbearing potential must agree to use a highly 
effective method of contraception. 
5. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests 
and other study procedures. 
5.2 
Exclusion Criteria 
Patients meeting any of the following criteria are ineligible for enrollment in the study. 
1. Discontinued treatment in the parent study for any reason other than study completion or 
Sponsor termination of the study. 
2. Pregnant or breastfeeding women. 
3. Local access to commercially available ARRY-371797. 


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5.3 
Lifestyle Guidelines 
5.3.1 Requirements for Contraception 
5.3.1.1 
Contraception Requirements for Female Patients 
Female patients of non-childbearing potential are not required to use contraception. To be 
considered of non-childbearing potential, a female patient must meet at least one of the following 
criteria: 
• Postmenopausal AND at least 55 years old. 
• Postmenopausal AND a follicle-stimulating hormone (FSH) value > 30 IU/L at the 
Screening Visit of the parent study. 
• Hysterectomy OR bilateral oophorectomy. 
• Tubal ligation at least 5 years prior to the Screening Visit with no subsequent 
pregnancies. 
Female patients of childbearing potential are required to use one of the following methods of 
contraception: 
• Hormonal contraceptive (e.g., oral, injected, intrauterine, extrauterine [e.g., vaginal ring], 
transdermal or implanted) for at least 2 full cycles prior to first dose of study drug until 
30 days after the last dose of study drug. 
• Any of the following mechanical contraceptive methods for at least 14 days prior to first 
dose of study drug until 30 days after the last dose of study drug: 
• Copper-containing intrauterine device (IUD). 
• Diaphragm with spermicidal foam/gel/film/cream/suppository. 
• Vaginal condom with spermicidal foam/gel/film/cream/suppository. 
• Cervical cap with spermicidal foam/gel/film/cream/suppository. 
In addition, female patients of childbearing potential must instruct male partners, even those who 
have undergone vasectomy, to use a condom. 


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5.3.1.2 
Contraception Requirements for Male Patients 
Male patients, even those who have undergone vasectomy, are required to use a condom as 
contraception with female partners of childbearing potential from the first dose of study drug 
through 90 days after the last dose of study drug. 
In addition to using a condom, male patients must ensure that female partners of childbearing 
potential use another form of contraception as described in Section 5.3.1.1. 
5.3.2 
Restrictions on Physical Activity and Other Activities 
Patients should abstain from strenuous exercise (e.g., heavy lifting, weight training and aerobic 
activity) for 48 hours prior to each blood collection for clinical laboratory tests.  
Male patients are restricted from sperm donation until 90 days after last dose of study drug. 
5.4 
Prior and Concomitant Medications 
Ancillary treatments will be administered according to labeled instructions as medically 
indicated for patients. All concomitant medications will be recorded in the electronic case report 
form (eCRF) using generic drug names when possible. 
Concomitant medications can be administered at the Investigator’s discretion to conform to 
standard practice during the treatment period. Caution should be used when initiating treatment 
with a drug known to prolong QT intervals. 
As with any novel therapeutic for which limited clinical experience exists, Investigators should 
exercise caution when prescribing concomitant medications. 


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6.0 
STUDY TREATMENT 
6.1 
Study Drug Supply 
6.1.1 Manufacturing and Formulation 
ARRY-371797 is supplied as 2 different manufactured drug products: 
• Formulated granules in Size “0” Swedish Orange opaque, hard gelatin capsules in 
100 mg and 200 mg dose strengths.  
• Brown capsule-shaped film-coated tablets in 100 mg dose strength. 
Patients will receive ARRY-371797 at the same dose and schedule they received at the 
conclusion of the parent study. Pending availability, all patients will receive the tablet 
formulation.  
All treatments must be processed by a pharmacist or by appropriately trained and designated 
study personnel. Instructions for dose calculations will be provided to the pharmacist or designee 
before study initiation. 
6.1.2 Packaging and Labeling 
ARRY-371797 will be packaged in bottles with a pre-counted number of capsules or tablets 
required for the appropriate dosage and treatment duration between visits. Detailed instructions 
for storage, handling and accountability of study drug will be provided in the Pharmacy Manual. 
6.1.3 Shipping, Storage and Handling 
ARRY-371797 capsules and tablets should be stored at room temperature (15 to 30°C). 
Labeled, packaged study drug will be shipped to each site by the Sponsor or designee following 
receipt of the necessary regulatory documents. The Investigator or an approved representative 
(e.g., registered pharmacist, trained and delegated study coordinator) will ensure that all study 
drugs are stored as outlined in the Pharmacy Manual and in accordance with applicable 
regulatory requirements. The drug storage area at the site must be secure, with access limited to 
authorized personnel. 
Stability studies to support drug storage conditions have been conducted by the Sponsor or an 
affiliate. The Sponsor will continue to monitor the stability of the study drug and will alert the 
site if a lot is nearing the end of its anticipated shelf life. 
Detailed instructions for storage and handling of study drug will be provided in the Pharmacy 
Manual. 


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6.1.4 Accountability and Return of Study Drug Supply 
The Investigator or an approved representative (e.g., pharmacist) must maintain accurate records 
of dates and quantities of study drug received, to whom study drug is dispensed 
(patient-by-patient accounting), and accounts of any study drug accidentally or deliberately 
destroyed. The Investigator must retain all unused or expired study drug supplies until the study 
monitor has confirmed the accountability data. If a site’s policy prohibits holding study drug 
supplies for monitor review, then a copy of the standard operating procedure (SOP) for 
processing drug returns must be provided to the Sponsor.  
Study drug will be returned to the Sponsor for destruction, as outlined in the Pharmacy Manual. 
If a site’s policy prohibits returning study drug for destruction by the Sponsor (e.g., it is 
destroyed locally), then a copy of the SOP for drug destruction must be provided to the Sponsor. 
To ensure adequate records, all study drug will be accounted for on a drug accountability 
inventory form as instructed by the Sponsor. Refer to the Pharmacy Manual for details on how to 
process all unused or expired study supplies. 
6.2 
Study Drug Dispensing and Administration 
Dosing should occur at roughly the same time each day and occur every 12 hours ± 2 hours. 
When administered at clinic visits, study drug should be given after all questionnaires have been 
completed and blood samples for clinical laboratory assessments have been collected. 
Study drug is to be taken orally with or without food. Patients will swallow the study drug 
whole, and will not chew the capsule(s) or tablet(s) prior to swallowing. 
Complete dosing instructions, including the timing of study drug administration, dosing in 
relation to meals and instructions for missed doses, will be provided in the Pharmacy Manual. 
6.3 
Dose Modification 
If a patient’s machine-read triplicate ECG includes 2 or more individual ECGs with a QTcF 
value > 500 msec, or QTcF value increases by ≥ 60 msec from Baseline, administration of study 
drug should be held until over-read mean triplicate values are available. The over-read should be 
conducted by the Investigator. The Medical Monitor will be advised of any QTcF alterations and 
will assess the clinical significance of QTcF values with the Investigator and determine actions 
to be taken with dosing (e.g., if the patient has cardiac resynchronization therapy/ICD/pacemaker 
the Investigator and Medical Monitor may determine that the patient can continue if findings are 
not clinically significant and/or unchanged from Baseline).  


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If the over-read mean triplicate value of both parameters is ≤ 500 msec, study drug 
administration may resume. Whenever possible, the over-read should be completed promptly in 
order to avoid or minimize treatment interruption. 
If the over-read value indicates that the mean triplicate value of either parameter is > 500 msec, 
action may be taken with study drug dosing if deemed necessary by the Investigator and Medical 
Monitor. Dosing should be held until QTcF returns to ≤ 480 msec.  
• If the patient is currently receiving 400 mg BID, the patient can be re-challenged at 
200 mg BID after QTcF returns to ≤ 480 msec.  
• If the patient is currently receiving 200 mg BID, the patient can be re-challenged at 
100 mg BID after QTcF returns to ≤ 480 msec.  
• If the patient is currently receiving 100 mg BID, the patient can be re-challenged at 
100 mg BID after QTcF returns to ≤ 480 msec. If upon re-challenge at 100 mg BID the 
QTcF remains > 500 msec on over-read, study drug treatment should be discontinued. 
6.4 
Treatment Compliance 
Compliance with protocol-specified study drug treatment will be evaluated by an accounting of 
supplied and returned drug product and patient interviews at each clinic visit. 


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7.0 
STUDY PROCEDURES AND ASSESSMENTS 
The procedures and assessments that will be conducted during this study are described in this 
section in narrative form, described by study visit in Section 8.0 and summarized in Table 2. 
Detailed instructions regarding all laboratory procedures, including collection and handling of 
samples, will be included in the Laboratory Manual. 
Written informed consent must be granted by each patient prior to the initiation of any study 
procedure or assessment (other than those considered standard of care). 
7.1 
Screening Assessments 
Screening assessments for determination of patient eligibility will be performed at the last visit in 
the treatment period of the parent study (e.g., the Week 48 visit of Clinical Study 
ARRAY-797-231). Assessments performed at that visit will represent the patient’s Baseline 
values for the current study. 
7.2 
Safety Assessments 
7.2.1 Adverse Events 
Adverse events will be assessed by direct observation and patient interviews. Patients should be 
questioned using non-leading questions. Assessment and reporting of AEs is described in detail 
in Section 10.0. 
7.2.2 Medical History 
The patient’s medical history documented in the parent study will be transferred to the eCRF of 
the current study. 
7.2.3 Physical Examination 
Physical examinations will be performed by trained medical personnel at the time points 
specified in Table 2. General physical well-being will be assessed by brief evaluation of the 
head, eyes, ears, nose, throat (HEENT), skin, cardiovascular (including assessment of peripheral 
pulses, heart, bruits, edema), lungs, abdomen, extremities and other conditions of note. Weight 
will be measured at every assessment. Height will be measured at the Screening Visit only. 
7.2.4 Vital Signs 
Vital sign measurements (BP, PR and temperature as appropriate) will be collected according to 
institutional standards at the time points specified in Table 2. When vital signs are to be collected 
at the same time point as a blood collection, vital signs should be collected first. 


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At each visit, sitting systolic and diastolic BP and PR will be measured and recorded on the 
eCRF. Sitting BP will be measured with the patient’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after 5 minutes of rest. The same arm (preferably the dominant 
arm) will be used throughout the study. The same size BP cuff and method (automated or 
manual), which has been properly sized and calibrated, will be used to measure BP throughout 
the study. The use of automated devices for measuring BP and PR is preferred; when done 
manually, PR will be measured in the brachial or radial artery for at least 30 seconds. Baseline 
BP is defined as the systolic and diastolic BP measures performed at the Screening Visit (i.e., the 
last assessment in the parent study) and will serve as the comparator for values obtained at later 
visits.  
7.2.5 Electrocardiogram 
Triplicate 12-lead ECGs will be performed at the time points specified in Table 2. At each 
measurement, three serial ECGs will be obtained over a period of 5 to 10 minutes. All ECGs will 
be over-read by the Investigator. The mean of the over-read triplicate ECG measurements 
performed at the Screening Visit (i.e., the last assessment in the parent study) will serve as each 
patient’s Baseline value for all post-dose comparisons. 
When ECGs are to be performed at the same visits as study drug administration, blood collection 
and/or vital sign measurements, ECGs should be performed first. Abnormal ECGs may be 
repeated at the Investigator’s discretion. 
In some cases, it may be appropriate to repeat abnormal ECGs. If a machine-read corrected QT 
value (QTc) is prolonged, repeat measurements may not be necessary if the Investigator’s 
interpretation determines that the QTc values is in the acceptable range. Interpretation will be 
documented on the ECG source and signed and dated by the reader. 
7.2.6 Pregnancy Test 
All females of childbearing potential are required to undergo urine pregnancy assessment at the 
Screening Visit and during the study at the time points specified in Table 2. Any positive test 
will result in immediate study drug discontinuation. Women of non-childbearing potential (see 
Section 5.3.1.1) do not require pregnancy tests.  
Urine collections and testing for pregnancy occurring on dosing days must be performed prior to 
study drug administration. 


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7.2.7 Clinical Laboratory Tests 
7.2.7.1 
Hematology and Chemistry 
Blood and urine samples for the laboratory tests listed in Table 1 will be collected as outlined in 
Section 8.0 and at the time points specified in Table 2. Additional clinical laboratory tests for 
safety can be obtained at any time during the study at the Investigator’s discretion. Clinically 
significant findings at the final assessment should be followed to resolution or stabilization. 
All blood and urine collections occurring on dosing days must be performed prior to study drug 
administration. 
Table 1: 
Summary of Clinical Laboratory Tests 
Hematology 
Chemistry 
Others 
Hemoglobin 
Hematocrit 
RBC 
Platelets 
WBC 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Albumin 
Alkaline phosphatase 
AST 
GGT 
ALT 
Bicarbonate (CO2) 
Total bilirubin 
BUN 
Calcium 
Chloride 
CK 
Creatinine 
Glucose 
Magnesium 
Inorganic Phosphate 
Potassium 
Total protein 
Sodium 
Uric acid 
Direct bilirubin (if total bilirubin values are abnormal) 
NT-proBNP 
Troponins 
If applicable: 
• 
Urine pregnancy test 
 


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7.2.7.2 
Urinalysis 
Urinalysis will not be performed during this study. However, urinalysis results from the last visit 
in the treatment period of the parent study will be captured on the eCRF as the patient’s Baseline 
urinalysis values. 
7.3 
Efficacy Assessments 
7.3.1 6-Minute Walk Test 
The 6MWT will be performed at the time points specified in Table 2. 
The 6MWT measures the distance that a patient can quickly walk on a flat, hard surface in a 
period of 6 minutes, evaluating the global and integrated responses of all the systems involved 
during exercise, including the pulmonary and cardiovascular systems, systemic circulation, 
peripheral circulation, blood, neuromuscular units, and muscle metabolism. 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. If the weather is comfortable, the test may be performed 
outdoors. The walking course must be 30 m in length. Testing should be performed in a location 
where a rapid, appropriate response to an emergency is possible. The appropriate location of a 
crash cart should be determined by the physician supervising the facility. The test should be 
performed at approximately the same time of day when assessed and by the same evaluator 
whenever possible. 
7.3.2 Echocardiogram Complete with Contrast 
The 2-dimensional (2D) echocardiogram complete with contrast will be performed by trained 
personnel at the time points specified in Table 2. 
These assessments will be standard transthoracic 2D echocardiograms (with contrast to optimize 
accuracy and precision of intracardiac measurements) and will include: 
1. Left ventricular: systolic and diastolic function; size, mass and geometry. 
2. Right ventricular size and function; pulmonary artery size. 
3. Left atrial dimensions, volumes and pressures. 
4. Valvular (aortic, mitral, tricuspid and pulmonary) stenosis and regurgitation (severity). 
7.3.3 SF-36 
The SF-36 questionnaire will be completed at the time points specified in Table 2. 


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Patients complete 36 questions to measure functional health and well-being from the patient's 
point of view. The SF-36 provides scores for each of 8 health domains and psychometrically 
based physical and mental component summary scores. The questionnaire takes approximately 
5 to 10 minutes to complete. 
7.3.4 QOL KCCQ 
The QOL KCCQ questionnaire will be completed at the time points specified in Table 2. 
The QOL KCCQ measures the effects of symptoms, functional limitations and psychological 
distress on an individual’s QOL. In completing the QOL KCCQ, patients indicate how each of 
23 facets prevented them from living as they desired using a 5 to 7-point Likert scale. 
7.4 
Pharmacokinetic Assessments 
For patients who previously participated in Clinical Study ARRAY-797-231, blood collection for 
measurement of plasma concentrations of ARRY-371797 and metabolites will be drawn at the 
time points specified in Table 2. Complete instructions for sample processing, handling and 
shipment will be provided in the Laboratory Manual. 


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8.0 
SCHEDULE OF PROCEDURES AND ASSESSMENTS 
The procedures and assessments that will be conducted during this study are described in this 
section by study visit, described in narrative form in Section 7.0 and summarized in Table 2. 
Detailed instructions regarding all laboratory procedures, including collection and handling of 
samples, will be included in the Laboratory Manual. 
During screening, a unique 14-digit number (based on the study number and patient number 
from the parent study) will be assigned to each patient who provides written informed consent. 
The unique 14-digit number will be the parent study number (e.g., 797-231) followed by the 
parent study patient number (e.g., 1020-0002), with a hyphen as a connector 
(e.g., 797-231-1020-0002). The patient will be identified by that number for the duration of the 
study.  
At the site, the Investigator will maintain a log for all screened patients (including patients who 
fail screening after providing written informed consent) and all enrolled patients. 
8.1 
Screening Visit (Final Visit in Parent Study) 
At the final visit in the parent study, the Investigator (or an appropriate delegate at the study site) 
will obtain written informed consent from each patient, after which confirmation of eligibility 
criteria will be performed. The following assessments, performed as part of the final visit in the 
parent study, will be documented on the eCRF for the current study to serve as the patient’s 
Baseline values. 
• Medical history (information documented in the parent study will be transferred to the 
eCRF of the current study) 
• Recording of prior/concomitant medications, including all prescription and 
nonprescription drugs, vitamins, and dietary or herbal supplements 
• Physical examination including height and body weight 
• Vital sign measurement 
• Triplicate 12-lead ECG 
• Collection of hematology/chemistry blood sample 
• 6MWT 
• Echocardiogram 
• SF-36 and QOL KCCQ 


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• Urine pregnancy test prior to dosing (females of childbearing potential only) 
• Urinalysis 
• Assessment of AEs 
• Patients who previously participated in Clinical Study ARRAY-797-231 only: 
Collection of PK blood sample pre-dose (after vital sign measurement) and 1 to 2 hours 
post-dose 
Following confirmation of eligibility and enrollment into the current study, study drug will be 
dispensed (initial dose in clinic). 
8.2 
Study Period 
8.2.1 Weeks 12 and 36 
• Recording of concomitant medications 
• Physical examination including body weight 
• Vital sign measurement 
• Triplicate 12-lead ECG 
• Collection of hematology/chemistry blood sample 
• Urine pregnancy test prior to dosing (females of childbearing potential only) 
• Dispense study drug (initial dose in clinic) 
• Assessment of AEs 
• Patients who previously participated in Clinical Study ARRAY-797-231 only: 
Collection of PK blood sample pre-dose (after vital sign measurement) and 1 to 2 hours 
post-dose (Week 12 only) 
8.2.2 Weeks 24, 48, 72, 96 
• Recording of concomitant medications 
• Physical examination including body weight 
• Vital sign measurement 


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• Triplicate 12-lead ECG 
• Collection of hematology/chemistry blood sample 
• 6MWT 
• Echocardiogram 
• SF-36 and QOL KCCQ 
• Urine pregnancy test prior to dosing (females of childbearing potential only) 
• Dispense study drug (initial dose in clinic) 
• Assessment of AEs 
• Patients who previously participated in Clinical Study ARRAY-797-231 only: 
Collection of PK blood sample pre-dose (after vital sign measurement) and 1 to 2 hours 
post-dose (Week 24 only) 
8.2.3 Every 24 Weeks After Week 96 
• Recording of concomitant medications 
• Physical examination including body weight 
• Vital sign measurement 
• Triplicate 12-lead ECG 
• Collection of hematology/chemistry blood sample 
• Urine pregnancy test prior to dosing (females of childbearing potential only) 
• Dispense study drug (initial dose in clinic) 
• Assessment of AEs 
8.3 
Termination Visit 
A Termination Visit should be completed as soon as possible after study drug discontinuation 
and every effort should be made to perform the following procedures: 
• Recording of concomitant medications 


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• Physical examination including body weight 
• Vital sign measurement 
• Triplicate 12-lead ECG 
• Collection of hematology/chemistry blood sample 
• 6MWT (if not performed for another visit within 30 days prior to the Termination Visit) 
• Echocardiogram (if not performed for another visit within 30 days prior to the 
Termination Visit) 
• SF-36 and QOL KCCQ (if not performed for another visit within 30 days prior to the 
Termination Visit) 
• Urine pregnancy test (females of childbearing potential only) 
• Assessment of AEs 
8.4 
Follow-Up Visit 30 Days After Last Dose 
• Recording of concomitant medications 
• Physical examination including body weight 
• Vital sign measurement 
• Triplicate 12-lead ECG 
• Collection of hematology/chemistry blood sample 
• Urine pregnancy test (females of childbearing potential only) 
• Assessment of AEs 
 


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Table 2: 
Schedule of Events 
Procedure or 
Assessment 
Screening 
Period 
Treatment Period 
Follow-up Period 
Screening 
(Final Visit 
in Parent 
Study) 
Weeks 
12, 36 
Weeks 
24, 48, 
72, 96 
Every 24 
Weeks 
After 
Week 96 
Termination 
Visit 
Follow-up 
Visit 
30 Days 
After Last 
Dose 
Informed Consent 
X 
 
 
 
 
 
Confirm Eligibility 
Criteria 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Concomitant 
Medicationsa 
 Xb 
X 
X 
X 
X 
X 
Physical Exam/Weight/ 
Vital Signsc 
 Xb 
X 
X 
X 
X 
X 
Triplicate ECGs 
 Xb 
X 
X 
X 
X 
X 
Hematology/Chemistry 
Blood Sampled 
 Xb 
X 
X 
X 
X 
X 
6-Minute Walk Test 
 Xb 
 
X 
 
 Xe 
 
Echocardiogram 
 Xb 
 
X 
 
 Xe 
 
SF-36 and QOL KCCQ 
 Xb 
 
X 
 
 Xe 
 
Urine Pregnancy Testf 
 Xb 
X 
X 
X 
X 
X 
Urinalysis 
 Xb 
 
 
 
 
 
Dispense Study Drug 
X 
X 
X 
X 
 
 
PK Blood Sampled,g 
X 
 Xh 
 Xi 
 
 
 
Assess AEs 
 Xb 
X 
X 
X 
X 
X 
All activities are performed predose with the exception of post-dose PK blood samples. Visit windows are 
± 14 days. 
a 
Include all prescription and nonprescription drugs, vitamins and dietary or herbal supplements. 
b 
These assessments are performed as part of the final visit of the parent study. 
c 
Blood pressure measurements to be performed in accordance with institutional standards. Height will be 
measured at the Screening Visit only. 
d 
Sample collection to be performed in accordance with the methods described in the Laboratory Manual. 
e 
To be performed at Termination Visit only if not performed within the prior 30 days.  
f 
Required for females of childbearing potential only. 
g 
In patients who previously participated in Clinical Study ARRAY-797-231, samples are to be collected 
pre-dose and 1 to 2 hours post-dose (exact post-dose time of blood draw must be documented). 
h 
Week 12 only. 
i 
Week 24 only. 


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9.0 
TREATMENT DISCONTINUATION 
9.1 
Treatment Discontinuation for Individual Patients 
ARRY-371797 administration must be discontinued for patients meeting any of the following 
criteria: 
• Withdrawal of consent 
• Unacceptable AE(s) or failure to tolerate ARRY-371797 
• Pregnancy or initiation of breastfeeding 
• Lost to follow-up 
In addition, the Investigator may discontinue study treatment if, in the opinion of the 
Investigator, it is not in the best medical interest of the patient to continue treatment. Wherever 
possible, procedures and evaluations scheduled to occur at the Termination and Follow-up visits 
should be conducted. The Sponsor should be notified of all study treatment withdrawals in a 
timely manner. The Sponsor may also request that a patient be removed from study treatment 
based on assessment of AEs, lack of compliance, protocol violation or the current medical status 
of the patient. 
Patients may withdraw their consent to participate in the study at any time for any reason. If a 
patient withdraws consent, the date and stated reason for withdrawal of consent should be 
documented in the patient source documents and the eCRF. Patient data collected up to the date 
of consent withdrawal will be included in analyses. 
In addition, a patient may decide to stop participating in the study at any time for any reason 
without prejudice to future medical care by the physician or at the institution. If a patient’s 
participation in the study is ended prematurely (whether due to patient request or Investigator or 
Sponsor decision), study drug will be discontinued and study staff must confirm if the patient 
wishes to also withdraw his/her consent to participate in the study. 
If a patient does withdraw consent to participate in the study, previously collected samples and 
data will be processed for analysis and assessment for study purposes. The study staff must 
determine whether the patient will allow further study-related contact (e.g., scheduling of a 
Follow-up Visit). These decisions along with the date and stated reason for withdrawal of 
consent must be documented. 
If a patient does not withdraw consent to participate in the study, a Termination Visit should be 
performed as soon as possible after treatment cessation, ideally no later than 7 days after the last 
dose of study drug. The date and stated reason for study discontinuation should be documented. 


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If a patient does not respond to 3 consecutive follow-up attempts (i.e., telephone calls), a 
certified letter will be sent to the patient. The patient will be considered lost to follow-up if they 
do not respond to the certified letter within 2 weeks or the patient cannot otherwise be contacted 
or located. 
9.2 
Sponsor Discontinuation Criteria 
This study may be discontinued at any time due to safety concerns, failure to meet expected 
enrollment goals, administrative reasons or at the discretion of the Sponsor. Should the study be 
terminated prematurely, the Sponsor will provide written notification to all Investigators and 
regulatory authorities and will specify the reason(s) for early termination. The Investigator must 
inform the Institutional Review Board (IRB) promptly and provide the reason(s) for the 
termination. 


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10.0 
ADVERSE EVENTS 
10.1 
Adverse Event 
An AE is any untoward medical occurrence, including the exacerbation of a pre-existing 
condition, in a patient administered a pharmaceutical product regardless of causality. 
10.2 
Serious Adverse Event 
An SAE is any untoward medical occurrence that meets any of the following criteria. 
• Results in death. 
• Is immediately life-threatening (refers to an event in which the patient is at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe). 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Based upon appropriate medical judgment, represents an important medical event that 
may jeopardize the patient or may require intervention to prevent one of the outcomes 
described above. 
10.3 
Clarifications to Serious Adverse Event Reporting 
• Death is an outcome of an SAE and not an SAE in itself. When death is an outcome, 
report the event(s) resulting in death as the SAE term (e.g., “pulmonary embolism”). If 
the cause of death is unknown, report “Death, unknown cause” as the SAE term. 
• Pre-planned or elective hospitalizations are excluded from SAE reporting. In addition, 
emergency room visits and admissions under 23-hour observation are excluded from 
SAE reporting; however, such events should still be reported on the appropriate AE 
eCRF page. 


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10.4 
Assessment of Severity 
The severity rating of an AE refers to its intensity. The severity of each AE will be categorized 
using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials. Intensity should be assigned a grade of 1 through 4, as 
outlined by the guidelines in Appendix 1. 
10.5 
Assessment of Causality 
Medical judgment should be used to determine the cause of the AE, considering all relevant 
factors such as (but not limited to) the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication and de-challenge or re-challenge. 
Yes (possibly, probably or definitely related): there is a reasonable possibility that the study drug 
caused the event; one or more of the following criteria apply: 
• The event follows a reasonable temporal sequence from administration of study drug. 
• The event could not be reasonably attributed to the known characteristics of the patient’s 
clinical state, environmental or toxic factors or other modes of therapy administered to 
the patient. 
• The event follows a known pattern of response to study drug. 
• The event disappears or decreases on cessation or reduction in dose of the study drug. 
(It should be noted that in some situations an AE will not disappear or decrease in 
intensity upon discontinuation of study drug despite other clear indications of 
relatedness).  
• The event reappears or worsens when the study drug is re-administered. 
No (unlikely, probably not related or definitely not related): there is no reasonable possibility 
that the study drug caused the event; one or more of the following criteria apply: 
• The event does not follow a reasonable temporal sequence from administration of study 
drug. 
• The event could be reasonably attributed to the known characteristics of the patient’s 
clinical state, concurrent illness, environment or toxic factors or other modes of therapy 
administered to the patient. 
• The event does not follow a known pattern of response to study drug. 
• The event does not disappear or decrease on cessation or reduction in dose of the study 
drug, and it does not reappear or worsen when the study drug is re-administered. 


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10.6 
Overdose 
An overdose of study drug (whether symptomatic or asymptomatic) will be reported as an AE. 
10.7 
Pregnancy or Drug Exposure During Pregnancy 
If a patient becomes pregnant during the study, administration of study drug is to be discontinued 
immediately. 
Pregnancies (both those of female patients and female partners of male patients) must be 
reported to the Sponsor within 24 hours of the Investigator’s knowledge using the Clinical 
Pregnancy Report form. All pregnancies will be followed through to outcome and the outcome 
must be reported to the Sponsor using the Clinical Pregnancy Outcome Report. 
Pregnancies themselves are not considered AEs or SAEs. However, any AEs or SAEs occurring 
during pregnancy are to be reported using the appropriate AE or SAE form.  
10.8 
Clinical Laboratory Abnormalities 
Clinical laboratory abnormalities will be graded using the Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (Appendix 1) 
and appropriate reference range(s). All abnormal values assessed to be of clinical concern and at 
least possibly related to study drug or of uncertain causality must be repeated. Persistent 
abnormal values and changes of possible clinical concern that remain within the normal range 
should be followed at the discretion of the Investigator. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE only if an action on the study drug is made as a result of the abnormality, if intervention for 
management of the abnormality is required, or at the discretion of the Investigator. 
10.9 
Reporting of Serious and Nonserious Adverse Events 
All AEs, serious and nonserious, will be fully documented on the appropriate eCRF. For each 
AE, the Investigator must provide its duration (start and end dates or ongoing), intensity, 
assessment of causality and whether specific action or therapy was required. 
Adverse events ongoing at the time of informed consent are to be followed under the parent 
protocol. 
Any AE that occurs from the signing of the informed consent form through the final study visit 
(e.g., Follow-Up Visit) must be recorded on the AE eCRF. After the final study visit, only SAEs 
assessed as related to study drug need to be captured on the AE eCRF and reported to the 
Sponsor. 


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All SAEs, regardless of relationship to study drug, must be reported to the Sponsor within 
24 hours of the Investigator’s knowledge. This should be done by faxing the completed SAE 
Form to the Sponsor at the number provided on the SAE report fax cover sheet. 
Investigators must follow patients with AEs/SAEs until the event has resolved, the condition has 
stabilized, withdrawal of consent, the patient is lost to follow-up, or completion of the Follow-up 
Visit. Nonserious AEs do not need to be followed beyond the Follow-up Visit. 
If the patient dies, this should be captured as the outcome of the associated SAE. If the cause of 
death is unknown, death will be reported as a separate event. If a patient is lost to follow-up, this 
should be captured accordingly within the AE eCRF and on a follow-up SAE report. 
10.10 Review of Safety Data 
The Medical Monitor and the Sponsor’s Drug Safety Department will be responsible for the 
ongoing review and evaluation of safety data, including AEs, laboratory data, and any other 
safety evaluations, throughout the duration of the study.  


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11.0 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
11.1.1 
General Considerations 
A detailed statistical analysis plan (SAP) will be finalized prior to database lock. 
11.1.2 
Safety Analysis 
The Safety Population will consist of all patients who receive at least 1 dose of study drug.  
Safety data will be presented in tabular and/or graphical format and summarized descriptively by 
study day, where appropriate.  
Adverse events, including deaths due to any cause, ECG, vital signs and laboratory data will be 
summarized. All AE, ECG and safety laboratory abnormalities of potential clinical concern will 
be described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively where appropriate. Absolute value data and change from Baseline data will be 
summarized as appropriate. 
Severity of AEs and laboratory abnormalities will be graded using the Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, as 
appropriate. Adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®). Incidence tables of patients with AEs will be presented for all AEs by 
maximum severity, serious AEs, AEs assessed as related to study drug and AEs resulting in 
discontinuation of study drug. Changes in ECG and laboratory measurements will be 
summarized.  
Listings of all safety data sorted by patient and assessment date will be provided. 
11.1.3 
Efficacy Analysis 
All efficacy endpoints are considered secondary endpoints (Section 3.2.2). Descriptive statistics 
for efficacy endpoints will be reported at 24, 48, 72 and 96 weeks and termination visit 
(if applicable). 
11.1.4 
Pharmacokinetic Analysis 
Plasma concentrations of ARRY-371797 and its metabolites will be summarized using 
descriptive statistics. Metabolite-to-parent ratio and drug accumulation will be assessed as 
appropriate. Results may also be used for separate cross-study analyses. Any additional 
cross-study analyses will be outlined in a separate analysis plan. 


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12.0 
DATA RECORDING, RETENTION AND MONITORING 
12.1 
Case Report Forms 
Data will be collected using an electronic data capture system (EDC) at the clinical site. The 
Investigator or designee will record data specified in the protocol using eCRFs. Changes or 
corrections to eCRFs will be made by the Investigator or an authorized member of the study staff 
according to the policies and procedures at the site. 
It is the Investigator’s responsibility to ensure eCRFs are complete and accurate. Following 
review and approval, the Investigator will electronically sign and date the pages. This signature 
certifies that the Investigator has thoroughly reviewed and confirmed all data on the eCRF. The 
Investigator is personally responsible for the accuracy and completeness of all data included in 
the eCRF. 
A portable document format (PDF) file of the eCRFs will be provided to the site after all data 
have been monitored and reconciled. An electronic copy will be archived at the site. 
12.2 
Data Monitoring 
This study will be closely monitored by representatives of the Sponsor throughout its duration. 
Monitoring will include personal visits with the Investigator and study staff as well as 
appropriate communications by telephone, fax, mail, email or use of the EDC system, if 
applicable. It is the monitor’s responsibility to inspect eCRFs at regular intervals throughout the 
study to verify the completeness, accuracy and consistency of the data and to confirm adherence 
to the study protocol and to Good Clinical Practice (GCP) guidelines. The Investigator agrees to 
cooperate with the monitor to ensure that any problems detected during the course of this study 
are resolved promptly. The Investigator and site will permit study-related monitoring, audits, 
IRB review and regulatory inspection, including direct access to source documents. 
It is understood that study monitors and any other personnel authorized by the Sponsor may 
contact and visit the Investigator and will be permitted to inspect all study records (including 
eCRFs and other pertinent data) on request, provided that patient confidentiality is maintained 
and that the inspection is conducted in accordance with local regulations. 
Every effort will be made to maintain the anonymity and confidentiality of patients during this 
study. However, because of the experimental nature of this treatment, the Investigator agrees to 
allow representatives of the Sponsor as well as authorized representatives of regulatory 
authorities to inspect the facilities used in the conduct of this study and to inspect, for purposes 
of verification, the hospital or clinic records of all patients enrolled in the study. 


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12.3 
Quality Control and Quality Assurance 
Quality control procedures will be conducted according to the Sponsor’s internal procedures. 
The study site may be audited by a quality assurance representative of the Sponsor. All necessary 
data and documents will be made available for inspection. 


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13.0 
REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
13.1 
Good Clinical Practice 
The study will be performed in accordance with the protocol, guidelines for GCP established by 
the International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use and applicable local regulatory requirements and 
laws.  
13.2 
Institutional Review Board Approval 
The Investigator must inform and obtain approval from the IRB for the conduct of the study at 
named sites, the protocol, informed consent documents and any other written information that 
will be provided to the patients and any advertisements that will be used. Written approval must 
be obtained prior to recruitment of patients into the study and shipment of study drug. 
Proposed amendments to the protocol and aforementioned documents must be submitted to the 
Sponsor for review and approval, then to the IRB. Amendments may be implemented only after 
a copy of the approval letter from the IRB has been transmitted to the Sponsor. Amendments that 
are intended to eliminate an apparent immediate hazard to patients may be implemented prior to 
receiving Sponsor or IRB approval. However, in this case, approval must be obtained as soon as 
possible after implementation. 
Per GCP guidelines, the Investigator will be responsible for ensuring that an annual update is 
provided to the IRB to facilitate continuing review of the study and that the IRB is informed 
about the end of the study. Copies of the update, subsequent approvals and final letter must be 
sent to the Sponsor. 
13.3 
Regulatory Authority Approval 
The study will be performed in compliance with the requirements of IRBs and each country’s 
regulatory authorities and will also meet all of the requirements of ICH GCP guidance. 
Amendments to the protocol will be submitted to the relevant regulatory authorities prior to 
implementation in accordance with applicable regulations. 
13.4 
Other Required Approvals 
In addition to IRB and regulatory authority approval, all other required approvals (e.g., approval 
from the local research and development board or scientific committee) will be obtained prior to 
recruitment of patients into the study and shipment of study drug. 


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13.5 
Informed Consent 
Informed consent is a process that is initiated prior to the patient’s agreeing to participate in the 
study and continues throughout the patient’s study participation. It is the Investigator’s 
responsibility (or designee) to obtain written informed consent from each patient after adequate 
explanation of the aims, methods, anticipated benefits and potential hazards of the study and 
before any study procedures are initiated. Each patient should be given a copy of the informed 
consent document and associated materials. The original copy of the signed and dated informed 
consent document must be retained at the site and is subject to inspection by representatives of 
the Sponsor or regulatory authorities. If any amendments occur throughout the course of the 
study that affect the informed consent form (i.e., when new study procedures or assessments 
have been added), all active patients should be re-consented using the same process for the initial 
consent. 
13.6 
Patient Confidentiality 
The Investigator must ensure that the patient’s privacy is maintained. On the eCRF or other 
documents submitted to the Sponsor, patients will be identified by a patient number only. 
Documents that are not submitted to the Sponsor (e.g., signed informed consent documents) 
should be kept in a confidential file by the Principal Investigator. 
The Investigator shall permit authorized representatives of the Sponsor, regulatory authorities 
and ethics committees to review the portion of the patient’s medical record that is directly related 
to the study. As part of the required content of informed consent documents, the patient must be 
informed that his/her records will be reviewed in this manner. 
13.7 
Disclosure of Information 
Information concerning the study, patent applications, processes, scientific data or other pertinent 
information is confidential and remains the property of the Sponsor. The Principal Investigator 
may use this information for the purposes of the study only. 
It is understood by the Principal Investigator that the Sponsor will use information obtained in 
this clinical study in connection with the clinical development program, and therefore may 
disclose it as required to other clinical investigators and to regulatory authorities. In order to 
allow the use of the information derived from this clinical study, the Principal Investigator 
understands that he/she has an obligation to provide complete test results and all data obtained 
during this study to the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should only 
be undertaken with written consent from the Sponsor. 


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13.8 
Publication of Study Data 
The conditions regulating dissemination of the information derived from this study are described 
in the Clinical Trial Agreement. 


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14.0 
ADHERENCE TO THE PROTOCOL 
Investigators must apply due diligence to avoid protocol deviations, and the Sponsor (and 
designee[s]) will not pre-authorize deviations. If the Investigator believes a change to the 
protocol would improve the conduct of the study, this must be considered for implementation in 
a protocol amendment. Protocol deviations will be recorded. 
14.1 
Amendments to the Protocol 
Only the Sponsor may modify the protocol. Amendments to the protocol will be made only after 
consultation and agreement between the Sponsor and the Investigator. The only exception is 
when the Investigator considers that a patient’s safety is compromised without immediate action. 
In these circumstances, immediate approval of the chairman of the IRB must be sought, and the 
Investigator should inform the Sponsor and the full IRB within 5 working days after the 
emergency occurred. All amendments that have an impact on patient risk or the study objectives 
or require revision of the informed consent document must receive approval from the IRB prior 
to implementation. 
 


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15.0 
REFERENCES 
1. 
Van Tintelen JP, Hofstra RMW, Katerberg H, et al. High yield of LMNA Mutations in 
Patients with Dilated Cardiomyopathy and/or Conduction Disease Referred to 
Cardiogenetics Outpatient Clinics. American Heart Journal 2007;154:1130-1139. 
2. 
Burkett EL, Hershberger RE. Clinical and Genetic Issues in Familial Dilated 
Cardiomyopathy. J Am Coll Cardiol 2005;45:969-981. 
3. 
Millat G, Bouvagnet P, Chevalier P, et al. Clinical and Mutational Spectrum in a Cohort 
of 105 Unrelated Patients with Dilated Cardiomyopathy. European Journal of Medical 
Genetics 2011;54:e570-e575. 
4. 
Dec GW, Fuster V. Idiopathic Dilated Cardiomyopathy. N Engl J Med 1994;331:1564-
75. 
5. 
Codd MB, Sugrue DD, Gersh BJ, et al. Epidemiology of Idiopathic Dilated and 
Hypertrophic Cardiomyopathy. A Population-based Study in Olmsted County, 
Minnesota, 1975 - 1984. Circulation 1989;80:564-72. 
6. 
Taylor MRG, Fain PR, Sinagra G, et al. Natural History of Dilated Cardiomyopathy Due 
to Lamin a/c gene Mutations. Journal of the American College of Cardiology 
2003;41:771-780. 
7. 
Parks SB, Kushner JD, Nauman D, et al. Lamin A/C Mutation Analysis in a Cohort of 
324 Unrelated Patients with Idiopathic or Familial Dilated Cardiomyopathy American 
Heart Journal 2008; 156(1):161-169. 
8. 
Fatkin D, MacRae C, Sasaki T, et al. Missense Mutations in the Rod Domain of the 
Lamin A/C Gene as Causes of Dilated Cardiomyopathy and Conduction-system Disease. 
N Engl J Med 1999 Dec 2;341(23):1715-24. 
9. 
Meune C, Van Berlo JH, Anselme F, et al. Primary Prevention of Sudden Death in 
Patients with Lamin A/C Gene Mutations. N Engl J Med 2006;354:209-210. 
10. 
Becane HM, Bonne G, Varnous S, et al. High Incidence of Sudden Death with 
Conduction System and Myocardial Disease due to Lamins A and C Gene Mutation. 
Pacing Clin Electrophysiol 2000;23:1661-1666. 
11. 
Van Berlo JH, de Voogt WG, van der Kooi AJ, et al. Meta-analysis of Clinical 
Characteristics of 299 carriers of LMNA Gene Mutations: Do Lamin A/C Mutations 
Portend a High risk of Sudden Death? J Mol Med 2005;83:79-83. 


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12. 
Brook M, Sully G, Clark AR, et al. Regulation of Tumour Necrosis Factor Alpha mRNA 
Stability by the Mitogen-activated Protein Kinase p38 Signaling cascade. FEBS Lett 
2000;483(1):57-61. 
13. 
Baldassare JJ, Bi Y, Bellone CJ. The role of p38 Mitogen-activated Protein Kinase in IL-
1 Beta Transcription. J Immunol 1999;162(9):5367-73. 
14. 
Kumar S, Boehm J, Lee JC. p38 MAP Kinases: Key Signaling Molecules as Therapeutic 
Targets for Inflammatory Diseases. Nat Rev Drug Discov 2003;2(9):717-26. 
15. 
Muchir A, Wu W, Choi J, et al. Abnormal p38a Mitogen-activated Protein Kinase 
Signaling in Dilated Cardiomyopathy Caused by Lamin A/C Gene Mutation Hum. Mol. 
Genet 2012;21(19):4325-4333. 
16. 
Saqib A, Tsubouchi T, Koch J, et al. Inhibition of Site Specific Phosphorylation of 
Retinoblastoma Protein by a p38 Inhibitor Decreases Apoptosis, Improves Survival and 
Prevents Cardiomyopathy Caused by a Mutation in LMNA gene. Circulation 
2011;124:A15685. 
17. 
Hacker T, et al. Pharmacologic of Inhibition p38 Mitogen Activated Protein Kinase 
Improves Left Ventricular Function and Prolongs Survival in a Murine Model of Lamin-
Associated Familial Dilated Cardiomyopathy (manuscript in preparation). 
 


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APPENDIX 1:  TOXICITY GRADING SCALE FOR HEALTHY ADULT AND 
ADOLESCENT VOLUNTEERS ENROLLED IN PREVENTIVE 
VACCINE CLINICAL TRIALS 
 
Guidance for Industry  
 
Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine 
Clinical Trials  
 
 
 
Additional copies of this guidance are available from the Office of Communication, Training and 
Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, 
or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at 
http://www.fda.gov/cber/guidelines.htm.  
 
For questions on the content of this guidance, contact the Division of Vaccines and Related Products 
Applications, Office of Vaccines Research and Review at 301-827-3070.  
 
 
 
 
 
U.S. Department of Health and Human Services  
Food and Drug Administration  
Center for Biologics Evaluation and Research  
September 2007 Contains Nonbinding Recommendations  
 
 


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Table of Contents  
I. INTRODUCTION  
II. BACKGROUND  
III. TOXICITY GRADING SCALE TABLES  
A. Tables for Clinical Abnormalities  
B. Tables for Laboratory Abnormalities  
IV. REFERENCES  


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Guidance for Industry 
Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials  
 
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this 
topic. It does not create or confer any rights for or on any person and does not operate to bind FDA 
or the public. You can use an alternative approach if the approach satisfies the requirements of the 
applicable statutes and regulations. If you want to discuss an alternative approach, contact the 
appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number 
listed on the title page of this guidance.  
 
I. INTRODUCTION  
 
Preventive vaccines are usually developed to prevent disease in a healthy population. The Office of 
Vaccines Research and Review, Center for Biologics Evaluation and Research, regulates preventive 
vaccines under authority of section 351 of the Public Health Service Act (42 U.S.C. 262), as well as 
specific sections of the Federal Food, Drug, and Cosmetic Act, and reviews investigational new drug 
applications (INDs) and biologics license applications (BLAs). (See, for example, Title 21 Code of 
Federal Regulations (CFR) Parts 312, 600, and 601). Most of the clinical trials of preventive vaccines 
conducted to support INDs and BLAs enroll healthy volunteers in all phases of vaccine testing. The 
enrollment of healthy volunteers warrants a very low tolerance for risk in those clinical trials.  
 
This guidance provides you, sponsors, monitors, and investigators of vaccine trials, with 
recommendations on assessing the severity of clinical and laboratory abnormalities in healthy adult 
and adolescent volunteers enrolled in clinical trials. The grading system described in the table can 
also be useful in defining a particular study’s stopping rules (e.g., a certain number of adverse events, 
as defined in the table, may call for stopping the study). Less extreme observations (e.g., mild) may 
not require discontinuing the study vaccine but can still contribute to evaluating safety by identifying 
parameters to focus upon in subsequent product development. Uniform criteria for categorizing 
toxicities in healthy volunteers can improve comparisons of safety data among groups within the 
same study and also between different studies. We, FDA, recommend using toxicity grading scale 
tables, provided below, as a guideline for selecting the assessment criteria to be used in a clinical trial 
of a preventive vaccine. We recommend incorporation of such appropriate, uniform, criteria into the 
investigational plan, case report forms, and study reports and correspondence with FDA, sponsors, 
monitors, investigators, and IRBs.  
 
This guidance finalizes the draft guidance of the same title dated April 2005 (70 FR 22664, May 2, 
2005).  
 
FDA’s guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe FDA’s current thinking on a topic and should be viewed 
only as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
the word should in FDA’s guidances means that something is suggested or recommended, but not 
required. 
 


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II. BACKGROUND  
 
Standardized toxicity assessment scales have been widely used to evaluate products treating specific 
diseases. For example, the National Cancer Institute’s Common Toxicity Criteria Scale and the 
Division of AIDS’ Toxicity Grading Scale standardize the evaluation of adverse events among 
patients with cancer and HIV/AIDS, respectively (Refs. 1, 2). The defined toxicity parameters in 
those scales are designed for patients who may already experience mild, moderate, or severe adverse 
clinical or laboratory events due to the disease process, and may not be appropriate for healthy 
volunteers.  
 
In the development of the toxicity grading scales for healthy volunteers, we chose parameter limit 
values based on published information, when such values were available (Refs. 1-6). For example, 
the Brighton Collaboration has developed case definitions and guidelines to evaluate some adverse 
events associated with administering vaccines (Ref. 3). In some cases, parameter limit values were 
based on clinical experience and experience reviewing vaccine clinical trials that enroll normal 
healthy subjects.  
 
Toxicity grading scales for laboratory abnormalities should consider the local laboratory reference 
values when the parameter limit values are defined. The characterization of laboratory parameters 
among some populations of healthy adults and adolescents may require the exercise of clinical 
judgment, for example, consideration of the potential for ethnic differences in white blood cell 
(WBC) counts or gender differences in creatine phosphokinase (CPK) values.  
 
III. TOXICITY GRADING SCALE TABLES  
 
Adverse events in a clinical trial of an investigational vaccine must be recorded and monitored and, 
when appropriate, reported to FDA and others involved in an investigation (sponsors, IRBs, and 
investigators). (See, for example, 21 CFR 312.32, 312.33, 312.50, 312.55, 312.56, 312.60, 312.62, 
312.64, 312.66). Although the use of a toxicity grading scale for adverse events would not replace 
these regulatory requirements, using a scale to categorize adverse events observed during a clinical 
trial may assist you in monitoring safety and making required reports. Nonetheless, we believe that 
categorization or grading of data as outlined in this document is supplementary to and should not 
replace full and complete data analysis.  
 
These guidelines for toxicity grading scales are primarily intended for healthy adult and adolescent 
volunteers. The parameters in the tables below are not necessarily applicable to every clinical trial of 
healthy volunteers. The parameters monitored should be appropriate for the specific study vaccine. 
For some preventive vaccines under development, it may be appropriate  
2 Contains Nonbinding Recommendations to include additional parameters to be monitored during 
a clinical trial or to alter the choice of values in the toxicity table. For example, additional parameters 
might be added based on one or more of the following: safety signals observed in pre-clinical 
toxicology studies, the biological plausibility of the occurrence of certain adverse events, or previous 
experience with a similar licensed product. 
 


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As discussed above, the tables do not represent a recommendation to monitor all the listed 
parameters in all clinical trials of healthy volunteers, nor do the tables represent all possible 
parameters to be monitored. In addition, these tables do not represent study inclusion or exclusion 
criteria. We recommend that the parameters monitored be appropriate for the study vaccine 
administered to healthy volunteers participating in the clinical trial. 
 
A. Tables for Clinical Abnormalities  
 
Local Reaction to  
Injectable Product  
Mild (Grade 1)  
Moderate(Grade 
2)  
Severe (Grade 3)  Potentially Life  
Threatening  
(Grade 4)  
Pain  
Does not interfere  
with activity  
Repeated use of 
non-narcotic pain 
reliever > 24 
hours or 
interferes with 
activity  
Any use of 
narcotic pain 
reliever or 
prevents daily  
activity  
Emergency room  
(ER) visit or  
hospitalization  
Tenderness  
Mild discomfort 
to touch  
Discomfort with 
movement  
Significant  
discomfort at rest  
ER visit or  
hospitalization  
Erythema/Redness *  
2.5 – 5 cm  
5.1 – 10 cm  
> 10 cm  
Necrosis or  
exfoliative 
dermatitis  
Induration/Swelling **  
2.5 – 5 cm and 
does not interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be  
recorded as a continuous variable.  
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 


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Vital Signs *  
Mild (Grade 1)  
Moderate(Grade 
2)  
Severe (Grade 3)  Potentially Life  
Threatening  
(Grade 4)  
Fever (°C) **  
(°F) **  
38.0 – 38.4  
100.4 – 101.1  
38.5 – 38.9  
101.2 – 102.0  
39.0 – 40  
102.1 – 104  
> 40  
> 104  
Tachycardia - beats per  
minute  
101 – 115  
116 – 130  
> 130  
ER visit or  
hospitalization for  
arrhythmia  
Bradycardia - beats per  
minute***  
50 – 54  
45 – 49  
< 45  
ER visit or  
hospitalization for  
arrhythmia  
Hypertension (systolic) -  
mm Hg  
141 – 150  
151 – 155  
> 155  
ER visit or  
hospitalization for  
malignant  
hypertension  
Hypertension (diastolic) -  
mm Hg  
91 – 95  
96 – 100  
> 100  
ER visit or  
hospitalization for  
malignant  
hypertension  
Hypotension (systolic) –  
mm Hg  
85 – 89  
80 – 84  
< 80  
ER visit or  
hospitalization for  
hypotensive 
shock  
Respiratory Rate – breaths  
per minute  
17 – 20  
21 – 25  
> 25  
Intubation  
* Subject should be at rest for all vital sign measurements.  
** Oral temperature; no recent hot or cold beverages or smoking.  
*** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgment when characterizing bradycardia 
among some healthy subject populations, for example, conditioned athletes. 
 


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Systemic (General)  
Mild (Grade 1)  
Moderate(Grade 
2)  
Severe (Grade 3)  Potentially Life  
Threatening  
(Grade 4)  
Nausea/vomiting  
No interference  
with activity or 1 
– 2 
episodes/24 hours  
Some interference  
with activity or > 
2  
episodes/24 hours  
Prevents daily  
activity, requires  
outpatient IV  
hydration  
ER visit or  
hospitalization for  
hypotensive 
shock  
Diarrhea  
2 – 3 loose stools 
or 
< 400 gms/24 
hours 
4 – 5 stools or  
400 – 800 gms/24  
hours  
6 or more watery  
stools or  
> 800gms/24 
hours  
or requires  
outpatient IV  
hydration  
ER visit or  
hospitalization  
Headache  
No interference 
with 
activity  
Repeated use of 
non-  
narcotic pain  
reliever > 24 
hours or 
some interference  
with activity  
Significant; any  
use of narcotic  
pain reliever or  
prevents daily  
activity  
ER visit or  
hospitalization  
Fatigue  
No interference 
with 
activity  
Some interference  
with activity  
Significant;  
prevents daily  
activity  
ER visit or  
hospitalization  
Myalgia  
No interference 
with 
activity  
Some interference  
with activity  
Significant;  
prevents daily  
activity  
ER visit or  
hospitalization  
 
Systemic Illness  
Mild (Grade 1)  
(Moderate(Grade 
2) 
Severe (Grade 3)  Potentially Life  
Threatening  
(Grade 4)  
Illness or clinical adverse  
event (as defined  
according to applicable  
regulations)  
No interference 
with 
activity  
Some interference  
with activity not  
requiring medical  
intervention  
Prevents daily  
activity and  
requires medical  
intervention  
ER visit or  
hospitalization  
 


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
6 5  
C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
 
A.  T a bles f or L a b or at or y A b n or m alities  
 
T he la b orat or y val ues 
pr o vi de d i n t he ta bles bel o w 
ser ve as g ui deli nes a n d are 
de pe n de nt u p o n i nstit uti o nal 
n or mal para meters. 
I nstit uti o nal n or mal refere nce 
ra n ges s h o ul d be pr o vi de d t o 
de m o nstrate t hat t he y are 
a p pr o priate. Ser u m *  
Mil d ( Gr a de 1)  
M o der ate ( Gr a de 
2)  
Se vere  
( Gr a de 3)  
P ote nti all y Life  
T hre ate ni n g  
( Gr a de 4) * *  
S o di u m –  H y p o natre mia 
m E q/ L  
1 3 2 –  1 3 4  
1 3 0 –  1 3 1  
1 2 5 –  1 2 9  
< 1 2 5  
S o di u m –  H y per natre mia 
m E q/ L  
1 4 4 –  1 4 5  
1 4 6 –  1 4 7  
1 4 8 –  1 5 0  
> 1 5 0  
P otassi u m –  H y per kale mia 
m E q/ L  
5. 1 –  5. 2  
5. 3 –  5. 4  
5. 5 –  5. 6  
> 5. 6  
P otassi u m –  H y p o kale mia 
m E q/ L  
3. 5 –  3. 6  
3. 3 –  3. 4  
3. 1 –  3. 2  
< 3. 1  
Gl uc ose –  H y p o gl yce mia 
m g/ d L  
6 5 –  6 9  
5 5 –  6 4  
4 5 –  5 4  
< 4 5  
Gl uc ose –  H y per gl yce mia  
Fasti n g – m g/ d L  
Ra n d o m – m g/ d L  
1 0 0 –  1 1 0  
1 1 0 – 1 2 5  
1 1 1 –  1 2 5  
1 2 6 – 2 0 0  
> 1 2 5  
> 2 0 0  
I ns uli n 
re q uire me nts or 
h y per os m olar 
c o ma  
Bl o o d Urea Nitr o ge n  
B U N m g/ d L  
2 3 –  2 6  
2 7 –  3 1  
> 3 1  
Re q uires dial ysis  
Creati ni ne –  m g/ d L  
1. 5 –  1. 7  
1. 8 –  2. 0  
2. 1 –  2. 5  
> 2. 5 or re q uir es 
dial ysis  
Calci u m –  h y p ocalce mia 
m g/ d L  
8. 0 –  8. 4  
7. 5 –  7. 9  
7. 0 –  7. 4  
< 7. 0  
Calci u m –  h y percalce mia 
m g/ d L  
1 0. 5 –  1 1. 0  
1 1. 1 –  1 1. 5  
1 1. 6 –  1 2. 0  
> 1 2. 0  
Ma g nesi u m –  
h y p o ma g nese mia m g/ d L  
1. 3 –  1. 5  
1. 1 –  1. 2  
0. 9 –  1. 0  
< 0. 9  
P h os p h or o us –  
h y p o p h os p hate mia m g/ d L  
2. 3 –  2. 5  
2. 0 –  2. 2  
1. 6 –  1. 9  
< 1. 6  
C P K –  m g/ d L  
1. 2 5 –  1. 5 x 
U L N * * *  
1. 6 –  3. 0 x U L N  
3. 1 – 1 0 x U L N  
> 1 0 x U L N  
Al b u mi n –  H y p oal b u mi ne mia 
g/ d L  
2. 8 –  3. 1  
2. 5 –  2. 7  
< 2. 5  
--  
T otal Pr otei n –  
H y p o pr otei ne mia g/ d L  
5. 5 –  6. 0  
5. 0 –  5. 4  
< 5. 0  
--  
Al kali ne p h os p hate –   
i ncrease b y fact or  
1. 1 –  2. 0 x U L N  
2. 1 –  3. 0 x U L N  
3. 1 –  1 0 x U L N  
> 1 0 x U L N  
Li ver F u ncti o n Tests – A L T, 
A S T  
i ncrease b y fact or  
1. 1 –  2. 5 x U L N  
2. 6 –  5. 0 x U L N  
5. 1 –  1 0 x U L N  
> 1 0 x U L N  


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Bilirubin – when 
accompanied  
by any increase in Liver 
Function Test  
increase by factor  
1.1 – 1.25 x ULN  
1.26 – 1.5 x ULN  
1.51 – 1.75 x ULN  > 1.75 x ULN  
Bilirubin – when Liver 
Function Test is normal; 
increase by factor  
1.1 – 1.5 x ULN  
1.6 – 2.0 x ULN  
2.0 – 3.0 x ULN  
> 3.0 x ULN  
Cholesterol  
201 – 210  
211 – 225  
> 226  
---  
Pancreatic enzymes – 
amylase, lipase  
1.1 – 1.5 x ULN  
1.6 – 2.0 x ULN  
2.1 – 5.0 x ULN  
> 5.0 x ULN  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.  
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as Potentially Life Threatening (grade 4). For example. a low sodium value that falls within 
a grade 3 parameter (125-129 mE/L) should be recorded as a grade 4 hyponatremia event if the subject had a new 
seizure associated with the low sodium value.  
***ULN” is the upper limit of the normal range. 


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
6 7  
C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
 
He m at ol o g y *  
Mil d ( Gr a de 1)  
M o der ate  
( Gr a de 2)  
Se vere ( Gr a de 3)  
P ote nti all y Life  
T hre ate ni n g 
( Gr a de 4)  
He m o gl o bi n ( Fe male) - 
g m/ d L  
1 1. 0 –  1 2. 0  
9. 5 –  1 0. 9  
8. 0 –  9. 4  
< 8. 0  
H e m o gl o bi n ( Fe male)  
c ha n ge fr o m Baseli ne val ue 
- g m/ d L  
A n y decrease –  1. 5  1. 6 –  2. 0  
2. 1 –  5. 0  
> 5. 0  
He m o gl o bi n ( Male) - g m/ d L  1 2. 5 –  1 3. 5  
1 0. 5 –  1 2. 4  
8. 5 –  1 0. 4  
< 8. 5  
He m o gl o bi n ( Male)  
c ha n ge fr o m Baseli ne val ue 
–  g m/ d L  
A n y decrease –  1. 5  1. 6 –  2. 0  
2. 1 –  5. 0  
> 5. 0  
W B C I ncrease - cell/ m m
3
 
1 0, 8 0 0 –  1 5, 0 0 0  
1 5, 0 0 1 –  2 0, 0 0 0  
2 0, 0 0 1 –  2 5, 0 0 0  
> 2 5, 0 0 0  
W B C Decrease - cell/ m m
3
 
2, 5 0 0 –  3, 5 0 0  
1, 5 0 0 –  2, 4 9 9  
1, 0 0 0 –  1, 4 9 9  
< 1, 0 0 0  
L y m p h oc ytes Decrease - 
cell/ m m
3
 
7 5 0 –  1, 0 0 0  
5 0 0 –  7 4 9  
2 5 0 –  4 9 9  
< 2 5 0  
Ne utr o p hils Decrease - 
cell/ m m
3
 
1, 5 0 0 –  2, 0 0 0  
1, 0 0 0 –  1, 4 9 9  
5 0 0 –  9 9 9  
< 5 0 0  
E osi n o p hils - cell/ m m
3
 
6 5 0 –  1 5 0 0  
1 5 0 1 - 5 0 0 0  
> 5 0 0 0  
H y pere osi n o p hilic  
Platelets Decrease d - 
cell/ m m
3
 
1 2 5, 0 0 0 –  1 4 0, 0 0 0  1 0 0, 0 0 0 –  1 2 4, 0 0 0  2 5, 0 0 0 –  9 9, 0 0 0  
< 2 5, 0 0 0  
P T –  i ncrease b y fact or  
( pr ot hr o m bi n ti me)  
1. 0 –  1. 1 0 x 
U L N * *  
1. 1 1 –  1. 2 0 x 
U L N  
1. 2 1 –  1. 2 5 x U L N  > 1. 2 5 U L N  
P T T –  i ncrease b y fact or  
( partial t hr o m b o plasti n ti me)  
1. 0 –  1. 2 x U L N  
1. 2 1 –  1. 4 x U L N  
1. 4 1 –  1. 5 x U L N  
> 1. 5 x U L N  
Fi br i n o ge n i ncrease - m g/ d L  4 0 0 –  5 0 0  
5 0 1 –  6 0 0  
> 6 0 0  
--  
Fi bri n o ge n decrease - 
m g/ d L  
1 5 0 –  2 0 0  
1 2 5 –  1 4 9  
1 0 0 –  1 2 4  
< 1 0 0 or 
ass ociate d  
wit h gr oss 
blee di n g  
or disse mi nate d 
i ntra vasc ular 
c oa g ulati o n ( DI C)  
* T he la b orat or y val ues pr o vi de d i n t he ta bles ser ve as g ui deli nes a n d are de pe n de nt u p o n i nstit uti o nal n or mal 
para meters. I nstit uti o nal n or mal refere nce ra n ges s h o ul d be pr o vi de d t o de m o nstrate t hat t he y are a p pr o priate.  
* * “ U L N” is t he u p per li mit of t he n or mal ra n ge.  
 
 
 
 
 
 
 


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Urine *  
Mild (Grade 1)  
Moderate  
(Grade 2)  
Severe (Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Protein  
Trace  
1+  
2+  
Hospitalization or  
dialysis  
Glucose  
Trace  
1+  
2+  
Hospitalization for  
hyperglycemia  
Blood (microscopic) –  
red blood cells per  
high power field (rbc/hpf)  
1 - 10  
11 – 50  
> 50 and/or gross  
blood  
Hospitalization or  
packed red blood  
cells (PRBC)  
transfusion  
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal 
parameters. Institutional normal reference ranges should be provided to demonstrate that they are appropriate.  
 
IV. REFERENCES  
1. National Cancer Institute Common Toxicity Criteria, April 30, 1999. 
(http://ctep.cancer.gov/reporting/CTC-3.html)  
 
2. Division of AIDS Table for Grading Severity of Adult Adverse Experiences; August 1992. 
(http://rcc.tech-res-intl.com/tox_tables.htm)  
 
3. The Brighton Collaboration. Finalized Case Definitions and Guidelines. 
(http://brightoncollaboration.org/internet/en/index/definition___guidelines.html)  
 
4. HIV Vaccine Trials Network Table for Grading Severity of Adverse Experiences; September 18, 
2002. (http://rcc.tech-res-intl.com/tox_tables.htm)  
 
5. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
December 2004. 
(http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/Safety/DAIDSAEGrading
Table.pdf)  
 
6. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Laboratory Reference Values. New England 
Journal of Medicine. 2004;351:1548-1563.  
 
 
 
 
 


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APPENDIX 2: NYHA CLASSIFICATIONS 
Doctors usually classify patients' heart failure according to the severity of their 
symptoms. The table below describes the most commonly used classification system, 
the New York Heart Association (NYHA) Functional Classification. It places patients in 
one of four categories based on how much they are limited during physical activity. 
 
Class Functional Capacity: How a patient with cardiac disease 
feels during physical activity 
I 
Patients with cardiac disease but resulting in no limitation of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea or 
anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea or 
anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  
If any physical activity is undertaken, discomfort increases. 
 
NOTE: Class IIIa: No Dyspnea at rest; Class IIIb: Recent Dyspnea at rest  
SOURCE: 
American Heart Association: Classes of Heart Failure 
Internet address: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-
Heart-Failure_UCM_306328_Article.jsp 
 


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APPENDIX 3: 6-MINUTE WALKING TEST 
 
ARRAY-797-001 
Instructions for the Six-Minute Walk Test 
 
SOURCE: 
ATS Statement: Guidelines for the Six-Minute Walk Test 
THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY WAS APPROVED 
BY THE ATS BOARD OF DIRECTORS MARCH 2002 
 
Am J Respir Crit Care Med Vol 166. pp 111–117, 2002 
DOI: 10.1164/rccm.166/1/111 
Internet address: www.atsjournals.org 
 
BACKGROUND: 
The Six-Minute Walk Test (6MWT) is a practical simple test that requires a 100-ft hallway but no 
exercise equipment or advanced training for technicians. Walking is an activity performed daily 
by all but the most severely impaired patients. This test measures the distance that a patient 
can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD). It evaluates the 
global and integrated responses of all the systems involved during exercise, including the 
pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, 
neuromuscular units, and muscle metabolism. It does not provide specific information on the 
function of each of the different organs and systems involved in exercise or the mechanism of 
exercise limitation, as is possible with maximal cardiopulmonary exercise testing. The self-
paced 6MWT assesses the submaximal level of functional capacity. Most patients do not 
achieve maximal exercise capacity during the 6MWT; instead, they choose their own intensity of 
exercise and are allowed to stop and rest during the test. However, because most activities of 
daily living are performed at submaximal levels of exertion, the 6MWD may better reflect the 
functional exercise level for daily physical activities. 
 
Contraindications and Patient Evaluation Preceding Test 
Absolute contraindications for the 6MWT include the following: unstable angina during the 
previous month and myocardial infarction during the previous month. Relative contraindications 
include a resting heart rate of more than 120, a systolic blood pressure of more than 180 mm 
Hg, and a diastolic blood pressure of more than 100 mm Hg.  
 
Patients with any of these findings should be referred to the physician ordering or supervising 
the test for individual clinical assessment and a decision about the conduct of the test. The 


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results from a resting electrocardiogram done during the previous 6 months should also be 
reviewed before testing. Stable exertional angina is not an absolute contraindication for a 
6MWT, but patients with these symptoms should perform the test after using their antiangina 
medication, and rescue nitrate medication should be readily available. 
 
Safety Considerations and Precautions for Six-Minute Walk Testing 
The following measures should be in place prior to starting the 6MWT at a site: 
1. Testing should be performed in a location where a rapid, appropriate response to an 
emergency is possible. The appropriate location of a crash cart should be determined by 
the physician supervising the facility. 
2. Supplies that must be available include oxygen, sublingual nitroglycerine, aspirin, and 
albuterol (metered dose inhaler or nebulizer). A telephone or other means should be in 
place to enable a call for help. 
3. The technician should be certified in cardiopulmonary resuscitation with a minimum of 
Basic Life Support by an American Health Association–approved cardiopulmonary 
resuscitation course. Advanced cardiac life support certification is desirable. Training, 
experience, and certification in related health care fields (registered nurse, registered 
respiratory therapist, certified pulmonary function technician, etc.) are also desirable. A 
certified individual should be readily available to respond if needed. 
4. Physicians are not required to be present during all tests. The physician ordering the test 
or a supervising laboratory physician may decide whether physician attendance at a 
specific test is required. 
5. If a patient is on chronic oxygen therapy, oxygen should be given at their standard rate 
or as directed by a physician or a protocol. 
 
Reasons for immediately stopping a 6MWT include the following: 
(1) chest pain, 
(2) intolerable dyspnea,  
(3) leg cramps,  
(4) staggering, 
(5) diaphoresis, and  
(6) pale or ashen appearance. 
 
Technicians must be trained to recognize these problems and the appropriate responses. If a 
test is stopped for any of these reasons, the patient should sit or lie supine as appropriate 
depending on the severity or the event and the technician’s assessment of the severity of the 
event and the risk of syncope. The following should be obtained based on the judgment of the 
technician: blood pressure, pulse rate, oxygen saturation, and a physician evaluation. Oxygen 
should be administered as appropriate. 
 
 
 
 


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TEST PROCEDURES: 
 
LOCATION 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. If the weather is comfortable, the test may be performed 
outdoors. The walking course must be 30 m in length. A 100-ft hallway is, therefore, required. 
The length of the corridor should be marked every 3 m. The turnaround points should be 
marked with a cone (such as an orange traffic cone). A starting line, which marks the beginning 
and end of each 60-m lap, should be marked on the floor using brightly colored tape. 
 
REQUIRED EQUIPMENT 
1. Countdown timer (or stopwatch) 
2. Mechanical lap counter 
3. Two small cones to mark the turnaround points 
4. A chair that can be easily moved along the walking course 
5. Worksheets on a clipboard 
6. A source of oxygen 
7. Sphygmomanometer 
8. Telephone 
9. Automated electronic defibrillator 
 
PATIENT PREPARATION 
1. Comfortable clothing should be worn. 
2. Appropriate shoes for walking should be worn. 
3. Patients should use their usual walking aids during the test (cane, walker, etc.). 
4. The patient’s usual medical regimen should be continued. 
5. A light meal is acceptable before early morning or early afternoon tests. 
6. Patients should not have exercised vigorously within 2 hours of beginning the test. 
 
MEASUREMENTS 
1. Repeat testing should be performed about the same time of day to minimize intraday 
variability. 
2. A “warm-up” period before the test should not be performed. 
3. The patient should sit at rest in a chair, located near the starting position, for at least 10 
minutes before the test starts. During this time, check for contraindications, measure 
pulse and blood pressure, and make sure that clothing and shoes are appropriate. 
Compete the first portion of the worksheet (See the Worksheet in Attachment1). 


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4. Pulse oximetry is optional. If it is performed, measure and record baseline heart rate and 
oxygen saturation (SpO2) and follow manufacturer’s instructions to maximize the signal 
and to minimize motion artifact. Make sure the readings are stable before recording. 
Note pulse regularity and whether the oximeter signal quality is acceptable. 
 
The rationale for measuring oxygen saturation is that although the distance is the 
primary outcome measure, improvement during serial evaluations may be manifest 
either by an increased distance or by reduced symptoms with the same distance walked 
(39). The SpO2 should not be used for constant monitoring during the exercise. The 
technician must not walk with the patient to observe the SpO2. If worn during the walk, 
the pulse oximeter must be lightweight (less than 2 pounds), battery powered, and held 
in place (perhaps by a “fanny pack”) so that the patient does not have to hold or stabilize 
it and so that stride is not affected. Many pulse oximeters have considerable motion 
artifact that prevents accurate readings during the walk.  
5. Have the patient stand and rate their baseline dyspnea and overall fatigue using the 
Borg scale (see the Borg scale and instructions here). 
 
THE BORG SCALE 
0  
Nothing at all 
0.5  
Very, very slight (just noticeable) 
1  
Very slight 
2  
Slight (light) 
3  
Moderate 
4  
Somewhat severe 
5  
Severe (heavy) 
6 
7  
Very severe 
8 
9 
10  
Very, very severe (maximal) 
 
This Borg scale should be printed on heavy paper (11 inches high and perhaps 
laminated) in 20-point type size. At the beginning of the 6-minute exercise, show 
the scale to the patient and ask the patient this: “Please grade your level of 
shortness of breath using this scale.” Then ask this: “Please grade your level of 
fatigue using this scale.” 
 
At the end of the exercise, remind the patient of the breathing number that they 
chose before the exercise and ask the patient to grade their breathing level 
again. Then ask the patient to grade their level of fatigue, after reminding them of 
their grade before the exercise. 


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6. Set the lap counter to zero and the timer to 6 minutes. Assemble all necessary 
equipment (lap counter, timer, clipboard, Borg Scale, worksheet) and move to the 
starting point. 
7. Instruct the patient as follows: 
 
“The object of this test is to walk as far as possible for 6 minutes. You will walk 
back and forth in this hallway. Six minutes is a long time to walk, so you will be 
exerting yourself. You will probably get out of breath or become exhausted. You 
are permitted to slow down, to stop, and to rest as necessary. You may lean 
against the wall while resting, but resume walking as soon as you are able. You 
will be walking back and forth around the cones. You should pivot briskly around 
the cones and continue back the other way without hesitation.  
 
Now I’m going to show you. Please watch the way I turn without hesitation.” 
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly. 
 
“Are you ready to do that? I am going to use this counter to keep track of the 
number of laps you complete. I will click it each time you turn around at this 
starting line. Remember that the object is to walk AS FAR AS POSSIBLE for 6 
minutes, but don’t run or jog.  
 
Start now, or whenever you are ready.” 
 
8. Position the patient at the starting line. You should also stand near the starting line 
during the test. Do not walk with the patient. As soon as the patient starts to walk, start 
the timer. 
9. Do not talk to anyone during the walk. Use an even tone of voice when using the 
standard phrases of encouragement. Watch the patient. Do not get distracted and lose 
count of the laps. Each time the participant returns to the starting line, click the lap 
counter once (or mark the lap on the worksheet). Let the participant see you do it. 
Exaggerate the click using body language, like using a stopwatch at a race. 
 
After the first minute, tell the patient the following (in even tones): “You are doing 
well. You have 5 minutes to go.”  
 
When the timer shows 4 minutes remaining, tell the patient the following: “Keep 
up the good work. You have 4 minutes to go.”  
 
When the timer shows 3 minutes remaining, tell the patient the following: “You 
are doing well. You are halfway done.” 
 


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When the timer shows 2 minutes remaining, tell the patient the following: “Keep 
up the good work. You have only 2 minutes left.”  
 
When the timer shows only 1 minute remaining, tell the patient: “You are doing 
well. You have only 1 minute to go.” 
 
Do not use other words of encouragement (or body language to speed up). 
 
If the patient stops walking during the test and needs a rest, say this: “You can 
lean against the wall if you would like; then continue walking whenever you feel 
able.” Do not stop the timer. If the patient stops before the 6 minutes are up and 
refuses to continue (or you decide that they should not continue), wheel the chair 
over for the patient to sit on, discontinue the walk, and note on the worksheet the 
distance, the time stopped, and the reason for stopping prematurely. 
When the timer is 15 seconds from completion, say this: “In a moment I’m going 
to tell you to stop. When I do, just stop right where you are and I will come to 
you.” When the timer rings (or buzzes), say this: “Stop!” Walk over to the patient. 
Consider taking the chair if they look exhausted.  
Mark the spot where they stopped by placing a bean bag or a piece of tape on 
the floor. 
 
10. Post-test: Record the postwalk Borg dyspnea and fatigue levels and ask this: “What, if 
anything, kept you from walking farther?” 
(see Borg Scale and instructions above in step 5) 
11. If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and then 
remove the sensor. 
12. Record the number of laps from the counter (or tick marks on the worksheet). 
13. Record the additional distance covered (the number of meters in the final partial lap) 
using the markers on the wall as distance guides. Calculate the total distance walked, 
rounding to the nearest meter, and record it on the worksheet. 
14. Congratulate the patient on good effort and offer a drink of water. 
 
Notes for Sites: 
• 
Whenever possible, the same technician should administer the 6MWT for a given 
patient, in order to minimize variability on coaching and patient performance 
• 
The technician must use only the standardized phrases for encouragement during the 
test (as specified previously here). 
• 
If oxygen supplementation is needed during the walks and serial tests are planned (after 
an intervention other than oxygen therapy), then during all walks by that patient oxygen 
should be delivered in the same way with the same flow. 
 
 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
76 
Confidential 
01 December 2014 
Attachment 1 
6MWT worksheet and report: 
 
Lap counter: __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ 
 
Patient name: ____________________ Patient ID# ___________ 
 
Walk # ______ Tech ID: _________ Date: __________ 
 
Gender: M    F  
 
Age: ____ Race: ____ Height: ___ft ____in, ____ meters 
 
Weight: ______ lbs, _____kg  
 
Blood pressure: _____ / _____ 
 
Medications taken before the test): _________________  Dose:___________ Time:____ : ____ 
 
 
 
 
 
 
 
 
 
 
 
_____________________  Dose:___________ Time:____ : ____ 
 
 
 
 
_____________________  Dose:___________ Time:____ : ____ 
 
 
 
 
_____________________  Dose:___________ Time:____ : ____ 
 
Supplemental oxygen during the test: (circle)     No       Yes,  flow ______ L/min, type _____ 
 
Baseline  
 
End of Test 
 
Time   
___:___  
 
___:___ 
 
Heart Rate  
_____   
 
_____ 
 
Dyspnea  
____  
 
____  (Borg scale) 
 
Fatigue  
____   
 
____   (Borg scale) 
 
SpO2   
____ %  
 
 
____% 
 
Stopped or paused before 6 minutes? (circle)    No     Yes, reason: _______________ 
 
Other symptoms at end of exercise: (circle all that apply) Angina / Dizziness / Hip, leg, calf pain 
 
Number of laps: ____ (_60 meters)  Final partial lap: _____ meters  
 
Total distance walked in 6 minutes:  ______ meters 
 
Predicted distance: _____ meters  
 
Percent predicted: _____% 
 
Tech comments: 
Interpretation (including comparison with a pre-intervention 6MWD): 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
77 
Confidential 
01 December 2014 
APPENDIX 4: SF-36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Your Health and Well-Being 
This sun-cy 
for your \'iews about your bn.Jth. This info,.,.jlio 
tr.aek of bow you feel and how 
you are abk to do y 
Tl1ank p mfor romplrlingllris sun·ey! 
For ead1 oftbt foUowing questions. pkasc mar·k an 
de scribes your answu, 
l. ln getl(ra.l. would you say your 1k 
2. 
ould you ralc your lkalth in l;(trral 
About tOO 
So!rewhot 
Mucbwoo;e 
sarre a.<> ore 
w""' 
now thlnooo 
wed: a.ao 
oow than ore 
""'kat<> 
week aao 
.... 
.... 
.... 
o . 
o. 
o. 
o. 
...... t' .... It>,_,.() 
... , ..,. __ 
!».,...!' ,.,..,.,,_,. ....... l!'lllniol 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
78 
Confidential 
01 December 2014 
 
 
 
 
3. Tlk foUowing que.!>1joos are about actn'ities you mighl do during a typica1 
day. Docs yoor Jw.alth now limit "·ou in the-se acth•ities? If so, how much? 
Yienmns arti'='Qj>s such as nmnina, iftio.a 
!)?.avy ol:!j.>cli. puU:ipatio.a in sttenoous sporiS 
MntRrm ¥1ivirf.s sudl a<> roovio.t a Llbta. pusltio.t 
a vacuum c.t>an?:r. bowtini. or pllyiut tolf 
Liftila or canyina a,roceri>:s.. 
Ctinili1t2 StW€rnl Oi£hiS of stairs ... 
Ctintli1t2 mn ftiahl of sr.airs •• 
v., 
limiled ... ... 
Yes. limited 
No. not 
a litlla 
tinnd 
lllll ... 
.......... o. 
.. ......... o . 
mH o ............ 0 . 
mH O• ........... o , 
o ... mH o ............ o . 
o ... mH o .. mH o . 
............ o ............ o ............ o . 
........ t' .... 
.... .,.._... 
.................... fii-1-.,.Taot 
lll'-.,....t' , ... ,.,,...._., ....... lllolliOI lb ... (t¥o0JI 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
79 
Confidential 
01 December 2014 
 
 
 
4. During t.lk past 
how much of the tinr ban you had any of the 
following probkms with your wor·k or other regular daily ad:h•itics 
of "·our physical hulth? 
All of 
ll\1 titre 
.... 
Most of 
Sotre or 
A tiltle of 
Nooo of 
lh1 tm: 
lh1 titre 
tOO lirre 
tOO litre 
atL down on l.be amount of 
tme }Ott spenl on work « 
otrer aclivirias ............................... 0 • ............ w •............. L.:J 
• Arcmmlisfrd tsc; ttnn you 
woukl tiba ..................................... 0 • .......... .. 
Were tinWd in l.be kind of 
w«k « olh.>.r actidtes ................... O , 
5. 
• 
Did wort or otM 31.tivities 
ban you had any of the 
regular daily ad:h•itics 
!! (siKll as freling 
or anxious)? 
Most of 
Sotre or 
A tiltle of 
Nooo of 
lh1 tm: 
lh1 titre 
tOO lirre 
tOO litre 
................ 
ttun usuai .................. D , ............ D .............. 0 .............. 0 .............. 0 • 
...... t' .... 
........ 
................ 
Pl' .... t' ....... ,...._., ....... 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
80 
Confidential 
01 December 2014 
 
 
 
6. During t.lk past week, to what extent bas your physical lkalth or emotional 
probkms 
with your normal social acth•itics with family, (riencls, 
neighbors, or groups? 
8. 
Not aLd. 
Stiahuy 
Moderately 
Quil.e a biL 
... 
... 
... 
... 
D· 
D· 
Nooo 
Very mild 
... 
... 
interfere with your norma] work 
,out•ode,.,Jiortl< aold hous<work)? 
Quil.e a biL 
... 
o. 
•
"Uo<t' , ... lt>s"""-1() 
.... 
lli'-"Uo<t' "'"*'"""1"' .... l!'lllniol 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
81 
Confidential 
01 December 2014 
 
 
 
9. T hese questions are about bow you fed and bow 
ba\-e bcu with you 
during the pw;t \I!'Cck. For cadi qucstiol\ please gh-e the one aOS\'Iu that 
comes closest to t.hr way you ba\-e been (('ding. How muclt of the time 
during the pw;t \I!'Cck ... 
All of 
tOO litre ... 
Most of 
lh'! tm: 
... 
Did you W I fuDorJia? .................. 0 .............. D ........... .. 
• Have }00 
re.rvous? .......... D .............. D 
L...l 
• Have }00 k it so down in tOO 
dumps thl1 nolltin£ cOUld 
dleeryou up? ................................. o 
, Have 
k lt calm and 
A 6tll3 of 
Nore of 
tOO titre 
... 
..0 ' 
.............. o ............. o' 
............. o ............. o .............. o ............. o . 
10. 
Most of 
So!ooof 
A litll3 of 
Noooof 
tlu titre 
tOO lirre 
tOO titre 
tOO titre 
... 
... 
... 
... 
D· 
D· 
D· 
D· 
....... t' .... Ito,......,() 
... , ..,. __ 
.. 11! .. ................ 
Pl'-.,...t' ..... ,......, ....... ._ 


ARRY-371797 (p38 MAP Kinase Inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-797-001 
 
Version 1 
82 
Confidential 
01 December 2014 
 
 
 
1 t 
How TRUE or FALSE is each of the following stalcnrats for you? 
OeliniLely 
M"'"Y 
""' 
... 
• • 
I JWm lo 
skit a lillie 
th:ar,nl'hlf IW"ff.,. 
D· 
D· 
o . 
• I am as relllhy a.<> 
anybody I know ............................ 0 • ............ 0 ... . 
I expect n:y realth to 
i-?1 worse ...................................... 0 • 
My haalthisexcetl>.nl .................... 0 '··· 
•"Uo<t' , ... 
,.,,..,_,.*""" 
lli'-"Uo<t' ..... ,.....,. ....... ._ 
Mostly 
false • 
D:lfioitely I 
,,,. • 
D· 
0. 
o . 


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
8 3  
C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
 
C CI


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
8 4  
C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
 
C CI


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
8 5  
C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
 
C CI


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
8 6  
C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
 
C CI


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
8 7  
C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
 
C CI


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
8 8  
C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
 
C CI


A R R Y -3 7 1 7 9 7 ( p 3 8 M A P Ki nase I n hi bit or ) 
Arra y Bi o P har ma I nc.  
Cli nical St u d y A R R A Y -7 9 7 -0 0 1  
 
Versi o n 1 
8 9  
C o nfi de ntial  
0 1 Dece m ber  2 0 1 4  
 
C CI

SAP_001.pdf: 
ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
STATISTICAL ANALYSIS PLAN
STUDY PRODUCT
ARRY-371797
PROTOCOL
ARRAY-797-001 V1.0
Protocol Date: 01DEC2014
SPONSOR
Array BioPharma, Inc.
3200 Walnut St.
Boulder, CO 80301
STUDY TITLE
An Open-label Rollover Study  of ARRY-371797 in Patients 
with Symptomatic Genetic
Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
Version: 1
Date: 07AUG2017


I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9 
St atistic al A n al ysis Pla n V J 
0 7 A U 0 2 0 1 7 
Si g n at u r e P a g e 
Arr a y Bi o P h ar m a, I n c, 
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1 
T his d oc u me nt has bee n pre pare d a n dl or re vie we d b y I he f oll o wi n g pers o n nel: 
, M S 
Se ni or Bi oslatisticia n I 
I C O N pic 
A p pr o ve d b y: 
. 
Se ni or Pr o gr a m M a n a ger, Bi ost atistics 
I C O N pic 
 P h D 
Arra y Bi o P harr na, I nc. 
/ 7 ;J,,' 1 P all 
Date 
Dale 
Date 
P P D
P P D
P P D
P P D
P P D
P P D
P P D


ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
3
TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS AND DEFINITIONS.......................................................................................5
 
2.
INTRODUCTION..............................................................................................................................................8 
3.
STUDY OBJECTIVES AND ENDPOINTS ....................................................................................................8  
3.1.
PRIMARY OBJECTIVE...................................................................................................................................8
3.2.
SECONDARY OBJECTIVES............................................................................................................................8
3.3.
ENDPOINTS..................................................................................................................................................8
3.3.1. 
Primary Endpoint ............................................................................................................... ...................8 
3.3.2. 
Secondary E ndpoints .............................................................................................................................8 
4.
STUDY DESIGN................................................................................................................... .............................9 
4.1.
GENERAL DESIGN CHARACTERISTICS AND STUDY TREATMENT .................................................................9
4.2.
DOSES AND SCHEDULE OF ADMINISTRATION ..............................................................................................9
4.3.
TREATMENT COMPLIANCE ........................................................................................................................10
4.4.
TREATMENT ARM ASSIGNMENT................................................................................................................10
4.5.
BLINDING..................................................................................................................................................10
4.6.
STUDY PROCEDURES AND EVALUATIONS..................................................................................................10
4.7.
TREATMENT DISCONTINUATION................................................................................................................10
4.7.1. 
Treatment Discontinuation fo r Individual Patients .............................................................................1 0 
4.7.2. 
Sponsor Discontinuation Criteria............................................................................................... .........11 
5.
STATISTICAL CONSIDERATIONS..................................................................................................... .......12 
5.1.
DEFINITIONS AND CONVENTIONS..............................................................................................................12
5.2.
ADJUSTMENT FOR COVARIATES ................................................................................................................13
5.3.
HANDLING DROPOUTS OR MISSING DATA.................................................................................................13
5.4.
INTERIM ANALYSIS AND DATA MONITORING............................................................................................14
5.5.
MULTICENTER STUDIES.............................................................................................................................14
5.6.
MULTIPLE COMPARISONS/MULTIPLICITY..................................................................................................14
5.7.
EXAMINATIONS OF SUBGROUPS ................................................................................................................14
5.8.
SAMPLE SIZE ESTIMATION ........................................................................................................................14
6.
ANALYSIS POPULATIONS........................................................................................................... ...............14 
6.1.
SAFETY ANALYSIS SET..............................................................................................................................14
6.2.
EFFICACY ANALYSIS SET ..........................................................................................................................14
6.3.
PHARMACOKINETIC ANALYSIS SET...........................................................................................................15


I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9
Arra y Bi o P har ma, I nc. 
Statistical A nal ysis Pla n V 1
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1
0 7 A U G 2 0 1 7
4
7.
A S S E S S M E N T S, A N A L Y S E S, A N D P R E S E N T A TI O N S........................................................................... 1 5  
7. 1.
P A TI E N T D I S P O SI TI O N ...............................................................................................................................1 6
7. 2.
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S ........................................................................ 1 6
7. 3.
M E DI C A L H I S T O R Y.................................................................................................................................... 1 6
7. 4.
P RI O R A N D C O N C O MI T A N T M E DI C A TI O N S ................................................................................................ 1 6
7. 5.
E F FI C A C Y A N A L Y S E S ................................................................................................................................ 1 7
7. 5. 1.  
Sec o n d ary Effic acy E n d p oi nt a n d A n alysis ....................................................................................... .. 1 7 
7. 5. 1. 1  6 M W T at We e ks 2 4, 4 8, 7 2 a n d 9 6 a n d, if a p plica ble, ter mi nati o n visit................................................. ........... 1 7
7. 5. 1. 2 Ec h o car di o gra m C o m plet e  wit h C o ntrast............................................................................................................ 1 7
7. 5. 1. 3 S F- 3 6.................................................................................................................. ................................................. 1 8
7. 5. 1. 4 Q O L  b y K C C Q ................................................................................................................................................... 1 9
7. 6.
S A F E T Y A N A L Y S E S .................................................................................................................................... 2 0
7. 6. 1.  
Exte nt of Ex p os ure............................................................................................................. .................. 2 0 
7. 6. 2.  
A dverse Eve nts a n d Seri o us A dverse Eve nts...................................................................................... .. 2 0 
7. 6. 3.  
De at h .......................................................................................................................... ......................... 2 2 
7. 6. 4.  
L a b or at or y d at a ................................................................................................................ ................... 2 3 
7. 6. 5.  
Vit al Si g ns.................................................................................................................... ........................ 2 3 
7. 6. 6.  
E C G ............................................................................................................................ ......................... 2 3 
7. 6. 7.  
P hysic al Ex a mi n ati o n ........................................................................................................... ............... 2 4 
7. 7  
P H A R M A C O KI N E TI C A N A L Y S E S ...................................................................................................................... 2 4
8.
P R O T O C O L D E VI A TI O N S A N D M A J O R P R O T O C O L VI O L A TI O N S ............................................... 2 5  
9.
R E F E R E N C E S..................................................................................................................... ............................ 2 5 
A P P E N DI X I. S C H E D U L E  O F E V E N T S.................................................................................................. ............. 2 6 
 
A P P E N DI X III. LI S T O F P L A N N E D T A B L E S, LI SI T N G S A N D FI G U R E S ................................................... 3 5  
C CI


ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
5
1.
LIST OF ABBREVIATIONS AND DEFINITIONS
Abbreviation 
or special 
term
Explanation
6MWT
6-minute walk test
AE
Adverse event
ATC
Anatomical therapeutic chemical classification codes
AUC
Area under the curve
BID
Twice daily
BLQ
Below the limit of quantitation
BP
Blood pressure
bpm
beats per minute
Cpostdose,SS
Post dose concentration at steady state
Cmax
Maximum concentration
CV
Coefficient of variation
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
ICD
Implantable cardioverter defibrillator
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IRB
Institutional Review Board
KCCQ
Kansas City Cardiomyopathy Questionnaire


ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
6
Abbreviation 
or special 
term
Explanation
LMNA
Gene encoding the Lamin A/C protein
LV
Left ventricular
MR
Metabolite-to-parent concentration ratio
MedDRA®
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
NBLQ
Number of BLQ observations
NC
Not calculated
Nvalid
Number of valid observations
PK
Pharmacokinetic(s)
PR
Pulse rate
R
Drug accumulation
QOL
Quality of life
QT
QT interval: a measurement of the time between the start of the Q wave and the 
end of the T wave in an ECG
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RV
Right ventricular
RVEDD
Right ventricular end-diastolic diameter
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure


ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
7
Abbreviation 
or special 
term
Explanation
SD
Standard Deviation
SF-36
Medical Outcomes Study 36-item Short-Form Health Survey
SOC
System Organ Class
SpO2
Oxygen saturation
TEAE
Treatment Emergent Adverse Event
VT
Vitality
WHODDE
WHO Drug Dictionary enhanced


ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
8
2.
INTRODUCTION
The purpose of this Statistical Analysis Plan (SAP) is to ensure the validity of the findings of
Array BioPharma Study ARRAY-797-001 by specifying a priori the statistical approaches to the 
analyses. It was developed based on International Conference on Harmonisation (ICH) E3 and 
E9 Guidelines, and information provided in Protocol ARRAY-797-001, Version 1.0, dated 01
December 2014 [1].
3.
STUDY OBJECTIVES AND ENDPOINTS
3.1.
Primary Objective

To evaluate the safety of ARRY-371797 administered after completion of the parent study.
3.2.
Secondary Objectives

To evaluate measures of efficacy of ARRY-371797

To determine the exposure of ARRY-371797 and metabolites
3.3.
Endpoints
3.3.1. Primary Endpoint

Incidence and severity of adverse events (AEs), clinical laboratory tests (hematology, 
chemistry), physical examination, vital signs (blood pressure [BP] and pulse rate [PR]) and 
12-lead electrocardiogram (ECG) values.
3.3.2. Secondary Endpoints
Assessed at 24, 48, 72 and 96 weeks and termination visit (if applicable):

6-minute walk test (6MWT)

Left ventricular (LV) end systolic volume index (LVESVI)

Left ventricular end diastolic volume index (LVEDVI)

LV mass

LV ejection fraction

LV mass-to-volume ratio

Right ventricular (RV) end-diastolic diameter (RVEDD) and RV fractional area

Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) and Quality of Life
(QOL) by Kansas City Cardiomyopathy Questionnaire (KCCQ)

Plasma concentrations of ARRY-371797 and metabolites pre-dose and at a single time
point 1 to 2 hours post-dose at the Screening Visit and at 12 and 24 weeks


ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
9
4.
STUDY DESIGN
4.1.
General Design Characteristics and Study Treatment
This rollover study is designed to investigate the safety and efficacy of ARRY-371797
administration in patients who previously received ARRY-371797 in a LMNA mutation study
sponsored by Array BioPharma and may, in the investigator’s opinion, derive benefit from
continued treatment.
Patients will be screened for eligibility at the last visit in the treatment period of the parent study.
Eligible patients will be enrolled into the study immediately upon confirmation of eligibility so
that ARRY-371797 administration is not interrupted.
Clinic visits for safety assessments and study drug dispensing will be performed every 12 weeks
(± 14 days) through 48 weeks, then every 24 weeks (± 14 days) until treatment discontinuation
criteria are met. Efficacy assessments (6MWT, echocardiogram, SF-36 and QOL KCCQ) will be
performed at 24, 48, 72 and 96 weeks and termination visit (if applicable). Patients will undergo
a termination visit as soon as possible after study drug discontinuation and a safety follow-up
visit 30 days (± 14 days) after the last dose of study drug.
4.2.
Doses and Schedule of Administration
Patients will receive ARRY-371797 at the same dose and schedule they were administered at the
conclusion of the parent study.
If a patient has tolerability concerns at 400 mg BID, they may be down-titrated to 200 mg BID
(400 mg total daily dose). If a patient has tolerability concerns at 200 mg BID, they may be
down-titrated to 100 mg BID (200 mg total daily dose).
If a patient’s machine-read post-Baseline visit triplicate ECG includes 2 or more individual
ECGs with a QTcF value > 500 msec, or QTcF mean 	


Baseline, administration of study drug should be held until over-read mean triplicate values are 
available. The over-read should be conducted by the Investigator or designated cardiologist 
reviewer. The Medical Monitor will be advised of any QTcF alterations and will assess the 
clinical significance of QTcF values with the Investigator and determine actions to be taken with 
dosing (e.g., if the patient has cardiac resynchronization therapy/ICD/pacemaker, the Investigator 
and Medical Monitor may determine that the patient can continue if findings are not clinically 
significant and/or unchanged from Baseline). Whenever possible, the over-read should be 
completed promptly in order to avoid or minimize treatment interruption.
If the over-read by the Investigator or designated cardiologist reviewer indicates that the mean 
triplicate value of either parameter is > 500 msec, action may be taken with study drug dosing if 
deemed necessary by the Investigator and Medical Monitor. Dosing should be held until QTcF 
	



ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
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If the patient is currently receiving 400 mg BID, the patient can be re-challenged at 
200 
!	


If the patient is currently receiving 200 mg BID, the patient can be re-challenged at 
100 
!	


If the patient is currently receiving 100 mg BID, the patient can be re-challenged at 
100 
!	 msec. If upon re-challenge at 100 mg BID the 
QTcF remains > 500 msec on over-read, study drug treatment should be discontinued.
4.3.
Treatment Compliance
Compliance with protocol-specified study drug treatment will be evaluated by an accounting of 
supplied and returned drug product and patient interviews at each clinic visit and may be further 
evaluated by plasma concentration analysis.
4.4.
Treatment Arm Assignment
Patients will receive ARRY-371797 at the same dose and schedule they received at the
conclusion of the parent study. Pending availability, all patients will receive the tablet
formulation.
4.5.
Blinding
Not applicable.
4.6.
Study Procedures and Evaluations
The anticipated overall length of the study for each patient is that patients may continue 
receiving ARRY-371797 as long as no treatment discontinuation criteria are met.
The primary endpoint will be Safety assessments assessed throughout the study. Secondary 
endpoints will be assessed at Weeks 24, 48, 72 and 96 and, if applicable, till termination visit.
Efficacy assessments include the 6MWT, LVESVI, LVEDVI, LV Mass, LV mass-to-volume 
ratio, RVEDD and RV fractional area, SF-36, and KCCQ. Safety assessments include adverse 
events, physical examination, vital signs and 12-lead ECG] and clinical laboratory tests
(Hematology and Chemistry).  PK assessments on blood samples will also be performed in this 
study. 
The study schedule of events is shown in Appendix I.
4.7.
Treatment Di scontinuation
4.7.1. Treatment Discontinuation for Individual Patients
ARRY-371797 administration must be discontinued for patients meeting any of the following 
criteria:


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• Withdrawal of consent
• Unacceptable AE(s) or failure to tolerate ARRY-371797
• Pregnancy or initiation of breastfeeding
• Lost to follow-up
In addition, the Investigator may remove a patient from the study if, in the opinion of the 
Investigator, it is not in the best medical interest of the patient to continue the study. Wherever 
possible, procedures and evaluations scheduled to occur at the Follow-up/Termination Visit
should be conducted for all patients who discontinue prior to study completion. The Sponsor 
should be notified of all study withdrawals in a timely manner. The Sponsor may also request 
that a patient be removed based on assessment of AEs, lack of compliance, protocol violation or 
the current medical status of the patient.
Patients may withdraw their consent to participate in the study at any time for any reason. If a 
patient withdraws consent, the date and stated reason for withdrawal of consent should be 
documented in the patient source documents and the eCRF. Patient data collected up to the date 
of consent withdrawal will be included in analyses.
In addition, a patient may decide to stop participating in the study at any time for any reason 
without prejudice to future medical care by the physician or at the institution. If a patient’s 
participation in the study is ended prematurely (whether due to patient request or Investigator or 
Sponsor decision), study drug will be discontinued and study staff must confirm if the patient 
wishes to also withdraw his/her consent to participate in the study.
If a patient does withdraw consent to participate in the study, previously collected samples and 
data will be processed for analysis and assessment for study purposes. 
If a patient does not withdraw consent to participate in the study, a Follow-up Visit should be 
performed as soon as possible after treatment cessation, ideally no later than 7 days after the last 
dose of study drug. The date and stated reason for study discontinuation should be documented.
If a patient does not respond to three consecutive follow-up attempts (i.e., telephone calls), a 
certified letter will be sent to the patient. The patient will be considered lost to follow-up if they 
do not respond to the certified letter within 2 weeks or the patient cannot otherwise be contacted 
or located.
4.7.2. Sponsor Discontinuation Criteria
This study may be discontinued at any time due to safety concerns, failure to meet expected 
enrollment goals, administrative reasons or at the discretion of the Sponsor. Should the study be 
terminated prematurely, the Sponsor will provide written notification to all Investigators and 
regulatory authorities and will specify the reason(s) for early termination. The Investigator must 


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inform the Institutional Review Board (IRB) promptly and provide the reason(s) for the 
termination.
5.
STATISTICAL CONSIDERATIONS
5.1.
Definitions and Conventions
Assessments of change from baseline to post-baseline will include only those patients with both 
baseline and post-baseline measurements. The handling of missing or dropout data is described 
in Section 5.3. The Baseline value for a parameter is defined as the last non-missing value before 
the initial administration of study treatment in parent study, unless otherwise specified.
For laboratory, vital signs, ECGs and echocardiograms, a last observation on treatment value 
will be defined as the last non-missing post-baseline value on or prior to the last dosing date 
before the patient is withdrawn from study treatment. This value will be set to missing if no such 
observation exists. The last observation on treatment may be a repeated or unscheduled test.
Electronic Case Report Form (eCRF) data will be captured and then converted to SAS datasets. 
All statistical analyses will be conducted using SAS® Version 9.3 or higher or SAS Enterprise 
Guide® version 4.3.
Medical history and adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus, version 16.1. All prior and concomitant medications will be 
coded according to the WHO Drug Dictionary enhanced (WHODDE), version March 1, 2012.
Adverse events and laboratory data will be graded for toxicity according to the Guidance for 
Industry Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials
[2]. 
For laboratory parameters where the Guidance does not provide cutoffs, shift tables will not be 
provided.
The following modifications will be made to the vaccine toxicity grading scale in this analysis:

The criteria to map hemoglobin laboratory values to severity grades are 2-fold. The first 
criterion is based only on actual hemoglobin value; the second is based on change from 
Baseline hemoglobin. For this study, only observed hemoglobin values will be used to 
determine severity grade; change from Baseline will not be used to determine severity 
grade.

Presentation of these laboratory shift data will depend upon the actual laboratory value as 
reported, and will not reference any action taken or any other clinical activity.
o
Example 1: By the vaccine toxicity grading scale, a Grade 4 creatinine is defined 
as creatinine > 2.5 mg/dL or requiring dialysis. In this study the severity will be 
determined from the creatinine value alone.


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o
Example 2: By the vaccine toxicity grading scale, Grade 4 urine protein requires 
that the patient was hospitalized or received dialysis. Because hospitalization and 
dialysis are clinical actions, not urine protein values, the highest grade that would 
be reported for urine protein (2+) using the vaccine toxicity grading scale would 
be Severe (Grade 3). However, clinical laboratory results for urinary protein may 
be reported in different way. E.g. if the reported lab data is using 4 levels of 
severity (“negative,” “t
"#$%"#$&#	'$ 300”), the urine protein results 
will be graded and reported as follows:
Assigned Grade
Laboratory Result
Vaccine Toxicity Grading 
Scale
Mild (1)
Trace
Trace
Moderate (2)
30
1+
Severe (3)
100
2+
Very Severe (4)
%
Hospitalization or dialysis
Through a querying process, an attempt will be made to reconcile the reported grade for the 
laboratory abnormality and the grade of an associated AE. Reporting of an AE will sometimes 
incorporate information beyond the laboratory value, so some differences in reporting may 
remain. 
When using this toxicity grading scale, lab data will be kept to one more significant digit than the 
scale and then rounded and graded according to the scale. E.g. for Sodium-Hyponatremia, Grade 
1 is 132-134mEq/L, Grade 2 is 130-131mEq/L. If the sodium level is 131.3mEq/L, it will be 
graded to Grade 2 toxicity.
5.2.
Adjustment for Covariates
Not applicable.
5.3.
Handling Dropouts or Missing Data
Missing item responses for the SF-36 and QOL by KCCQ scales are assumed to be the same as 
*<	*
=	?'@\^__

?
<'?*	`{
of the items are non-missing. If fewer than 50% of the items are non-missing the scale score will 
be set to missing.  
No other imputation will be performed in this study.


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5.4.
Interim Analysis and Data Monitoring
No interim analysis is planned for this study. 
This study will not have a data monitoring committee (DMC). However, data from this study
may be made available to a DMC associated with another study evaluating ARRY-371797.
5.5.
Multicenter Studies
The sample size in this study is too small to permit incorporation of study center into the 
analyses. Centers will be pooled for all tabular summaries.
5.6.
Multiple Compar isons/Multiplicity
Not applicable.
5.7.
Examinations of Subgroups
Not applicable.
5.8.
Sample Size Estimation
The parent study enrolled 12 patients. Eligible patients from parent study may rollover to this 
study. 
6.
ANALYSIS POPULATIONS
6.1.
Safety Analysis Set
The safety analysis set will include all enrolled patients who received at least one dose of study 
drug. The safety analysis set will be used for the analysis of all safety endpoints.
6.2.
Efficacy Analysis Set
The Efficacy Analysis Set will include patients who had at least one post-Baseline efficacy 
evaluation. Patients who have no post-Baseline efficacy assessments will not be included in the 
efficacy analyses. 


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6.3.
Pharmacokinetic Analysis Set
The PK analysis set will include all patients who had at least one plasma sample with associated 
PK concentration results.
7.
ASSESSMENTS, ANALYSES, AND PRESENTATIONS
Unless otherwise indicated, continuous variables will be summarized using the following 
descriptive statistics: the number of patients (n), mean, standard deviation, median, minimum, 
and maximum. Means and medians will be reported to one decimal place more than what is 
reported on the eCRF or by the laboratory. Standard deviations (SD) will be reported to two 
decimal places more than what is reported in the data. Minimum and maximum values will be 
reported to the same number of decimal places displayed on the eCRF or by the laboratory. 
Percentages will be reported to one decimal point only.
The frequency and percentage of observed levels will be reported for categorical measures. 
Percentages will be based on the number of patients in the relevant analysis set. In general, all 
data will be listed and sorted by dose group at baseline, and then patient number. When 
appropriate, data will further sorted by study day and study hour within patient. Dates will be 
displayed as DDMMMYYYY in the listings. For displays that include the relative study day, the 
day of the first dose of the follow up study drug administration is defined as Study Day 1.
Tabular summaries will present results for overall. Demographic and baseline data and safety 
summaries will be based on the safety analysis set. Efficacy summaries will utilize the efficacy 
analysis set for all relevant visits. No p-values will be presented. 
Relative study day will be flagged in the listings to indicate dose down titrations.  Flags will be 
as follows: * = 1st down titration, ** = 2nd down titration. Flags will be displayed for all study 
days beginning with the study day on which the dose change occurred. 
Unless otherwise specified, listings will be based on the safety analysis set. The listing of 
disposition data will be based on all screened patients. 
Summary tables and supportive individual patient data listings will be numbered in accordance 
with ICH guidelines for the structure and content of clinical study reports.  Complete lists of the 
proposed tables, graphs and patient data listings are provided in Appendix III.


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7.1.
The format of the final tables and listing
s is expected to re
semble pre-specified 
templates as closely as possible regarding
 the choice of variables, labeling of 
categories, formatting of headers, etc. All data listings will present data in dose
group, patient and date/time order. Patient Disposition
Frequency counts and percentages of all patients who enrolled, completed this follow up study, 
and discontinued early will be presented. In addition, reason for termination will be summarized 
by frequency counts and percentages in the table. The number of screened patients will be 
included. 
A by-patient listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented for all screened patients with the reasons for screen 
failure listed.
7.2.
Demographic and Other Baseline Characteristics
Descriptive statistics will be used to summarize continuous demographic and baseline variables 
including age, height, weight and 6MWT distance at baseline for overall for the safety analysis 
set. Categorical demographic and baseline characteristics variables will be summarized using the 
number and percentage of patients in each level of such variables (including sex, ethnicity and 
race) for overall for the safety analysis set. A listing of demographic and baseline characteristics 
will be provided.
7.3.
Medical History
Significant (at the Investigator’s discretion) past and present medical history will be recorded at 
the Screening visits only. Any ongoing condition observed prior to the initiation of study drug 
will be recorded as medical history. Any new condition, or worsening of a pre-existing 
condition, during study conduct after the start of follow up study or at any time after consent, if 
thought to be related to a study procedure, will be recorded as an adverse event.
Medical history data will be coded using MedDRA 16.1 and summarized by system organ class 
(SOC) and preferred term (PT) with the number and percentage presented for overall for the 
Safety Analysis Set. A by-patient listing of medical history information will be provided.
7.4.
Prior and Concomitant Medications
Prior and concomitant medications will be coded using WHODDE and summarized for overall 
for the safety analysis set using anatomical therapeutic chemical classification codes (ATC) class 
level 2 and preferred term. Patients will be counted only once within a medication class, and 
once for each medication. Prior and concomitant medications will also be provided as a listing.


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7.5.
Efficacy Analyses
7.5.1. Secondary Efficacy Endpoint and Analysis
Secondary efficacy endpoints include:

Change from Baseline in 6MWT at Day 1(parent study Week 48),Weeks 24, 48, 72 and 96 
and, if applicable, termination visit

Measures of cardiac function as described below

Quality of life assessments (SF-36 and KCCQ) at Day 1, Weeks 24, 48, 72 and 96 and, if 
applicable, termination visit
As the SAP section 5.1 noted, the Baseline value for a parameter is defined as the last non-
missing value before the initial administration of study treatment in parent study, unless 
otherwise specified. The study Day 1 for this follow-up study is the final visit from patent study (
e.g. the Week 48 visit of the parent study). Both the pre-dose baseline values and the study Day 1 
values will be included in tables.
7.5.1.1 6MWT at Weeks 24, 48, 72 and 96 and, if applicable, termination visit
A summary of actual values, change from Baseline, and percent change from Baseline in 6MWT 
distance and the associated 80% CIs for overall will be provided for the following timepoints: 
Baseline, Day 1, Weeks 24, 48, 72 and 96 and, if applicable, termination visit. The number and 
percentage of patients who had at least 10% improvement in 6MWT will be summarized for 
overall. The predicted distance and percent predicted distance will also be summarized.
Plots for the mean of actual values, the mean percent change and the mean change from Baseline 
including 80% CIs of 6MWT distance at each timepoint for overall will be provided. 6MWT
data will be listed for the Safety Analysis Set. 
Heart rate, Borg scales for dyspnea and fatigue, SpO2, whether oxygen was given during the test, 
whether the patient paused before 6 minutes, and other symptoms at end of exercise (angina, 
dizziness, and calf pain) will be summarized by timepoint. 
7.5.1.2 Echocardiogram Complete with Contrast
A 2 dimensional (2D) echocardiogram complete with contrast will be performed at the following 
timepoints: Baseline, Day 1, Weeks 24, 48, 72 and 96 and, if applicable, termination visit.
Descriptive statistics will be used to summarize actual values and the change from Baseline 
(post-Baseline) for overall. The following cardiac function parameters will be summarized:

LVESVI and LVEDVI


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LV mass 

LV ejection fraction 

LV mass-to-volume ratio 

RV end-diastolic diameter 

RV fractional area 
Echocardiogram data will be listed for the Safety Analysis Set.
7.5.1.3 SF-36
The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their 
section. Each scale is directly transformed into a 0-100 scale where it is assumed that each 
question carries equal weight. The eight sections are:

Vitality (VT)

Physical functioning (PF)

Bodily pain (BP)

General health (GH)

Role Physical (RP)

Role Emotional (RE)

Social functioning (SF)

Mental health (MH)
Detailed information on SF-36 scoring is described in the User’s Manual for the SF-36v2 Health 
Survey (3rd ed.)[3]. The SF-36 will be scored using QualityMetric Health Outcomes Scoring 
Software 4.5. A brief description of the scoring process will be given here.
Scoring the SF-36 raw score is a two-step process. First, precoded numeric values are recoded so 
that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 
100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores 
represent the percentage of total possible score achieved. In step 2, items in the same scale are 
averaged together to create the 8 scale scores. The table below shows the items averaged together 
to create each scale. 
Table 1:
SF-36 Scale Components 
Scale
Number of items
Items
Physical functioning 10
3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j
Role physical 
4
4a,4b,4c,4d


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Role emotional 
3
5a,5b,5c
Vitality
4
9a, 9e, 9g, 9i
Mental health
5
9b, 9c, 9d, 9f, 9h
Social functioning
2
6,10
Bodily Pain
2
7,8 
General health
5
1, 11a, 11b, 11c, 11d
After the scale scores are obtained, a norm-based transformation is applied so that component-
specific scales can be meaningfully compared with one another. First, a z score is computed by 
subtracting each health domain scale’s 2009 U.S. general population mean from the 0–100 score 
for that scale, and then dividing the difference by the given scale’s standard deviation. The z-
scores are then transformed to T scores (mean = 50, SD = 10). This is done by multiplying each z
score by 10 and adding 50 to the resulting product. 
The mental and physical summary scores (MCS, PCS) are computed by aggregating the norm-
based component scores using factor score coefficients from the 1998 general U.S. population. 
The aggregated summary scores are standardized to have a mean of 50 with a standard deviation 
of 10, again in the general 2009 U.S. population.
Descriptive summaries for the eight SF-36 scales, MCS and PCS will be provided. Actual values 
and the change from Baseline for overall will be provided at Baseline, Day1, Weeks 24, 48, 72 
and 96 and, if applicable, termination visit. SF-36 scale scores and summary scores will be listed 
for the Safety Analysis Set.
7.5.1.4 QOL by KCCQ
The Quality of Life (QOL) Kansas City Cardiomyopathy Questionnaire (KCCQ) measures the 
effects of symptoms, functional limitations and psychological distress on an individual’s QOL. 
In completing the QOL KCCQ, patients indicate how each of 23 facets prevented them from 
living as they desired using a 5- to 7-point Likert scale.
Ten scores are generated from the KCCQ-12, representing seven scales and three summary 
scores: Physical Limitation Score (KCCQ12-PL), Symptom Stability Score, Symptom 
Frequency Score (KCCQ12-SF), Symptom Burden Score, Total Symptom Score, Self-Efficacy 
Score, Quality of Life Score (KCCQ12-QL), Social Limitation Score (KCCQ12-SL), Clinical 
Summary Score, and Overall Summary Score (KCCQ12). Instructions for scoring the QOL 


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KCCQ are provided in the Kansas City Cardiomyopathy Questionnaire Scoring Instructions 
(Spertus J, revised 3/27/01) Appendix II.
A descriptive summary of actual values and the change from Baseline for the four scales and 
summary score will be provided for overall at Baseline, Day 1, Weeks  24, 48, 72, 96 and Early 
Termination (if applicable). QOL KCCQ scale scores and summary scores will be listed for the 
Safety Analysis Set.
7.6.
Safety Analyses
Safety is determined by the incidence and severity of AEs, clinical laboratory tests (hematology, 
chemistry, urinalysis), physical examination, vital signs (blood pressure and pulse rate) and 12-
lead ECGs at all visits and, if applicable, termination visit. All safety analyses are based on the 
safety analysis set. Listings of all safety data sorted by dose group, patient and assessment date 
will be provided.
7.6.1. Extent of Exposure
Total cumulative dose and compliance will be summarized for the safety analysis set. The total 
cumulative dose for a patient is the dose in mg that the patient took during the treatment period. 
Compliance will be calculated based on the following study drug administration eCRF fields and 
summed over all visits:
%
100
 taken
be
 to
expected
capsules
of
number 
Total
 taken
capsules
of
number 
Total

*		'<
	<	?*{	'{
<	
?'for
overall.
A summary table of dose modifications will be presented based on the safety analysis set. The 
number of patients at each dose will be tabulated by timepoint.  A by-patient listing of study drug 
exposure information will be provided.
7.6.2. Adverse Events and Serious Adverse Events 
An adverse event (AE) is any untoward medical occurrence, including the exacerbation of a 
pre-existing condition, in a patient administered a pharmaceutical product regardless of causality. 
An overdose of study drug (whether symptomatic or asymptomatic) will be reported as an AE.
An overdose will be only based on patient reporting; it will not be based on pill counting. Any 
new condition, or worsening of pre-existing condition, during study conduct after the start of 
study drug or at any time after consent, if thought to be related to a study procedure, will be 
recorded as an AE. 


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A treatment emergent AE (TEAE) is defined as an AE that: occurs during treatment, having been 
absent at pre-treatment; or one that re-occurs during treatment, having been present during 
screening but stopped prior to treatment; or one that worsens in severity since treatment relative 
to the pre-treatment state, when the AE is continuous. 
A serious adverse event (SAE) is any untoward medical occurrence that meets any of the 
following criteria.

Results in death.

Is immediately life-threatening (refers to an event in which the patient is at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.

Is a congenital anomaly/birth defect.

Based upon appropriate medical judgment, represents an important medical event that 
may jeopardize the patient or may require intervention to prevent one of the outcomes 
described above.
The severity rating of an AE refers to its intensity. The severity of each AE will be categorized 
using the Toxicity Grading Scale for Healthy Adu
lt and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials . Intensity should be assigned a grade of 1 through 4, as 
outlined by the guidelines in protocol Appendix 1.
Causality is determined for the cause of the AE, considering all relevant factors such as (but not 
limited to) the underlying study indication, coexisting disease, concomitant medication, relevant 
history, pattern of the AE, temporal relationship to the study medication and de-challenge or re-
challenge.

Yes (possibly, probably or definitely related): there is a reasonable possibility that the 
study drug caused the event.

No (unlikely, probably not related or definitely not related): there is no reasonable 
possibility that the study drug caused the event.
Adverse events and serious adverse events will be summarized by system organ class, preferred 
term within each system organ class.  Adverse events and serious adverse events also will be 
summarized by relationship to study medication and by toxicity grade.
The MedDRA (version 16.1) will be used to map the AE verbatim to preferred term, and system 
organ class for summary purposes.  All AEs, including the AE verbatim term and the associated 
AE preferred term, will be provided in the patient data listings.  


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The following summaries will be presented for the safety analysis set by system organ class 
(SOC) and preferred term for overall:

Overall Incidence of Treatment-Emergent Adverse Events 

Number and Percentage of Patients with Treatment-Emergent Adverse Events 
Summarized by Worst Toxicity Grade, System Organ Class, and Preferred Term 

Number and Percentage of Patients with Treatment-Emergent Serious Adverse Events 
Summarized by Worst Toxicity Grade, System Organ Class, and Preferred Term 

Number and Percentage of Patients with Treatment-Emergent Adverse Events Related to 
Study Medication Summarized by Worst Toxicity Grade, System Organ Class, and 
Preferred Term 

Number and Percentage of Patients with Treatment-Emergent Adverse Events Leading to 
Treatment Discontinuation Summarized by Worst Toxicity Grade, System Organ Class, 
and Preferred Term 
The incidence of AEs will be calculated by dividing the number of patients who have 
experienced the event by the number of patients.  If a patient has repeated episodes of a 
particular AE, only the worst toxicity episode, or the episode with the strongest causal 
relationship to study medication, will be counted. A patient with more than one type of AE in a 
particular SOC will be counted only once in the total of patients experiencing AEs in that
particular SOC.  Since a patient may have more than one type of AE within a particular SOC, the 
sum of patients experiencing different AEs within the SOC may appear larger than the total 
number of patients experiencing AEs in that SOC.  Similarly, a patient who has experienced an 
AE in more than one SOC will be counted only once in the total number of patients experiencing 
AEs in all SOCs.  
All occurrences of all AEs will be listed for each patient, grouped by dose group.  In the listing 
of individual patients who have adverse events, the following information on each episode will 
be provided: MedDRA SOC/preferred term, toxicity grade, relationship to study medication, day 
of onset, duration, treatment given for the adverse event, and the outcome. A listing for SAEs 
and a listing with all AEs that resulted in study treatment discontinuation will also be presented.
Adverse events ongoing at the time of informed consent are to be followed under the parent
protocol. Any AE that occurs from the signing of the informed consent form through the final 
study visit (e.g., Follow-Up Visit) must be recorded on the AE eCRF. After the final study visit, 
only SAEs assessed as related to study drug need to be captured on the AE eCRF and reported to 
the Sponsor.
7.6.3. Death
Detailed listings of each death will be provided based on the safety analysis set.


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7.6.4. Laboratory data
Descriptive statistics for chemistry and hematology will be presented at Baseline, Day 1, Weeks
12, 24, 36, 48, 72, 96 and, if applicable, Termination and Follow-Up. Actual values and the 
change from baseline will be summarized. A categorical summary for urinalysis lab data will be 
provided showing the number and percentage of patients in each category. 
Shift tables of baseline to the worst post baseline toxicity grade in chemistry and hematology 
tests will be provided. Repeated or unscheduled tests will be included. For a given patient, if the 
toxicity grade is missing for all post baseline assessments for one laboratory test, the patient will 
be counted only once for that laboratory test under the “Missing” toxicity grade category. If a 
patient has both missing and non-missing toxicity grades for one laboratory test, the missing 
toxicity grade of that laboratory test will be treated as the lowest grade. For each test condition, 
percentages are calculated based on the number of patients in the safety analysis set who have a 
baseline and at least one post-baseline assessment. 
Laboratory tables and listings will be based on the safety analysis set.
7.6.5. Vital Signs
Vital sign measurements including temperature (°C), pulse rate (bpm), diastolic blood pressure 
(DBP) and systolic blood pressure (SBP) (mm Hg) will be collected according to institutional 
standards at Baseline, Day 1, Weeks 12, 24, 36, 48, 72, 96  and, if applicable, Termination and 
Follow-Up. Actual values and the change from baseline will be summarized using descriptive 
statistics and listed based on the safety analysis set. 
7.6.6. ECG
Triplicate 12-lead ECGs will be performed at the timepoints specified in the schedule of 
assessments. The mean of the triplicate ECG measurements performed at each timepoint will be 
used for this summary. The following ECG parameters will be summarized: heart rate, PR, QRS, 
RR, QT and QTcF. Parameters will be summarized for actual results and the change from 
baseline for the safety analysis set for overall at Day 1, Weeks 12, 24, 36, 48, 72, 96  and, if 
applicable, Termination and Follow-Up.
A frequency table with values divided into classes of interest for individual patients’ maximum
baseline and post-baseline QT interval values and QTcF values will be provided for overall.  The 
classes of interest will be QT interval > 500 msec, QTcF > 450 msec, QTcF >480 msec, QTcF
>500 msec, and change from baseline in QTcF >30 msec and >60 msec.
Each individual QT/QTcF value within a triplicate ECG will be considered when deriving the 
frequency classes QT > 500 msec, QTcF > 450 msec, QTcF >480 msec, and QTcF >500 msec,.
For the change from baseline in QTcF >30 msec and >60 msec, the mean of the triplicate QTcF 
will be used. Percentages will be calculated based on the number of patients in the Safety 
Analysis Set who had a baseline and at least one post-baseline ECG assessment.


ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
24
ECG data will be presented in a listing. Values with QT interval > 500 msec, QTcF > 450 msec, 
> 480 msec, and >500 msec, and change from baseline in QTcF >30 msec and >60 msec will be 
flagged. Both the individual and the mean of the triplicate QT and QTcF records at each 
timepoint will be listed. 
7.6.7. Physical Examination
A complete physical examination will assess general physical well-being and it will be 
performed at screening. A brief physical examination will be performed at all other timepoints, 
but may include further evaluation if any areas of concerns are identified. Abnormal results will 
be recorded as adverse events. The number and percent of patients with physical examination 
abnormalities at Screening will be summarized based on the safety analysis set for overall. 
Physical examination findings will be presented as the patient listing.
7.7
Pharmacokinetic Analyses 
For the presentation of concentration related descriptive statistics where BLQ observations may 
be observed are to be handled as follows. If the BLQ ratio (NBLQ/Nvalid) is equal to 0, all values in 
a designated group are numeric (i.e no BLQ values were observed), the descriptive statistics to 
be reported include minimum, maximum, median, mean, geometric mean, SD, CV, geometric 
_	'
*&%"	*		
will be used and all descriptive statistics listed above will be presented and the value for the 
minimum will be reported as BLQ. If the BLQ ratio is <0.5 and >1/3, only the median, minimum 
and maximum will be reported, and the minimum will be reported as BLQ. The SD, CV, 
geometric SD, geometric CV will be reported as not calculated (NC). If the BLQ ratio for a 
given group is equal to 0.5, only the maximum will be reported and the minimum will be listed 
as BLQ. The mean, geometric mean, median, SD, CV, geometric SD, geometric CV will be 
listed as NC. If the BLQ ratio is <1 and >0.5 only the maximum will be reported, and the 
minimum and median will be reported as BLQ. Mean, geometric mean, SD, CV, geometric SD, 
geometric CV, will be reported as NC. If all observations in a given group are listed as BLQ 
(BLQ ratio of 1), the minimum, maximum, median, mean and geometric mean will be reported 
as BLQ. The SD, CV, geometric SD, geometric CV and listed as NC.
Blood collection for the measurement of plasma concentrations of ARRY-371797 and the 
metabolites AR00420643, AR00428028 and AR00486705 will be drawn at the timepoints 
specified in the protocol. Plasma concentrations of ARRY-371797 and AR00420643, 
AR00428028 and AR00486705 will be summarized by timepoint and analyte using descriptive 
statistics and will be contained in a listing and will be accompanied by a figure of individual 
concentration-time profiles grouped by actual dose. Geometric mean concentration versus time 
profiles, with geometric SD error bars, grouped by dose, will be presented on a linear and 
logarithmic scale for the screening, Week 12, and Week 24 visits. 
For the calculation of secondary PK parameters, metabolite-to-parent concentration ratio (MR) 
based on pre- (MRpredose) and postdose (MRpostdose) measurements will be calculated and listed by 
determining the ratio of each metabolite concentration to the corresponding parent concentration 
for each given sample timepoint and analyte and listed as MRpredose and MRpostdose for each 


ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
25
patient, timepoint and analyte. MRpredose and MRpostdose will be grouped by actual dose and 
summarized using descriptive statistics by timepoint and analyte. Drug and metabolite
accumulation (R) will be calculated and listed (Rpredose and Rpostdose) for each patient by timepoint 
and actual dose. R will be calculated by dividing the concentration of parent drug or metabolite 
for week N and postdose or predose timepoint by the respective parent or metabolite 
concentration at the screening visit and corresponding predose or postdose timepoint. R will be 
grouped by actual dose and summarized using descriptive statistics by timepoint and analyte.       
8.
PROTOCOL DEVIATIONS AND MAJOR PROTOCOL 
VIOLATIONS 
Protocol deviations/violations will be listed by category. Criteria to identify protocol 
deviations/violations will be determined prior to database lock.
9.
REFERENCES
1. An Open-label Rollover Study of ARRY-
371797 in Patients with Symptomatic Genetic
Dilated Cardiomyopathy Due to  a Lamin A/C Gene Mutation.
Array BioPharma, Inc.
Protocol No. ARRAY-797-001, Version 1, dated 01 December 2014.
2. Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials.
U.S. Department of Health 
and Human Services, Food and Drug Administration, Center for Biologics Evaluation 
and Research, September 2007.
3. Maruish, M. E. (Ed.). User’s Manual for the SF-36v2 Health Survey 
(3rd ed.). Lincoln, 
RI: QualityMetric Incorporated.


ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
26
APPENDIX I. SCHEDULE OF EVENTS
All activities are performed predose with the exception of post-dose PK blood samples. Visit windows are ± 14 days.
a        Include all prescription and nonprescription drugs, vitamins and dietary or herbal supplements.
b        These assessments are performed as part of the final visit of the parent study.
c        Blood pressure measurements to be performed in accordance with institutional standards. Height will be
measured at the Screening Visit only.
d        Sample collection to be performed in accordance with the methods described in the Laboratory Manual.
e        To be performed at Termination Visit only if not performed within the prior 30 days.
f        Required for females of childbearing potential only.
g        In patients who previously participated in Clinical Study ARRAY-797-231, samples are to be collected
pre-dose and 1 to 2 hours post-dose (exact post-dose time of blood draw must be documented).
h        Week 12 only.
i        Week 24 only.


 
I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9
Arra y Bi o P har ma, I nc. 
Statistical A nal ysis Pla n V 1
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1
0 7 A U G 2 0 1 7
2 7
C CI


 
I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9
Arra y Bi o P har ma, I nc. 
Statistical A nal ysis Pla n V 1
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1
0 7 A U G 2 0 1 7
2 8
C CI


 
I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9
Arra y Bi o P har ma, I nc. 
Statistical A nal ysis Pla n V 1
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1
0 7 A U G 2 0 1 7
2 9
C CI


 
I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9
Arra y Bi o P har ma, I nc. 
Statistical A nal ysis Pla n V 1
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1
0 7 A U G 2 0 1 7
3 0
C CI


I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9
Arra y Bi o P har ma, I nc. 
Statistical A nal ysis Pla n V 1
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1
0 7 A U G 2 0 1 7
3 1
C CI


I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9
Arra y Bi o P har ma, I nc. 
Statistical A nal ysis Pla n V 1
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1
0 7 A U G 2 0 1 7
3 2
C CI


I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9
Arra y Bi o P har ma, I nc. 
Statistical A nal ysis Pla n V 1
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1
0 7 A U G 2 0 1 7
3 3
C CI


I C O N St u d y N u m ber 2 0 3 3- 0 0 1 9
Arra y Bi o P har ma, I nc. 
Statistical A nal ysis Pla n V 1
Pr ot oc ol A R R A Y- 7 9 7- 0 0 1
0 7 A U G 2 0 1 7
3 4
C CI


 
ICON Study Number 2033-0019
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Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
35
APPENDIX III. LIST OF PLANNED TABLES, LISITNGS AND FIGURES
Type
Number
Title
TABLES
Table
14.1.1
Summary of Patient Disposition (All Screened Patients)
Table
14.1.4
Summary of Demographics and Baseline Characteristics (Safety Analysis Set)
Table
14.1.5.1
Summary of Study Drug Exposure (Safety Analysis Set)
Table
14.1.5.2
Summary of Dose Modifications (Safety Analysis Set)
Table
14.1.6
Summary of Medical History by System Organ Class and Preferred Term (Safety Analysis Set)
Table
14.1.7
Summary of Concomitant Medications by Medication Class and Preferred Term (Safety 
Analysis Set)
Table 
14.1.7.1
Summary of Prior Medications by Medication Class and Preferred Term (Safety Analysis Set)
Table
14.1.8
Summary of Physical Examination Screening Results (Safety Analysis Set)
Table
14.2.1.1
Summary of Six Minute Walk Results, Change and Percent Change from Baseline (Efficacy 
Analysis Set)
Table
14.2.1.2
Summary of Six Minute Walk Responders (Efficacy Analysis Set)
Table
14.2.2
Summary of Echocardiographic Results and Change from Baseline (Efficacy Analysis Set)
Table
14.2.3
Summary of SF-36 Results and Change from Baseline (Efficacy Analysis Set) 
Table
14.2.4
Summary of KCCQ-12 Results and Change from Baseline (Efficacy Analysis Set) 
Table
14.3.1.1
Overall Incidence of Treatment-Emergent AEs(Safety Analysis Set)
Table
14.3.1.2
Number and Percentage of Patients with Treatment-Emergent Adverse Events Summarized by 
Worst Toxicity Grade, System Organ Class, and Preferred Term (Safety Analysis Set)
Table
14.3.1.3
Number and Percentage of Patients with Treatment-Emergent Serious Adverse Events 
Summarized by Worst Toxicity Grade, System Organ Class, and Preferred Term (Safety 
Analysis Set)
Table
14.3.1.4
Number and Percentage of Patients with Treatment-Emergent Adverse Events Related to Study 
Medication Summarized by Worst Toxicity Grade, System Organ Class, and Preferred Term 
(Safety Analysis Set)
Table
14.3.1.5
Number and Percentage of Patients with Treatment-Emergent Adverse Events Leading to 
Treatment Discontinuation Summarized by Worst Toxicity Grade, System Organ Class, and 
Preferred Term (Safety Analysis Set)
Table
14.3.1.6
Number and Percentage of Patients with Treatment-Emergent Adverse Events Summarized by 
Preferred Term in Descending Order of Frequency (Safety Analysis Set)
Table
14.3.4.1
Summary of Results and Change from Baseline in Laboratory Tests – Hematology (Safety 
Analysis Set)
Table
14.3.4.2
Summary of Results and Change from Baseline in Laboratory Tests – Chemistry (Safety 
Analysis Set)
Table
14.3.4.3
Summary of Results in Laboratory Tests – Urinalysis Safety Analysis Set)
Table
14.3.4.4
Shift Table from Baseline to the Worst Post Baseline Toxicity Grade in Laboratory Tests –
Hematology (Safety Analysis Set)
Table
14.3.4.5
Shift Table from Baseline to the Worst Post Baseline Toxicity Grade in Laboratory Tests –
Chemistry (Safety Analysis Set)
Table
14.3.5
Summary of Vital Signs Results and Change from Baseline (Safety Analysis Set)
Table
14.3.6.1
Summary of 12-Lead Electrocardiogram (ECG) Results and Change from Baseline (Safety 
Analysis Set)
Table
14.3.6.2
Summary of Patients Meeting Pre-Specified QT/QTcF Criteria (Safety Analysis Set)
Table
14.3.8.1
Summary of Plasma ARRY-371797 and AR00420643, AR00428028, AR00486705 


 
ICON Study Number 2033-0019
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Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
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Concentrations by Actual Dose Level (PK Analysis Set)
Table
14.3.8.2
Summary of PK Parameters (PK Analysis Set)
LISTINGS
Listing
16.2.1.1
Listing of Patient Disposition (All Screened Patients)
Listing
16.2.1.2
Listing of Deaths (Safety Analysis Set)
Listing
16.2.2.1
Listing of Protocol Deviations and Violations
Listing
16.2.2.2
Listing of Patients Not Meeting Inclusion/Exclusion Criteria
Listing
16.2.4.1
Listing of Demographic and Baseline Characteristics (Safety Analysis Set)
Listing
16.2.4.2
Listing of Medical History (Safety Analysis Set)
Listing
16.2.4.3
Listing of Prior and Concomitant Medications (Safety Analysis Set)
Listing
16.2.5.1
Listing of Study Drug Administration (Safety Analysis Set)
Listing
16.2.5.2
Listing of Study Drug Exposure (Safety Analysis Set)
Listing
16.2.6.1
Listing of Six Minute Walk Assessment (Safety Analysis Set)
Listing
16.2.6.2
Listing of Echocardiographic Assessment (Safety Analysis Set)
Listing
16.2.6.3
Listing of SF-36 Scores (Safety Analysis Set)
Listing
16.2.6.4
Listing of KCCQ-12 Assessment (Safety Analysis Set)
Listing
16.2.7.1
Listing of Treatment-Emergent Adverse Events (Safety Analysis Set)
Listing
16.2.7.2
Listing of Treatment-Emergent Serious Adverse Events (Safety Analysis Set)
Listing
16.2.7.3
Listing of Treatment-Emergent Adverse Events Related to Study Medication (Safety Analysis 
Set)
Listing
16.2.7.4
Listing of Treatment-Emergent Serious Adverse Events Related to Study Medication (Safety 
Analysis Set)
Listing
16.2.7.5
Listing of Treatment-Emergent Adverse Events Leading to Treatment Discontinuation (Safety 
Analysis Set)
Listing
16.2.7.6
Listing of Treatment-Emergent Adverse Events Related to Study Drug Leading to Treatment 
Discontinuation (Safety Analysis Set)
Listing
16.2.8.1
Listing of Laboratory Tests – Hematology (Safety Analysis Set)
Listing
16.2.8.2
Listing of Laboratory Tests – Chemistry (Safety Analysis Set)
Listing
16.2.8.3
Listing of Laboratory Tests – Urinalysis (Safety Analysis Set)
Listing
16.2.9
Listing of Vital Signs Data (Safety Analysis Set)
Listing
16.2.10
Listing of 12-Lead Electrocardiogram (ECG) Data (Safety Analysis Set)
Listing
16.2.11
Listing of Physical Examination (Safety Analysis Set)
Listing
16.2.13.1
Listing of Plasma ARRY-371797 and AR00420643, AR00428028, AR00486705 
Concentrations (PK Analysis Set)
Listing
16.2.14.1
Listing of PK Parameter Data (PK Analysis Set)
FIGURES
Figure
14.2.1.1
Plot of Six Minute Walk Distance by Visit (Efficacy Analysis Set)
Figure
14.2.1.2
Plot of Mean Change from Baseline in Six Minute Walk Distance by Visit (Efficacy Analysis 
Set)
Figure
14.2.1.3
Plot of Percent Change from Baseline in Six Minute Walk Distance by Visit (Efficacy Analysis 
Set)
Figure
14.3.8.1
Geometric Mean Plasma ARRY-371797 and AR00420643, AR00428028, AR00486705 
Concentrations Versus Time (Linear Scale) by Actual Dose Level (PK Analysis Set)


 
ICON Study Number 2033-0019
Array BioPharma, Inc. 
Statistical Analysis Plan V1
Protocol ARRAY-797-001
07AUG2017
37
Figure
14.3.8.1.1
Geometric Mean Plasma ARRY-371797 and AR00420643, AR00428028, AR00486705 
Concentrations Versus Time (Logarithmic Scale) by Actual Dose Level (PK Analysis Set)
Figure 
14.3.8.5
Individual 
Plasma 
ARRY-371797 
and 
AR00420643, 
AR00428028, 
AR00486705 
Concentrations Versus Time (Linear Scale) by Actual Dose Level (PK Analysis Set)
Figure 
14.3.8.5.1
Individual 
Plasma 
ARRY-371797 
and 
AR00420643, 
AR00428028, 
AR00486705 
Concentrations Versus Time (Logarithmic Scale) by Actual Dose Level (PK Analysis Set)