Conditions: Crohn's Disease
Keywords: Crohn's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 220
Healthy volunteers: no

Brief summary:
To determine the efficacy and safety of multiple doses of ABT-494 in subjects with moderately to severely active Crohn's Disease with a history of inadequate response to or intolerance to Immunomodulators or anti-Tumor Necrosis Factor (TNF) therapy.

Detailed description:

Arms:
arm 1: Induction Period ABT-494 Twice Daily Medium/High Dose orally dosed twice a day arm 2: Extension Phase ABT-494 High Dose orally dosed twice a day arm 3: Induction Period Placebo orally dosed twice a day arm 4: Induction Period ABT-494 Low Dose orally dosed twice a day arm 5: Induction Period ABT-494 Once Daily Medium/High Dose orally dosed once a day arm 6: Extension Phase ABT-494 Low Dose orally dosed twice a day arm 7: Induction Period ABT-494 High Dose orally dosed twice a day arm 8: Induction Period ABT-494 Low/Medium Dose orally dosed twice a day arm 9: Extension Phase ABT-494 Medium Dose orally dosed twice a day

Interventions: intervention 1: Placebo intervention 2: ABT-494
Intervention descriptions: intervention 1: Oral Dosing intervention 2: Oral Dosing

Protocol document:
Prot_000.pdf: 
ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
1
1.0
Title Page
Clinical Study Protocol M13-740
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study of ABT-494 for the 
Induction of Symptomatic and Endoscopic 
Remission in Subjects with Moderately to Severely 
Active Crohn's Disease who have Inadequately 
Responded to or are Intolerant to 
Immunomodulators or Anti-TNF Therapy
Incorporating Administrative Changes 1 and 2 and 
Amendments 1, 2, 3, 4 and 5
AbbVie Investigational
  Product:
ABT-494
Date:
07 November 2016
Development Phase:
2
Study Design:
A randomized, double-blind, placebo-controlled, multicenter study of multiple 
doses of ABT-494 in subjects with moderately to severely active Crohn's 
disease.
EudraCT Number:
2014-003240-12
Investigators:
Multicenter.  Investigator information is on file at AbbVie.
Sponsor:
For EU Member States:
AbbVie Deutschland
GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
For non-EU Member States:
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL  60064
Sponsor/Emergency 
  Contact:
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT02365649
 


ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
17 October 2014
Protocol Amendment 1
19 February 2015
Administrative Change 1
12 March 2015
Protocol Amendment 2
20 October 2015
Administrative Change 2
03 December 2015
Protocol Amendment 3
05 February 2016
Protocol Amendment 4
15 April 2016
The purpose of this amendment is to:
●
Section 5.1, Overall Study Design and Plan:  Description, 36-Week Extension
Phase, Follow-up Period:  Updated the window for subject rollover to the 
Open Label Extension study to allow for extension on a case by case basis 
after consultation with the medical monitor.
Rationale:  To allow for subjects who are eligible for the Open Label 
Extension study because administrative and/or logistical challenges precludes 
rollover within the previously allotted 10 day period.
●
Section 5.2.3.1, Prior Therapy, second paragraph:  Clarify that 
immunosuppressants taken by subjects who inadequately responded to or were 
intolerant to immunomodulators should be documented beyond the 90 days.
Rationale:  To ensure appropriate documentation of immunosuppressants use 
prior to study entry which is important information taken into consideration 
when analyzing study results.
●
Section 8.1, Statistical and Analysis Plans:  Update the timing of the 
second interim analysis for the double-blind extension phase from when 50% 
of subjects who were re-randomized at Week 16 complete Week 32 – to when 
100% of subjects who were re-randomized at Week 16 complete Week 36.


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M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
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Rationale:  To update the timing from Week 32 to Week 36 as there is no 
Week 32 study visit, and to ensure sufficient sample size for robust interim 
analyses of the extension phase. 
●
Section 5.2.1, Inclusion Criteria 9 and 10; Section 5.2.4, Contraceptive 
Recommendations:  Clarify the duration of required contraception for females 
of childbearing potential, and for male subjects who are sexually active with 
female partner(s) of childbearing potential receiving ABT-494 to be 30 days 
after last dose of study drug. 
Rationale:  To ensure an adequate period of contraception after the last dose 
of study drug based on the ABT-494 pharmacokinetic characteristics, being 
non-genotoxic, no testicular findings in chronic animal toxicology studies and 
had no impact on male or female fertility.  
●
Section 5.2.1, Inclusion Criteria 9; Section 5.2.4, Contraceptive 
Recommendations:  Clarify the duration of required contraception for male 
subjects who are sexually active with female partner(s) of childbearing 
potential receiving ABT-494 for concomitant methotrexate to follow local 
approved label. 
Rationale:  To ensure that the contraception requirements while non-study 
drug concomitant medication is used after study completion are followed 
based on the local approved label.
●
Section 5.2.4, Contraceptive Recommendations, Contraception 
Recommendation for Males; Section 6.1.6, Pregnancy:  Correct the length of 
post-study allowance for donation of sperm from 90 to 30 days after study end.
Rationale:  To ensure an adequate period after study end before sperm 
donation because ABT-494 is not considered to be non-genotoxic, has no 
testicular findings in chronic animal toxicology studies and had no impact on 
male or female fertility. 
●
Section 5.2.4, Contraceptive Recommendations, Contraception 
Recommendation for Males:  Correct the requirement for male subject condom 
use and female partner using at least one contraceptive measure OR true 
abstinence, and not both.
Rationale:  To correct a typographical error, as the two options are mutually 
exclusive. 


ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
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●
Section 5.3.1.6, Collection of Samples for Gene Expression, and 
Section 5.3.6.3, Gene Expression Variables:  Update the number of subjects 
participating in the Gene Expression testing to 80.
Rationale:  To maintain the originally planned sample size for robust 
analyses, accounting for subject drop out, even stratification, and inadequate 
samples.  
●
Section 6.1.3, Relationship to Study Drug:  To update the definitions of 
"reasonable possibility" and "no reasonable possibility" that are used by the 
investigator to assess the relationship of an adverse event to the use of the 
study drug.
Rationale:  To Updated protocol template language and parameters that need 
to be assessed when available, for determining relationship to study drug.
●
Section 9.1, Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB):  To clarify that an investigator will be required to submit, 
maintain and archive study essential documents according all other applicable 
regulatory requirements in addition to ICH GCP.
Rationale:  Clarification. 
●
Section 10.1, Source Documents:  To clarify that the Investigator Awareness 
Date data point required for eCRF completion can be entered directly in the 
SAE eCRF and the CRF page can be considered the source for this data point.
Rationale:  Clarification. 
●
Section 13.0, Completion of the Study:  To clarify that the investigator must 
submit, maintain, and archive  any records related to the study according to 
ICH GCP and all other applicable regulatory requirements.
Rationale:  Clarification. 
An itemized list of all changes made to this protocol amendment can be found in 
Appendix J.


ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M13-740
Name of Study Drug:  ABT-494 
Phase of Development:  2
Name of Active Ingredient:  ABT-494
Date of Protocol Synopsis:  07 November 2016
Protocol Title:  A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of ABT-494 for 
the Induction of Symptomatic and Endoscopic Remission in Subjects with Moderately to Severely Active 
Crohn's Disease who have Inadequately Responded to or are Intolerant to Immunomodulators or 
Anti-TNF Therapy
Objectives:  The objectives of this study are to determine the efficacy and safety of multiple doses of 
ABT-494 versus placebo and to assess the pharmacokinetics (PK) of ABT-494 following oral 
administration in subjects with moderately to severely active Crohn's Disease with a history of inadequate 
response to or intolerance to immunomodulators or anti-TNF therapy.
Investigators:  Multicenter
Study Sites:  Approximately 165 sites worldwide.
Study Population:  Males and females ≥ 18 and ≤ 75 years of age with a diagnosis of moderately to 
severely active Crohn's disease and evidence of mucosal inflammation.
Number of Subjects to be Enrolled:  Approximately 210 subjects worldwide.
Methodology:  
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate 
the efficacy, safety, and PK of ABT-494 as induction therapy in subjects with moderately to severely 
active Crohn's disease with a history of inadequate response to or intolerance to immunomodulators or 
anti-TNF therapy.  The study will allow enrollment of up to 30% of subjects with primary non-response 
to prior anti-TNF treatment.
Approximately 210 adult subjects with moderately to severely active Crohn's disease, with evidence of 
mucosal inflammation, defined by:

SES-CD ≥ 6, (or SES-CD ≥ 4 for patients with disease limited to the ileum), and

CDAI ≥ 220 and ≤ 450, and

Average daily liquid/soft stool frequency ≥ 2.5 or average daily abdominal pain score ≥ 2.0. 
Will be enrolled at approximately 165 sites worldwide.  SES-CD score will be confirmed by a central 
reader.  Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be enrolled 
into the study and randomized in a 1:1:1:1:1:1 ratio to receive one of the six treatment groups 
(double-blind ABT-494 induction doses or matching placebo).
The following are the treatment groups:
Group 1:  ABT-494 3 mg BID
Group 2:  ABT-494 6 mg BID
Group 3:  ABT-494 12 mg BID
Group 4:  ABT-494 24 mg BID
Group 5:  ABT-494 24 mg QD
Group 6:  Placebo


ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
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Methodology (Continued):
The randomization at Baseline will be stratified by endoscopic disease severity (SES-CD < 15 and ≥ 15) 
prior anti-TNF use (naïve and experienced) and by participation in the substudy of the gene expression in 
intestinal biopsies (Yes and No).  As part of the randomization at Baseline, subjects will be randomly 
assigned (1:1) to have their follow-up ileocolonoscopy done at Week 12 or Week 16.
At Week 16, all subjects will be re-randomized into a 36-week extension phase in a ratio of 1:1:1 to one 
of three double-blind doses of ABT-494 (3 mg BID, 6 mg BID or 12 mg BID).  The re-randomization 
will be stratified by the induction dose received during the first 16 weeks and overall response status 
(responder versus non-responder) at Week 16.  The subjects who were re-randomized at Week 16 to 
ABT-494 24 mg QD prior to Protocol Amendment 2 will continue to receive the same double-blind dose 
until Week 52/PD.
Overall response consists of both Endoscopic response and Clinical response.  The central reader 
endoscopic score will be used for calculating the Endoscopic response for the evaluation of the efficacy 
endpoints.  However, for stratification re-randomization, the endoscopic score at baseline from central 
reader and the endoscopic score at Week 12 or Week 16 from site local reader will be used in order to 
determine response status.
Subjects will be expected to remain on blinded therapy throughout the 36 weeks extension phase.  
Subjects who are considered by the investigator to have not achieved meaningful symptomatic relief and 
meet the criteria for inadequate response at or after Week 20 will be eligible to receive open-label therapy 
with ABT-494 12 mg BID.  Subjects who were re-randomized at Week 16 prior to Protocol 
Amendment 2 and are taking open-label ABT-494 24 mg QD will be transitioned to ABT-494 12 mg 
BID.
Subjects who continue to meet the criteria for inadequate response following a 4-week course of 
open-label ABT-494 12 mg BID, will be eligible to dose escalate to open-label ABT-494 24 mg BID.
Subjects with persistent inadequate response while on ABT-494 12 mg BID or 24 mg BID may be 
withdrawn from the study at the investigator's discretion.
Criteria for inadequate response is as follows:

Average daily liquid/soft Stool Frequency > 2.2 OR average daily Abdominal Pain score > 1.8, 
AND

An increase level of hs-CRP of at least 1 mg/L from Baseline or hs-CRP ≥ 5 mg/L, either at the 
previous visit or at the current visit.
Assessment of inadequate response should include consideration by the Investigator to rule out symptoms 
caused by reasons other than Crohn's disease related inflammation. 
In the open-label period, if a subject treated with ABT-494 24 mg BID has an occurrence of an adverse 
event thought to be possibly related to study medication that in the opinion of the investigator warrants 
dose reduction, then the dose can be de-escalated to ABT-494 12 mg BID at the investigator's discretion.  
Note:  Dose escalation and de-escalation are permitted only once during the study.
The duration of the study could be up to 60 weeks, including a Screening Period (35 days), a 16-week 
double-blind induction period, a 36-week double-blind extension phase and a 30-day follow-up period.
Visits for clinical evaluation will occur at Baseline, Weeks 2, 4, 8, 12, 16, 20, 28, 36, 44 and 52/Early 
Termination.  An electronic diary will be dispensed at the Screening Visit.  At each Study Visit, routine 
physical examination including evaluation of extra intestinal manifestations, average daily abdominal 
pain score, average daily liquid/soft Stool Frequency, fistula counts, CDAI calculation, diary review, and 
laboratory, adverse event, concomitant medication and vital sign assessments will be collected.  


ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
7
Methodology (Continued):
In addition, the following will be conducted during the study as noted below:

Results of QoL and work productivity questionnaires (IBDQ, EQ-5D, WPAI) at Baseline, 
Week 8, and Weeks 16, and 52/Early Termination.

Serum for measurement of ABT-494 concentrations at Week 2, Week 4, Week 8, Week 12, 
Week 16, Week 20, Week 28, Week 36, Week 44 and Week 52/Early Termination.

A serum pharmacodynamics sample will be drawn at Baseline, Week 8, Week 16 and 
Week 52/Early Termination.

Endoscopic evaluations using SES-CD, confirmed by central reader, will be done during 
Screening, Week 12 or Week 16, and Week 52/Early Termination.  The Week 12 or Week 16 
endoscopy will not be performed if a subject discontinues the study prior to Week 8.  In 
addition, if a subject prematurely discontinues from the extension phase of the study before or at 
Week 28, the endoscopy at the Early Termination Visit will not be required.  Biopsy to confirm 
diagnosis (during Screening) or to rule out dysplasia/malignancy may be performed during the 
same time points as the endoscopy specified above.

Stool samples for measurement of fecal calprotectin during Screening, Week 4, Week 16, 
Week 28 and Week 52/Early Termination Visit and at Unscheduled Visits resulting in dose 
change.

Results of Abdominal Pain Rating Scale (0 – 10 scale) evaluating Abdominal Pain Intensity will 
be collected at Baseline, Week 12 and Week 16.  (Note:  this is an additional pain scale to the 
daily pain assessment that is collected as part of the CDAI).

An optional serum for evaluation of biomarkers at Baseline and Week 16.

An optional whole blood mRNA sample will be drawn at Baseline and Week 16. 

An optional whole blood pharmacogenetic sample will be drawn at Baseline.

An optional biopsy for Gene expression sub-study will be collected during colonoscopy 
at/during Screening, and at Week 12/16 for approximately 80 subjects in the study.
Throughout the study, subjects will only be allowed to change the dosage of CD-specific concomitant 
medications as specified below:

Starting at Week 2, subjects who are taking corticosteroids at Baseline must have their steroid 
dose tapered.

Aminosalicylates dose must remain unchanged for the entire study period.

MTX dose must remain unchanged for the entire study period.

Crohn's disease related antibiotics must remain unchanged during the induction period, except in 
cases of treatment related toxicity or concerns about development of antibiotic resistance.

If a subject should experience an inadequate response during the corticosteroid taper, the subject 
may have their corticosteroid dose increased, per the investigator's discretion, up to and beyond 
the dose used at Baseline.
Note:
Subjects in whom the maximum steroid dose exceeds the dose used at Baseline will be 
considered non-responders and will be censored for efficacy assessments from that point 
forward through the end of the study.  These subjects will continue to be evaluated in the 
safety population.


ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
8
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Male or female ≥ 18 and ≤ 75 years of age at Baseline.
2.
Diagnosis of ileal, colonic, or ileocolonic Crohn's disease for ≥ 3 months prior to Baseline and 
confirmed by endoscopy during the Screening Period or endoscopy performed within 15 days of the 
Screening Visit.  Appropriate documentation of biopsy results consistent with the diagnosis of CD, in 
the assessment of the Investigator, must be available.
3.
Average daily liquid/very soft stool frequency score ≥ 2.5 or average daily abdominal pain score 
≥2.0.
4.
CDAI ≥ 220 and ≤ 450.
5.
Simplified Endoscopic Score for Crohn's disease (SES-CD) ≥ 6 (or ≥4 for subjects with disease 
limited to the ileum), confirmed by a central reader.

A video-recorded ileocolonoscopy performed within 15 days prior to Screening can be used for 
the local and central reader assessment.
6.
Subject has inadequately responded to or experienced intolerance to previous treatment with 
immunomodulators (e.g., azathioprine, 6-mercaptopurine, or methotrexate) and/or an anti-TNF agent 
(e.g., infliximab, adalimumab, or certolizumab pegol).  The clinical measures that defined inadequate 
response should be based on the physician/investigator clinical assessment. 
Note:  Criteria for inadequate response to or experienced intolerance to previous treatment with 
immunomodulator or an anti-TNF agent defined as:

Signs and symptoms of persistently active disease despite a history induction regimen with one 
of the following agents:
o
At least a consecutive 90-day course of azathioprine, 6-mercaptopurine or injectable MTX 
prior to Baseline, with a stable dose for at least 28 days prior to Baseline of azathioprine 
≥1.5 mg/kg/day or 6-MP ≥ 1 mg/kg/day (rounded to the nearest available tablet or 
half tablet formulation or a documented 6-TGN level of at least 230 pmol/8 × 108 RBC or 
higher on the current dosing regimen) or MTX ≥ 15 mg/week (subcutaneous 
[SC]/Intramuscular [IM]), or a dose that is the highest tolerated by the subject (e.g., due to 
leukopenia, elevated liver enzymes, nausea) during that time.
o
At least one 6-week induction with Infliximab:  5 mg/kg IV, 3 doses at least 2 weeks apart
o
At least one 4-week induction with Adalimumab:  one 160 mg SC dose (or 80 mg SC dose 
in approved countries) followed by one 80 mg SC dose (or 40 mg SC dose in approved 
countries) followed by one 40 mg dose at least 2 weeks apart
o
At least one 4-week induction with Certolizumab pegol:  400 mg SC, 2 doses at least 
2 weeks apart OR

Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit 
(discontinuation despite clinical benefit does not qualify) OR

History of intolerance of at least one TNF antagonist (including, but not limited to infusion 
related reaction, demyelination, congestive heart failure and infection)
7.
Subject has a negative tuberculosis (TB) Screening Assessment.  If the subject has evidence of a 
latent TB infection, the subject must initiate and complete a minimum of 2 weeks (or per local 
guidelines, whichever is longer) of an ongoing TB prophylaxis or have documented completion of a 
full course of anti-TB prophylaxis, prior to Baseline.


ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
9
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion:
1.
Subject with a current diagnosis of ulcerative colitis (UC), collagenous colitis or indeterminate 
colitis.
2.
Subject with previous exposure to JAK inhibitor (e.g., tofacitinib, baricitinib).
3.
Subjects who discontinued biologic therapy such as Infliximab (REMICADE), Certolizumab pegol 
(CIMZIA), Adalimumab (HUMIRA), Vedolizumab (ENTYVIO), Natalizumab (TYSABRI) 
< 8 weeks prior to Baseline.  Subjects who discontinued Ustekinumab (Stelara®) less than 12 weeks 
prior to Baseline.
4.
Subject received azathioprine or 6-mercaptopurine (6-MP) within 10 days of Baseline.
5.
Subject who previously or currently use oral aminosalicylates or MTX and meets one of the 
following criteria:

Has not been on stable doses for at least 14 days prior to Baseline; or

Has discontinued use of aminosalicylates or MTX within 14 days of Baseline.
6.
Subject who previously or currently use oral corticosteroid and meets one of the following criteria:

Is receiving prednisone or prednisone equivalent > 30 mg/day within 7 days of Baseline;

Is receiving budesonide > 9 mg/day within 7 days of Baseline;

Has discontinued use of corticosteroid within 7 days of Baseline;

Has not been on stable doses of corticosteroid for at least 7 days prior to Baseline; or

Has been taking both oral budesonide and prednisone (or equivalent) simultaneously.
7.
Received intravenous corticosteroids within 14 days prior to Screening or during the Screening 
Period.
8.
Subject on probiotics who has not been on stable dose for at least 14 days prior to Baseline.
9.
Subject who previously or currently use Crohn's disease related antibiotics and meets one of the 
following criteria:

Has not been on stable doses for at least 14 days prior to Baseline;

Has discontinued Crohn's disease related antibiotics within 14 days of Baseline.
10. Subject received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior to 
Baseline.
11. Subject has received therapeutic enema or suppository, other than required for endoscopy, within 
7 days prior to Screening and/or during the Screening Period.
12. Subject who has had surgical bowel resection within the past 6 months or is planning any resection 
while enrolled in the study.
13. Subject with an ostomy, ileoanal pouch or symptomatic bowel stricture.
14. Subject with an abdominal or peri-anal abscess.
15. Subject who has short bowel syndrome.
16. Subject who previously received stem cell transplantation or Subject who previously received fecal 
microbial transplantation in the past 1 month.
17. Subject who received non-steroidal anti-inflammatory drugs (NSAIDs) (except topical NSAIDs and 
the use of low dose aspirin for cardiovascular (CV) protection) within 14 days prior to Screening and 
during the Screening Visit.


ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
10
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):  
18. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the 
Baseline Visit or oral anti-infectives within 14 days prior to the Baseline Visit.
19. Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during 
the course of the study.
20. Subject with positive Clostridium difficile (C. difficile) toxin stool assay during the Screening Period.
21. Screening laboratory and other analyses show any of the following abnormal results:

Serum Aspartate Transaminase (AST) or Alanine transaminase (ALT) > 1.5 × upper limit of the 
reference range (ULN);

Estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal 
Disease (MDRD) formula < 40 mL/min/1.73 m2;

Total White Blood Cell (WBC) count < 3,000/µL;

Absolute neutrophil count (ANC) < 1,200/µL;

Platelet count < 100,000/µL;

Absolute lymphocytes count < 750/µL;

Hemoglobin < 9 g/dL.
22. Any active or recurrent viral infection that based on the investigator's clinical assessment makes the 
subject an unsuitable candidate for the study, including recurrent/disseminated herpes zoster or 
known history of human immunodeficiency virus (HIV).
23. Hepatitis B (HBs Ag positive [+] or detected sensitivity on the HBV DNA PCR qualitative test for 
HBc Ab positive subjects) or hepatitis C (HCV RNA detectable in any subject with anti-HCV Ab).
24. Subject with any active or chronic recurring infections or untreated latent TB.
25. History of moderate to severe congestive heart failure (NYHA class III or IV), cerebrovascular 
accident and any other condition within 6 months, which in the opinion of the Investigator, would put 
the subject at risk by participation in the study.
26. Use of known strong CYP3A inhibitors (e.g., clarithromycin, conivaptan, itraconazole, ketoconazole, 
posaconazole, telithromycin, voriconazole, grapefruit juice) or strong CYP3A inducers 
(e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) from Screening through the end of the 
study.
27. Receipt of any live vaccine within 1 month prior to the Screening Visit, or will require live 
vaccination during study participation including up to 1 month after the last dose of study drug.
28. Evidence of current colonic dysplasia, history of high grade colonic dysplasia, or history of 
malignancy (including of the gastrointestinal tract) other than a successfully treated non-metastatic 
cutaneous squamous cell or basal cell carcinoma or localized carcinoma in situ of the cervix.
29. Has had any uncontrolled and/or clinically significant (per Investigator's judgment) illness or has had 
any surgical procedure within 30 days prior to Screening.
30. Positive pregnancy test at Screening (serum) or Baseline (urine).
31. Female subjects who are breastfeeding or considering becoming pregnant during the study.
32. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.


ABT-494
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EudraCT 2014-003240-12
11
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
33. Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to 
Baseline, whichever is longer.
34. History of clinically significant drug or alcohol abuse in the last 12 months.
Investigational Product:
ABT-494
Double-Blind Induction 
Doses:
ABT-494 3 mg BID
ABT-494 6 mg BID
ABT-494 12 mg BID
ABT-494 24 mg BID
ABT-494 24 mg QD
Double-Blind Extension 
Period Doses:
ABT-494 3 mg BID
ABT-494 6 mg BID
ABT-494 12 mg BID
ABT-494 24 mg QD
Open-Label Extension 
Period Doses:
ABT-494 12 mg BID
ABT-494 24 mg BID
Mode of Administration:
Oral
Reference Therapy:
Matching Placebo
Doses:
N/A
Mode of Administration:
Oral
Duration of Treatment:  52 weeks
The study will include a Screening Period of up to 35 days and a double-blind induction period of 
16 weeks and an extension phase of 36 weeks.
A 30-day follow-up visit will be completed for all subjects who complete the study or discontinue from 
the study prematurely.
Criteria for Evaluation:
Endpoint Definitions:
The following definitions apply to the efficacy variables described below:

Remission:  Endoscopic remission AND Clinical remission

Response:  Endoscopic response AND Clinical response

Endoscopic remission:  SES-CD ≤ 4 and at least two point reduction versus baseline and no 
subscore > 1 in any individual variable

Endoscopic response:  SES-CD at least 25% reduction from baseline

Clinical remission:  average daily stool frequency ≤ 1.5 and not worse than baseline AND 
average daily abdominal pain ≤ 1.0 and not worse than baseline

Clinical response:  average daily stool frequency at least 30% reduction from baseline and 
average daily abdominal pain not worse than baseline OR average daily abdominal pain at least 
30% reduction from baseline and average daily stool frequency not worse than baseline


ABT-494
M13-740 Protocol Amendment 5
EudraCT 2014-003240-12
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Criteria for Evaluation (Continued):
Efficacy:
The co-primary endpoints are:

Proportion of subjects who achieve endoscopic remission at Week 12/16.

Proportion of subjects who achieve clinical remission at Week 16.
The secondary endpoints (Double-Blind Induction Treatment Period) include:

Proportion of subjects who achieve CDAI < 150 at Week 16.

Proportion of subjects with decrease in CDAI ≥ 70 points from Baseline at Week 16.

Proportion of subjects who achieve clinical remission at Week 12.

Proportion of subjects who achieve remission at Week 16 (endoscopic remission at Week 12/16 
and clinical remission at Week 16).

Proportion of subjects who achieve response at Week 16 (endoscopic response at Week 12/16 
and clinical response at Week 16).

Proportion of subjects with endoscopic response at Week 12/16.

Proportion of subjects who achieve clinical response at Week 16.

Proportion of subjects with an average daily SF ≥ 2.5 AND average daily AP ≥ 2.0 at Baseline 
who achieve clinical remission at Week 16.

Proportion of subjects taking corticosteroids at Baseline who discontinued corticosteroid use and 
achieve CDAI < 150 at Week 16.

Proportion of subjects taking corticosteroids at Baseline who discontinued corticosteroid use and 
achieve endoscopic remission at Week 12/16 and clinical remission at Week 16.

Proportion of subjects taking corticosteroids at Baseline who discontinued corticosteroid use and 
achieve clinical remission at Week 16.

Proportion of subjects taking corticosteroids at Baseline who discontinued corticosteroid use and 
achieve endoscopic remission at Week 12/16.

Change from Baseline in fecal calprotectin level at Week 16.

Change from Baseline in hs-CRP at Week 16.

Change in IBDQ from Baseline at Week 16.

Proportion of subjects with isolated ileal Crohn's disease who achieve remission at Week 16.


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EudraCT 2014-003240-12
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Criteria for Evaluation (Continued):
Efficacy (Continued):
The secondary endpoints (Double-Blind Extension Phase) include:

Proportion of subject who achieve remission at Week 52.

Proportion of subjects who achieve endoscopic remission at Week 52.

Proportion of subjects who achieve clinical remission at Week 52.

Proportion of subject who achieve response at Week 52.

Proportion of subjects who achieve endoscopic response at Week 52.

Proportion of subjects who achieve clinical response at Week 52.

Proportion of subjects taking corticosteroids at Baseline who discontinued corticosteroid use and 
achieved CDAI < 150 at Week 52.

Proportion of subjects taking corticosteroids at Baseline who discontinued corticosteroid use and 
achieve remission at Week 52.

Proportion of subjects taking corticosteroids at Baseline who discontinued corticosteroid use and 
achieve clinical remission at Week 52.

Proportion of subjects taking corticosteroids at Baseline who discontinued corticosteroid use and 
achieve endoscopic remission at Week 52.

Proportion of subjects who achieve CDAI < 150 at Week 52.

Proportion of subjects with decrease in CDAI ≥ 70 points from Baseline at Week 52.

Change from Baseline in fecal calprotectin level at Week 52.

Change from Baseline in hs-CRP at Week 52.

Change in IBDQ from Baseline at Week 52.

Proportion of subjects with isolated ileal Crohn's disease who achieve remission at Week 52.

Change in EIMs from Baseline at Week 52.
Additional endpoints include assessment of the above endpoints over time.
Pharmacokinetic:
Blood samples will be collected for measurement of ABT-494 plasma concentration at Week 2, Week 4, 
Week 8, Week 12, Week 16, Week 20, Week 28, Week 36, Week 44 and Week 52/Early Termination.  
Safety:
Safety analyses will be performed on all subjects who receive at least one dose of study drug.  Incidence 
of adverse events, changes in vital signs, electrocardiogram, physical examination results, and clinical 
laboratory data will be assessed.


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Statistical Methods:
Efficacy:
A total of 210 subjects will be equally allocated to five treatment groups and the placebo group, 
representing a randomization ratio of 1:1:1:1:1:1.  The sample size for this study is based on the expected 
proportion of subjects who achieve endoscopic remission at Week 12/16 and on the expected proportion 
of subjects who achieve clinical remission at Week 16.  Assuming an endoscopic remission (as well as 
clinical remission) rate of 12% in the placebo arm and maximum of 35% in at least one of the ABT-494 
BID treatment arms (3 mg BID, 6 mg BID, 12 mg BID and 24 mg BID) at Week 12/16, a sample size of 
35 subjects per treatment group is sufficient to test for the presence of a dose response signal, to select the 
best dose response model for the observed data out of a pre-specified set of candidate models, and to 
estimate target doses of interest (e.g., the minimum effective dose, MED) via modeling using MCP-Mod 
(Multiple comparison procedure and modeling) approach.  This approach provides at least 80% average 
power to detect a dose effect at 5% level of significance (one-sided) with the linear, Emax, exponential, 
logistic and sigEmax models pre-specified as likely candidates to characterize the dose-response for 
ABT-494 for the two co-primary endpoints of clinical and endoscopic remission.  Efficacy analysis will 
be based on all modified intended to treat subjects.  The modified intent-to-treat (MITT) analysis set 
includes all randomized subjects who have taken at least one dose of study drug in the double-blind 
induction period.
The co-primary efficacy endpoints are the proportion of subjects with endoscopic remission (an SES-CD 
≤ 4 and at least 2 point reduction from Baseline) and no subscore > 1 in any individual variable at 
Week 12/16 and the proportion of subjects with clinical remission (average daily liquid/soft stool 
frequency ≤ 1.5 and not worse than baseline AND average daily abdominal pain score ≤ 1.0 and not 
worse than baseline) at Week 16.  The comparisons between an ABT-494 treatment group and placebo 
on the two co-primary efficacy endpoints will be performed using MCPMod approach.  Subjects with 
missing primary endpoint data SES CD at Week 12/16 will be classified as "not achieved" (non-
responder imputation [NRI] method) for the endoscopic remission endpoint.  A sensitivity analysis using 
observed cases, which excludes those subjects with missing post-baseline endoscopy, will also be done.
The stool frequency and abdominal pain scores at an assessment visit (e.g., Week 12, Week 16) will be 
the average of the daily values reported during the 7 usable days preceding the scheduled assessment 
visit.
If 7 days daily values are not available, an average will be calculated based on the number of days with 
available data as follows:

An average for the most recent 6 days will be calculated if data for only 6 days are available, 

An average for the most recent 5 days will be calculated if data for only 5 days are available,

An average for the most recent 4 days will be calculated if data for only 4 days are available.


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Statistical Methods (Continued):
Efficacy (Continued):
If the minimum number of days of diary data (i.e., 4 days for SF and AP) are not available, then the 
subject's score for that visit will be considered missing and NRI will be used for any endpoints 
(e.g., clinical remission) relating to data for this visit.  Subjects who discontinue prior to Week 16 for any 
reason will be considered as "not-achieved" for clinical remission endpoint. 
The following sensitivity analyses for the primary endpoint of clinical remission will be conducted:

An analysis of observed cases, which excludes those subjects with missing SF or AP data at 
scheduled assessment visits.

The primary analysis will be repeated using mixed-imputation.  Subjects who discontinue prior 
to Week 16 due to lack of efficacy or adverse events will be considered as "not achieved" for the 
clinical remission.  Subjects who discontinue for other reasons will be categorized according to 
LOCF.
The dose-response relationships using the most significant model in MCPMod among the five ABT-494 
treatment groups and placebo group will be characterized for the primary endpoints endoscopic remission 
at Week 12/16 and clinical remission at Week 16.  The response function will be the log odds (logit) of 
the proportion of subjects with endoscopic/clinical remission.  The fitted curve will be shown graphically 
with confidence intervals for each dose.  Estimates of the treatment differences in the response function 
and associated 95% confidences for each active dose against placebo will be calculated from the most 
significant model, as well as the average of all significant models.  These results will be 
back-transformed to give point estimates of the difference in proportions and associated 95% confidence 
intervals.
In general, continuous secondary efficacy variables with repeated measurements will be analyzed using a 
Mixed Effect Repeated Measure (MMRM) model.  Continuous secondary efficacy variables will also be 
analyzed using an Analysis of Covariance (ANCOVA) model including factors for treatment group and 
stratification variable, Crohn's disease severity (SES-CD < 15, ≥ 15) at Baseline and prior anti-TNF use 
(naïve and experienced).  Baseline values will be used as a covariate in the MMRM and ANCOVA 
models.  Categorical secondary efficacy variables will be analyzed using the CMH test controlling for 
stratification variables Crohn's disease severity (SES-CD < 15, ≥ 15) at Baseline and prior anti-TNF use 
(naïve and experienced).
Pharmacokinetics:
Individual plasma concentrations of ABT-494 will be tabulated and summarized.  A non-linear 
mixed-effects modeling approach will be used to estimate the population central value and the empirical 
Bayesian estimates of the individual values for ABT-494 oral clearance (CL/F) and volume of 
distribution (Vss/F).  Additional parameters may be estimated if useful in the interpretation of the data.
Safety:
Safety analyses will be carried out using the safety population, which includes all subjects who receive at 
least one dose of study medication.  Incidence of adverse events, changes in vital signs, physical 
examination results, ECGs, and clinical laboratory values will be analyzed.  Treatment-emergent adverse 
events will be tabulated by system organ class and by MedDRA preferred term for each treatment group 
for the induction treatment period, extension phase and over the entire study.  Mean change from 
Baseline for laboratory and vital signs data will be summarized.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
6-MP
6-mercaptopurine
AE
Adverse Event
ALT
Alanine Transaminase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AST
Aspartate Transaminase
ANC
Absolute Neutrophil Count
AUC
Area under the plasma concentration-time curve
BID
Twice daily
BMI
Body Mass Index
BP
Blood pressure
BUN
Blood Urea Nitrogen
CD
Crohn's Disease
CDC
Centers for Disease Control and Prevention
CDAI
Clinical Disease Activity Index
CD4, CD8
Cluster of Differentiation
CGC
Common Gamma-Chain
CHF
Congestive Heart Failure
CI
Confidence Interval
Cmax
Maximum Observed Plasma Concentration
CMH 
Cochran-Mantel-Haenszel
CPK
Creatine Phosphokinase
CR
Clinical Remission
CRF
Case Report Form
CRP
C-Reactive Protein
Ctrough
Trough Plasma Concentration
CXR
Chest X-Ray
CYP3A
Cytochrome P450 3A
CYP2D6
Cytochrome P450 2D6
DM
Diabetes Mellitus
DMARD
Disease-Modifying Anti-Rheumatic Drug


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DMC
Independent Data Monitoring Committee
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC 
Electronic Data Capture
EIM
Extra-Intestinal Manifestations
EQ-5D
EuroQoL-5D
ET
Early termination
FDA
US Food and Drug Administration
GCP
Good Clinical Practice
gp130
Glycoprotein 130
HBc Ab 
Hepatitis B Core Antibody
HBs Ab
Hepatitis B Surface Antibody
HBs Ag
Hepatitis B Surface Antigen
HBV
Hepatitis B virus
Hbs Ab
Hepatitis B surface antibodies
Hbs Ag
Hepatitis B surface antigen
HCV Ab
Hepatitis C Virus Antibody
HDL
High Density Lipoprotein
HIV
Human Immunodeficiency Virus
hsCRP
High-Sensitivity C-Reactive Protein
IBDQ
Inflammatory Bowel Disease Questionnaire
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
IL
Interleukin
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
JAK
Janus Activated Kinase
LDL
Low Density Lipoprotein
LOCF
Last Observation Carried Forward


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MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Effect Repeated Measure 
MTX
Methotrexate
NK
Natural Killer Cells
NOAEL
No Observable Adverse Effect Level
NRI
Non-Responder Imputation
NSAID
Non-Steroidal Anti-Inflammatory Drug
NYHA
New York Heart Association
OC
Observed Cases
PE
Physical Examination
PG
Pharmacogenetic
PK
Pharmacokinetic
PPD
Purified Protein Derivative
QTc
QT Interval Corrected for Heart Rate
QTcF
QT Interval Corrected for Heart Rate by Fridericia's Formula
RA
Rheumatoid Arthritis
RAVE®
EDC System from Medidata
RBC
Red Blood Cell Count
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SDP
Study designated physician
SES-CD
Simplified Endoscopic Score for Crohn's Disease
SFPS
CDAI components "Number of liquid or very soft stools" and "Abdominal pain" 
(Stool [liquid/soft] Frequency + Abdominal Pain Score; SFPS)
SGOT/AST
Serum Glutamic-Oxaloacetic Transaminase/Aspartate Transaminase
SGPT/ALT
Serum Glutamic-Pyruvic Transaminase/Alanine Transaminase
STAT
Signal Transduction Activators of Transcription
TB
Tuberculosis
TEAE
Treatment-Emergent Adverse Event
Tmax
Time to Maximum Observed Plasma Concentration
TNF
Tumor Necrosis Factor
TPN
Total Parenteral Nutrition
Tyk2
Tyrosine Kinase 2
UC
Ulcerative Colitis
ULN
Upper Limit of Normal


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WBC
White Blood cell Count
WPAI
Work Productivity and Impairment Questionnaire


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................5
1.3
List of Abbreviations and Definition of Terms........................................16
2.0
Table of Contents...................................................................20
3.0
Introduction ...........................................................................25
3.1
Differences Statement..............................................................................31
3.2
Benefits and Risks....................................................................................31
4.0
Study Objective......................................................................33
5.0
Investigational Plan...............................................................33
5.1
Overall Study Design and Plan:  Description ..........................................33
5.2
Selection of Study Population..................................................................39
5.2.1
Inclusion Criteria .....................................................................................40
5.2.2
Exclusion Criteria ....................................................................................42
5.2.3
Prior and Concomitant Therapy...............................................................46
5.2.3.1
Prior Therapy ...........................................................................................46
5.2.3.2
Concomitant Therapy...............................................................................46
5.2.3.3
Prohibited Therapy...................................................................................48
5.2.4
Contraceptive Recommendations ............................................................50
5.3
Efficacy and Safety Assessments/Variables ............................................52
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................52
5.3.1.1
Study Procedures .....................................................................................59
5.3.1.2
Blood Samples for Pharmacogenetic Analysis........................................74
5.3.1.3
Collection and Handling of In Vivo Pharmacodynamic Biomarker 
Variables ..................................................................................................75
5.3.1.4
Collection of Samples for Serologic Markers..........................................75
5.3.1.5
Collection of Samples for mRNA Assays ...............................................76
5.3.1.6
Collection of Samples for Gene Expression ............................................76
5.3.2
Drug Concentration Measurements .........................................................77
5.3.2.1
Handling/Processing of Samples .............................................................77
5.3.2.2
Disposition of Samples ............................................................................77


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5.3.2.3
Measurement Methods.............................................................................77
5.3.3
Efficacy Variables....................................................................................78
5.3.3.1
Primary Variables ....................................................................................78
5.3.3.2
Secondary Variables ................................................................................78
5.3.3.3
Additional Efficacy Variables..................................................................80
5.3.4
Safety Variables.......................................................................................81
5.3.5
Pharmacokinetic Variables ......................................................................82
5.3.6
Pharmacogenetic and Serologic Variables...............................................82
5.3.6.1
Pharmacogenetic Variables......................................................................82
5.3.6.2
Serologic Marker and mRNA Variables..................................................82
5.3.6.3
Gene Expression Variables......................................................................83
5.4
Removal of Subjects from Therapy or Assessment.................................84
5.4.1
Discontinuation of Individual Subjects....................................................84
5.4.2
Discontinuation of Entire Study...............................................................86
5.5
Treatments................................................................................................86
5.5.1
Treatments Administered.........................................................................87
5.5.2
Identity of Investigational Product...........................................................88
5.5.2.1
Packaging and Labeling...........................................................................88
5.5.2.2
Storage and Disposition of Study Drug ...................................................88
5.5.3
Method of Assigning Subjects to Treatment Groups...............................89
5.5.4
Selection and Timing of Dose for Each Subject......................................90
5.5.5
Blinding....................................................................................................90
5.5.5.1
Blinding of Investigational Product.........................................................91
5.5.5.2
Blinding of Data for Independent Data Monitoring Committee 
(IDMC) ....................................................................................................91
5.5.6
Treatment Compliance.............................................................................91
5.5.7
Drug Accountability.................................................................................92
5.6
Discussion and Justification of Study Design..........................................92
5.6.1
Appropriateness of Measurements...........................................................93
5.6.2
Suitability of Subject Population .............................................................93
5.6.3
Selection of Doses in the Study ...............................................................93
6.0
Complaints .............................................................................94
6.1
Medical Complaints.................................................................................94


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6.1.1
Definitions................................................................................................95
6.1.1.1
Adverse Event..........................................................................................95
6.1.1.2
Serious Adverse Events ...........................................................................96
6.1.2
Adverse Event Severity............................................................................97
6.1.3
Relationship to Study Drug......................................................................97
6.1.4
Adverse Event Collection Period.............................................................98
6.1.5
Adverse Event Reporting.........................................................................99
6.1.6
Pregnancy...............................................................................................100
6.1.7
Toxicity Management ............................................................................101
6.1.8
Cardiac Adjudication Committee ..........................................................103
6.1.9
Independent Data Monitoring Committee .............................................104
6.2
Product Complaint .................................................................................104
6.2.1
Definition ...............................................................................................104
6.2.2
Reporting................................................................................................104
7.0
Protocol Deviations..............................................................105
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................106
8.1
Statistical and Analysis Plans ................................................................106
8.1.1
Datasets for Analysis .............................................................................107
8.1.1.1
Modified Intent-to-Treat Analysis Set...................................................107
8.1.1.2
Intent-to-Treat Responder and Non-Responder Analysis Sets ..............107
8.1.1.3
Safety Analysis Set ................................................................................108
8.1.2
Subject Accountability...........................................................................108
8.1.3
Definition of Missing Data Imputation..................................................108
8.1.4
Demographics and Baseline Characteristics..........................................110
8.1.4.1
Baseline Characteristics and Treatment Group Comparability .............110
8.1.4.2
Medical Histories...................................................................................110
8.1.4.3
Prior Therapy and Medications..............................................................110
8.1.4.4
Concomitant Medications ......................................................................111
8.1.5
Subject Disposition and Study Drug Exposure......................................111
8.1.5.1
Subject Disposition ................................................................................111
8.1.5.2
Study Drug Exposure.............................................................................112
8.1.6
Efficacy Analysis...................................................................................112


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8.1.6.1
Primary Efficacy Variable .....................................................................112
8.1.6.1.1
Analysis of Primary Endpoint................................................................112
8.1.6.1.2
Sensitivity Analysis of the Primary Efficacy Variable..........................114
8.1.6.2
Secondary Efficacy Variables................................................................115
8.1.6.2.1
Analysis of Secondary Endpoints ..........................................................115
8.1.6.3
Additional Efficacy Endpoints...............................................................115
8.1.6.3.1
Analysis of Additional Endpoints..........................................................115
8.1.6.4
Multiple Comparisons............................................................................116
8.1.7
Safety Analysis ......................................................................................116
8.1.7.1
General Considerations..........................................................................117
8.1.7.2
Analysis of Adverse Events...................................................................117
8.1.7.2.1
Treatment-Emergent Adverse Events....................................................117
8.1.7.2.2
Serious Adverse Events and Death........................................................119
8.1.7.3
Analysis of Laboratory and Vital Sign Data..........................................119
8.1.8
Pharmacokinetic and Exposure-Response Analyses .............................119
8.1.9
Statistical Analysis of Biomarker Data..................................................121
8.1.10
Interim Analysis.....................................................................................122
8.2
Determination of Sample Size ...............................................................123
9.0
Ethics.....................................................................................123
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................123
9.2
Ethical Conduct of the Study .................................................................124
9.3
Subject Information and Consent...........................................................124
10.0
Source Documents and Case Report Form 
Completion ...........................................................................125
10.1
Source Documents .................................................................................125
10.2
Case Report Forms.................................................................................126
10.3
Electronic Patient Reported Outcomes (ePRO).....................................127
10.4
Data Collection Process .........................................................................128
11.0
Data Quality Assurance ......................................................128
12.0
Use of Information...............................................................129
13.0
Completion of the Study .....................................................130
14.0
Investigator's Agreement....................................................132


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15.0
Reference List ......................................................................133
List of Tables
Table 1.
Study Activities........................................................................................53
Table 2.
Clinical Laboratory Tests.........................................................................66
List of Figures
Figure 1.
Study Design Schematic ..........................................................................34
Figure 2.
Study Design Schematic for Open-Label Extension Option for 
Patients Who Do Not Adequately Respond During the Extension 
Phase ........................................................................................................35
Figure 3.
Adverse Event Collection ........................................................................99
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator..........................................137
Appendix B.
List of Protocol Signatories....................................................................139
Appendix C.
Sample Work Productivity and Activity Impairment 
Questionnaire:  Crohn's Disease V2.0 (WPAI-CD)...............................140
Appendix D.
Crohn's Disease Activity Index (CDAI) ................................................142
Appendix E.
Standard Weights...................................................................................143
Appendix F.
SES-CD Scoring ....................................................................................146
Appendix G.
Latent TB Risk Factor Questionnaire Example.....................................147
Appendix H.
Bristol Stool Chart .................................................................................148
Appendix I.
Abdominal Pain Rating Scale (0 – 10 Scale).........................................149
Appendix J.
Protocol Amendment:  List of Changes.................................................150


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3.0
Introduction
Crohn's disease (CD) encompasses a spectrum of clinical and pathological processes 
manifested by focal asymmetric, transmural, and occasionally granulomatous 
inflammation that can affect any segment of the gastrointestinal tract.1  The disease can 
affect persons of any age, and its onset is most common in the second and third decades.  
Females are affected slightly more than males, and the risk for disease is higher in some 
ethnic groups.2,3  In North America, the incidence of CD is estimated to be 3.1 to 
14.6 cases per 100,000 persons.  Prevalence rates range from 26 to 99 cases per 
100,000 persons.  In Europe, CD has an incidence of 0.7 to 9.8 cases per 100,000 persons 
and a prevalence of 8.3 to 214 cases per 100,000 persons.2
CD has been characterized as a progressive disease that leads to complications.  In a 
population based study from southeastern Norway, a substantial number of patients 
demonstrated a stricturing or penetrating phenotype at 10 years after diagnosis.4  
Moreover, approximately 80% of patients diagnosed with CD will require at least 
one surgery related to the disease at some point in time.5
Given that no known medical or surgical cure currently exists for CD, the therapeutic 
strategy is to reduce symptoms, improve quality of life, reduce endoscopic evidence of 
inflammation, and minimize short- and long-term toxicity and complications.6  Currently, 
patients with moderate to severe disease are usually treated with conventional 
pharmacologic interventions, which include corticosteroids and immunomodulatory 
agents such as azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX).1,7  
However, the use of these agents is limited by slow onset of action (3 to 6 months) and 
sub-optimal efficacy in early disease and in more severe patients.8,9  The potential risks 
from long-term use of corticosteroids are well-known.  Adverse events (AEs) associated 
with short-term use of corticosteroids include acne, moon face, edema, skin striae, glucose 
intolerance, and sleep/mood disturbances; potential AEs observed with longer term use 
(usually 12 weeks or longer but sometimes shorter durations) include posterior 
subcapsular cataracts, osteoporosis, osteonecrosis of the femoral head, myopathy, and 


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susceptibility to infection.10,11  The safety risks for AZA and 6-MP include pancreatitis, 
bone marrow depression, infectious complications, and malignant neoplasms.12  MTX 
may be associated with bone marrow depression and liver and pulmonary toxicity.  
Patients who do not respond to conventional therapies may be treated with biologics, such 
as anti-TNF α therapies.1,7  Potential risks with anti-TNF α include infusion or injection 
site reactions, serious infections, lymphoma, heart failure, lupus-like syndromes, and 
demyelinating conditions.12  Despite the beneficial results achieved with the available 
anti-TNF α agents, approximately 40% of patients who receive them for the first time do 
not have a clinically meaningful response (primary non-responders).13-17  Among patients 
who initially respond and continue to receive maintenance treatment for longer durations, 
approximately 38% become non-responders after 6 months and approximately 50% 
become non-responders at 1 year (secondary non-responders).14,16  Patients who initially 
respond to a first anti-TNF agent but then lose response tend to have lower response and 
remission rates to the second anti-TNF agent.16,18  A new class of biologics, anti-integrin 
antibodies, has been studied in patients with prior anti-TNF use.  Natalizumab, a 
humanized monoclonal antibody to α4β1 and α4β7 integrins, showed promise for patients 
with prior exposure to anti-TNF-α therapy; more than half of the patients had a response 
to the induction regimen.19  However, natalizumab's use after approval in 2008 has been 
severely limited due to the serious risk for progressive multifocal leukoencephalopathy 
(PML) attributed to activation of the latent JC virus.20  Clearly, the medical need for 
additional therapeutic options in CD for patients with inadequate response to or 
intolerance to conventional therapies and anti-TNF α agents remains.
Targeting the JAK (Janus activated kinase) signaling pathway for autoimmune diseases, 
such as RA and CD, is well-supported by the involvement of various pro-inflammatory 
cytokines that signal via JAK pathways in the pathogenesis of these immune-related 
disorders.  The activation of the JAK signaling initiates expression of survival factors, 
cytokines, chemokines, and other molecules that facilitate leukocyte cellular trafficking 
and cell proliferation, which contribute to inflammatory and autoimmune disorders.21


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Although the pathogenesis of CD is not completely understood, the imbalance between 
anti-inflammatory and pro-inflammatory cytokines in the mucosal immune system is 
thought to play an important role in CD.  Cells from the innate mucosal immune system, 
i.e., TH1 or TH17, are over-activated and secrete various pro-inflammatory cytokines 
such as interferon (INF)-g, TNFα, interleukin IL-6, IL-1b, IL-12, IL-23.  These cytokines 
signal via JAK pathways.22
The JAK comprise 4 family members:  JAK1, 2, 3, and Tyrosine kinase 2 (Tyk2).  These 
cytoplasmic tyrosine kinases transduce cytokine-mediated signals, and are associated with 
membrane cytokine receptors such as common gamma-chain (CGC) receptors and the 
glycoprotein 130 (gp130) trans-membrane proteins.23
JAK3 and JAK1 are components of the CGC cytokine receptor complexes and blockade 
of either inhibits signaling by the inflammatory cytokines IL-2, -4, -7, -9, -15 and -21.24  
Cytokines such as IL-6 bind to gp130 and transduce its signal predominantly via JAK1.25  
Targeting the IL-6 receptor (IL-6R) is a promising approach given the fact that expression 
of IL-6 and soluble IL-6 receptors is elevated in patients with active CD.26  Further, a 
proof of concept study in patients with active CD with tocilizumab, a humanized 
monoclonal antibody against IL-6R, showed an encouraging clinical response.27  Thus, 
inhibition of JAK1 is expected to attenuate the signaling of IL-6 and other 
pro-inflammatory cytokines (i.e., IFN-g), that are involved in development of CD.
ABT-494 is a novel JAK1 inhibitor being developed for the treatment of adult patients 
with inflammatory diseases.  Based on in vitro selectivity assays and in vivo animal 
models, ABT-494 has demonstrated that inhibiting JAK1 with minimal impact on JAK2 
is feasible at efficacious drug exposure levels.  Thus, the enhanced selectivity of ABT-494 
has the potential for an improved benefit/risk profile by mitigating JAK2 inhibitory 
effects on erythropoiesis and myelopoiesis.  Also, the minimum of activity of ABT-494 
against JAK3, which is involved in IL-15 signal transduction cascade, could potentially 
minimize a decrease in NK cell counts observed with tofacitinib that may have 
contributed to increased incidences of viral infection, particularly reactivation of herpes 
zoster.


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The toxicology profile of ABT-494 was initially evaluated in repeat-dose 4-week studies 
in rats and dogs, and the dog has been identified as the most sensitive species.  Adverse 
findings in dogs included dose-related decreases in hemoglobin and red cell mass (red 
blood cell counts, hemoglobin concentration, hematocrit) and microscopic findings in 
popliteal lymph nodes (mixed cell infiltrates with extension into pericapsular tissues) in 
animals administered 3 or 5 mg/kg/day ABT-494.  However, there were no changes 
observed for these nodes on physical exam and no systemic manifestation of this finding 
or evidence of this at other lymph node sites or organs.
In a 4-week toxicity study in rats, mild decreases in red blood cell counts and hemoglobin 
and non-adverse, dose-dependent decreases in circulating lymphocytes were observed, 
both effects being reversible.  In rats, discolored urine, either brown or black, was 
observed at high doses.  While this was not observed at the end of the recovery period at 
any dose, the significance of this observation is not known as no correlating 
histopathologic findings were identified.  At a very high dose of 100 mg/kg/day of 
ABT-494 in rats, the adverse findings included mortality as well as tubular 
degeneration/regeneration in the kidney and liver necrosis.
Subsequent longer chronic toxicity studies in dogs (9 months) and rats (6 months) have 
confirmed the earlier findings in both species.  In the 9-month toxicity study in dogs, 
ABT-494 was administered at 0.1, 0.5, and 1.5 mg/kg/day.  There were no adverse 
findings at any dose group, and the overall results confirmed the earlier 4-week study 
findings, with mixed cell infiltration in interdigital skin of paws and draining lymph nodes 
which was considered secondary to ABT-494 related immune modulation.  There was 
only a mild decrease (not adverse) in red cell mass at 0.5 and 1.5 mg/kg/day.  In the 
6-month toxicity study in rats, ABT-494 was dosed up to 50 mg/kg/day and was 
associated with renal tubular degeneration/regeneration.
ABT-494 is currently in clinical development for the treatment of patients with 
rheumatoid arthritis (RA).  There have been two Phase 1 studies with ABT-494.  
Study M13-401, a single-dose ascending dose study of ABT-494 at 1 mg up to 48 mg, has 
been completed.  This study also looked at the effects of ketoconazole and food on the 


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pharmacokinetics (PK) of ABT-494.  Single doses of ABT-494 were well tolerated.  
Plasma concentration of ABT-494 increased approximately dose proportionally in the 
dose range studied.  Ketoconazole, a strong CYP3A inhibitor, increased ABT-494 AUC 
and Cmax approximately 1.7- to 1.8-fold.  Therefore, to minimize overlap in drug 
concentrations between dosing groups coadministration of strong CYP3A inhibitors or 
inducers is restricted in the present study.  Food had no effect on the exposure (AUC) of 
ABT-494.  Therefore, ABT-494 can be administered with or without food in the present 
study.
Study M13-540 evaluated the effects of rifampin on the PK and safety of a single dose of 
ABT-494 in healthy adult subjects.  Preliminary results suggested that rifampin, a potent 
CYP3A inducer, decreased ABT-494 AUC and Cmax approximately 2- to 2.5-fold 
following 8 days of rifampin administration.
Preliminary results after multiple ascending doses of ABT-494 in healthy volunteers are 
available from Study M13-845.  The randomized, double-blind, placebo-controlled study 
was designed to evaluate the safety, tolerability and pharmacokinetics of ABT-494 at 
four dose levels of 3, 6, 12 and 24 mg BID.  In each dose group, 11 subjects were 
randomized (8 to ABT-494 and 3 to placebo) and received study medication twice daily 
(BID) for 14 consecutive days.  No serious or fatal adverse events or AEs leading to 
discontinuation were reported during the study.  Treatment-emergent adverse events 
(TEAE) were reported in 7 (58.3%) subjects receiving placebo and in 11 (34.3%) subjects 
receiving ABT-494 with the overall incidence of TEAEs at 2 (25.0%), 2 (25.0%), 
3 (37.5%) and 4 (50%) of subjects experienced TEAEs in the 3 mg, 6 mg, 12 mg and 
24 mg dose groups, respectively.  All TEAEs were considered mild (Grade 1) in severity 
and reported to have a reasonable possibility of being related to study drug except 
2 events in one subject in the placebo group were considered as having no reasonable 
possibility of being related.  Most common TEAE in the ABT-494 treatment groups 
(n = 32) were headache (15.6%), abdominal pain (6.3%), diarrhea (6.3%), and 
nasopharyngitis (6.3%).  No clinically meaningful changes in laboratory values, vital 
signs or ECG findings were observed during the study.


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Preliminary results indicated that at steady state, ABT-494 had minimal to no 
accumulation with a median Tmax of approximately 2 hours.  ABT-494 exposure was 
approximately dose-proportional across the dose range studied, with concentrations 
rapidly decreasing following Tmax followed by an elimination phase with an apparent 
elimination half-life of approximately 8 to 16 hours following the last dose on Day 14.  
Approximately 19% to 21% of ABT-494 was excreted as unchanged parent in the urine 
during a dose interval in the steady state.
A detailed discussion of the preclinical toxicology, metabolism, pharmacology and safety 
experience with ABT-494 can be found in the current Investigator's Brochure.28
Rationale for Development of a JAK Inhibitor in CD
Preclinical pharmacology studies run in the mouse CD45RBhi transfer colitis model 
demonstrate efficacy of an AbbVie JAK inhibitor, ABT-317.  In this model, CD4 + 
CD45Rbhi T cells are transferred into RAG-/-SCID mice.  The resulting colonic 
inflammation has histopathological features of inflammatory bowel disease including 
goblet cell loss, lymphocyte/monocyte-mediated inflammation, and mucosal thickening 
and "cobblestone" appearance as measured by endoscopy.  This model has been validated 
with clinical benchmarks including anti-TNF antibodies, anti-p40 (IL-12/IL-23) 
antibodies, and steroids.  Studies performed with ABT-494 showed a trend towards 
efficacy in the model, but did not reach statistical significance due to variable responses 
across all of the animals.  The in vivo pharmacology of ABT-494 is challenging to study 
in mice due to poor PK in this species.  By contrast, ABT-317 is a JAK1-selective 
inhibitor, similar to ABT-494 in potency, that exhibits adequate murine PK to enable 
these studies.  Also, ABT-317 exhibits similar efficacy to ABT-494 in preclinical RA 
models in rats, where pharmacokinetics enable study of both compounds.  In the transfer 
colitis model, ABT-317 mitigates weight loss and improves both the endoscopy score and 
histology in treated animals relative to the vehicle controls.  The efficacy observed with 
ABT-317 was equivalent to that observed with the anti-p40 positive control.  These data
support JAK blockade as a possible effective treatment for CD.


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3.1
Differences Statement
This Phase 2 study differs from other ABT-494 studies as it is the first to evaluate the 
efficacy, safety and pharmacokinetics of ABT-494 in subjects with CD.
3.2
Benefits and Risks
CD is a chronic inflammatory condition involving the gastrointestinal tract.  The disease 
is associated with significant morbidity (including abdominal pain, diarrhea, weight 
lost/malnutrition and gastrointestinal fistulas/strictures/abscesses) related to the 
underlying inflammation.  Although newer treatments such as the anti-TNF antibodies 
have improved the standard of care for patients with CD, there remains significant unmet 
medical need for patients with inadequate or loss of response to these agents, and efforts 
are ongoing to develop novel therapies.  This protocol will study patients who are unable 
to tolerate anti-TNF therapies and/or have had an insufficient response to treatment with 
an anti-TNF therapy.  Currently these patients have limited options for treatment, and may 
be subjected to repeated courses of corticosteroids, which are associated with a wide 
ranging spectrum of toxic effects affecting multiple organ systems.  Natalizumab, an 
antibody directed against α4 integrin, is approved for patients with inadequate response or 
intolerance to anti-TNF agents, but the risk of associated progressive multifocal 
leukoencephalopathy has greatly limited its use.  Vedolizumab, a monoclonal antibody 
that binds to the α4β7 integrin and inhibits the migration of memory T-lymphocytes 
across the endothelium into inflamed gastrointestinal parenchymal tissue, was recently 
approved for adult patients with moderately to severely active CD who have had an 
inadequate response with, lost response to, or were intolerant to a TNF blocker or 
immunomodulator.
Clinical efficacy in targeting proinflammatory cytokines and downstream signaling 
pathways has been demonstrated in RA and may be helpful in treating patients with CD.  
Several JAK inhibitors demonstrated proof of concept in RA subjects.29,30  These drugs 
are also being studied for the treatment of patients with inflammatory bowel disease.


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The second generation of JAK inhibitors currently in development display varying 
potency and selectivity directed at members of the JAK family.31  Tofacitinib is a 
non-selective JAK inhibitor targeting JAK1, JAK2 and JAK3, but most potently inhibits 
JAK3.31  Although tofacitinib improves the clinical signs and symptoms of RA, questions 
remain surrounding the safety profile regarding apparent increases in the incidences of 
serious infection, malignancies, herpes zoster, and hematologic adverse events.
Tofacitinib has also been associated with reduced levels of hemoglobin, absolute 
lymphocytes counts, and total white blood cell counts in some subjects and also increased 
serum creatinine; total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol 
(HDL-C); and liver transaminases (ALT and AST).32,34  The increases in serum creatinine, 
lipids, and liver transaminase values typically have been asymptomatic, reversible, and 
were not associated with any overt declines in renal or hepatic function.
ABT-494 is a novel JAK1 selective inhibitor with minimal inhibitory effects on JAK2 and 
JAK3, which could potentially minimize some of the reported safety concerns with 
non-selective JAK inhibition which are thought to be mediated by inhibition of JAK2 and 
JAK3 signaling pathways.  We propose to initiate a Phase 2 study in CD subjects with 
multiple doses of ABT-494 based on the following supportive findings:  1) demonstrated 
improved potency of ABT-494 versus tofacitinib in preclinical models of inflammation; 
2) confirmed JAK1 selectivity of ABT-494 in both preclinical and clinical settings; 
3) acceptable preclinical toxicological findings in chronic toxicity studies in two species; 
4) acceptable safety and tolerability profile of ABT-494 in single ascending dose (SAD) 
and multiple ascending dose (MAD) studies in healthy volunteers and 5) evidence that 
JAK inhibition in preclinical models of inflammatory bowel disease results in clinical and 
endoscopic improvement.  The current Phase 2 Study M13-740 will assess the benefit to 
risk profile of ABT-494 in CD subjects who have had an insufficient clinical response to 
anti-TNF therapies.
ABT-494 is a potent JAK1 selective inhibition that has been associated with endoscopic 
improvement and healing of the intestinal mucosa in preclinical animal models.  More 
recently, filgotinib, a JAK1 inhibitor in Phase 2 clinical development in Crohn's disease 


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was associated with superior clinical remission versus placebo.33  This study included 
subjects who could have been inadequate responders or intolerant to either 
immunomodulators or anti-TNF therapies.  Of note, this treatment effect was more 
prominent in subjects who have inadequate responders to immunomodulators only.  
AbbVie proposes to include this patient population to assess the effect of ABT-494 and 
whether they would benefit the most from such therapy.
4.0
Study Objective
The objective of this study is to determine the efficacy and safety of multiple doses of 
ABT-494 versus placebo and to assess the pharmacokinetics of ABT-494 following oral 
administration in subjects with moderately to severely active Crohn's disease with a 
history of inadequate response to or intolerance to immunomodulators or anti-TNF 
therapy.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy, safety, and pharmacokinetics of ABT-494 as induction 
therapy in subjects with moderately to severely active Crohn's disease and evidence of 
mucosal inflammation defined by a SES-CD ≥ 6 (or ≥ 4 for subjects with disease limited 
to the ileum) and average daily soft/liquid stool frequency ≥ 2.5 or average daily 
abdominal pain score of ≥ 2.0; and CDAI ≥ 220 and ≤ 450, with a history of inadequate 
response or intolerance to immunomodulators or anti-TNF therapy.  The study will allow 
enrollment of up to 30% of subjects who were primary non responders to anti-TNF 
treatment.
The study is designed to enroll 210 subjects to meet scientific and regulatory objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.  
Therefore, if the target numbers of subjects have been enrolled, there is a possibility that 
additional subjects in screening will not be enrolled.


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The study duration could be up to 60 weeks, including a Screening Period of up to 
35 days, a 16-week double-blind induction period, a 36-week double-blind extension 
phase, and a 30-day follow-up period.  Subjects who meet eligibility criteria will be 
randomized in a 1:1:1:1:1:1 ratio to one of the double-blinded induction treatment arms.
The schematics of the overall study design are shown in Figure 1.
Figure 1.
Study Design Schematic


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Figure 2.
Study Design Schematic for Open-Label Extension Option for 
Patients Who Do Not Adequately Respond During the Extension 
Phase
Screening Period
Within 35 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and undergo the 
screening procedures as outlined in Table 1.
An e-diary will be dispensed and training will be provided to the subject at the Screening 
Visit.
Laboratory tests performed during the Screening period can be repeated in case the 
abnormalities are considered to be transient by the investigator.
16-Week Induction Period
This period will begin at the Baseline Visit (Week 0) and will end at the Week 16 Visit.  
At the Baseline Visit, subjects who meet all the inclusion criteria and none of the 
exclusion criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the 


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study and randomized to double-blind induction period.  The randomization at Baseline 
will be stratified by endoscopic disease severity (SES-CD < 15 and ≥ 15), prior anti-TNF 
use (naïve and experienced) and by participation in the substudy of the gene expression in 
intestinal biopsies (Yes and No).  As part of the randomization at Baseline, subject will be 
randomly assigned (1:1) to have their follow-up ileocolonoscopy done at Week 12 or 
Week 16.  During this period of the study, subjects will visit the study site at Weeks 2, 4, 
8, 12 and 16.  A ± 3-day window is permitted around scheduled study visits.  The last 
dose of study drug during this period is taken the evening prior to the Week 16 visit.
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects that end study participation early will have an Early Termination (ET) Visit and 
complete the procedures outlined for the ET Visit in Table 1 as soon as possible after the 
last dose of study drug and preferably prior to the administration of any new therapies.
36-Week Extension Phase
At Week 16, subjects who have completed the induction period will be re-randomized in a 
ratio of 1:1:1 to one of the three double-blinded doses of ABT-494 3 mg BID, 6 mg BID 
or 12 mg BID.  The re-randomization will be stratified by dose received during the 
first 16 weeks, and overall response (responder versus non-responder) at Week 16.  The 
subjects who were re-randomized at Week 16 to ABT-494 24 mg QD prior to Protocol 
Amendment 2 will continue to receive the same double-blind dose until Week 52/PD.
The central reader endoscopic score will be used for calculating the Endoscopic response 
for the evaluation of the efficacy endpoints.  However, for stratification at the time of 
re-randomization, the endoscopic score at BL from central reader and the endoscopic 
score at Week 12 or Week 16 from site local reader will be used in order to determine 
response status. 
Clinical response is defined as average daily liquid/soft stool frequency reduction of at 
least 30% from Baseline and average daily abdominal pain not worse than Baseline OR 


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average daily abdominal pain reduction at least 30% from baseline and average daily stool 
frequency not worse than Baseline.  
During this period of the study, subjects will visit the study site at Weeks 20, 28, 36, 44, 
and 52/Early Termination.  A ± 3-day window is permitted around scheduled study visits.  
The last dose of study drug is taken the evening prior to the Week 52 visit.
Subjects will be expected to remain on double-blinded therapy throughout the entire 
36-week extension phase.  However, subjects who are considered by the investigator to 
have not achieved meaningful symptomatic relief and meet the criteria for inadequate 
response at or after Week 20 will be eligible to receive the open-label therapy with 
ABT-494 12 mg BID, Figure 2.  Subjects who were re-randomized at Week 16 prior to 
Protocol Amendment 2 and are taking open-label ABT-494 24 mg QD will be 
transitioned to ABT-494 12 mg BID.
Subjects who still continue to meet criteria for inadequate response following a 4-week 
course of open-label ABT-494 12 mg BID will be eligible to dose escalate to open-label 
ABT-494 24 mg BID.
Subjects with persistent inadequate response while on ABT-494 12 mg BID or 24 mg BID 
may be withdrawn from the study at the investigator's discretion.
Criteria for Inadequate response are as follows:
●
Average daily liquid/soft Stool Frequency > 2.2 OR average daily Abdominal 
Pain score > 1.8 AND
●
An increase level of hs-CRP of at least 1mg/L from Baseline or a hs-CRP 
≥5 mg/L, either at the previous visit or at the current visit.  
Note:  hs-CRP will be performed by Central Lab.  However, for the purpose of evaluating 
Inadequate Response criteria, hs-CRP can also be done at local lab.


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Assessment of inadequate response should include consideration by the Investigator to 
rule out symptoms caused by reasons other than Crohn's disease related inflammation.
In the open-label period, if the subject treated with 24 mg BID has an occurrence of an 
adverse event thought to be possibly related to study medication that in the opinion of the 
investigator warrants dose reduction, then the dose can be de-escalated to ABT-494 12 mg 
BID at the investigator's discretion.
Note:  Dose escalation and de-escalation are permitted only once during the study.
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects that end study participation early will have an ET Visit and complete the 
procedures outlined for the ET Visit in Table 1 as soon as possible after the last dose of 
study drug and preferably prior to the administration of any new therapies.
Subjects who are not re-randomized at Week 16 or subjects who early terminated from the 
study will have a follow-up visit approximately 30 days after the last administration of 
study drug to obtain information on any new or ongoing adverse events (AEs), and to 
collect vital signs and clinical laboratory tests.
Follow-Up Period
Subjects who have completed the Week 52 visit and do not enter the Open Label 
Extension Study (Study M14-327) will have a follow-up visit approximately 30 days after 
the last administration of study drug to obtain information on any new or ongoing adverse 
events (AEs), and to collect vital signs and clinical laboratory tests.
Subjects will be evaluated for entry into the Open Label Extension at the final study visit 
(Week 52) of Study M13-740 or up to 10 days following the Last Visit (Week 52) of 
Study M13-740.  The 10 day window for subject rollover may be extended on a case by 
case basis after consultation with the medical monitor.  The Week 52 visit of 
Study M13-740 will be considered Week 0 (Baseline) of Open Label Extension Study.


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Re-Screen
Subjects that initially screen fail for the study may be permitted to re-screen following 
re-consent.  The subject must meet all the inclusion and none of the exclusion criteria at 
the time of re-screening in order to qualify for the study.  There is no minimum period of 
time a subject must wait to re-screen for the study.  If the subject had a complete initial 
screening evaluation including the assessment of a purified protein derivative (PPD) test 
(or equivalent), or Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold test 
or T-SPOT TB test), chest x-ray, HBV, HCV and ECG, these tests will not be required to 
be repeated for re-screening provided the conditions noted in Section 5.3.1.1 are met and 
no more than 90 days have passed.
An endoscopy with biopsy will not be required to be repeated for re-screening provided 
the conditions noted in Section 5.3.1.1 are met and no more than 30 days have passed 
(from the previous screening endoscopy).  All other screening procedures will be 
repeated.  As appropriate, sites are encouraged to contact the AbbVie Medical Monitor to 
confirm if subjects should or should not be re-screened.
Unscheduled Visits
Unscheduled Visits are for purposes when the subject is coming in for a medical visit for 
evaluation and assessment.  During Unscheduled Visits, blood and urine samples will be 
obtained for the laboratory tests listed in Table 2.
Visits for dispensing new study drug in case of temperature excursion, loss or damage are 
not considered an Unscheduled Visit.  In addition, visits to only retest a lab will not be 
considered an Unscheduled Visit.
5.2
Selection of Study Population
It is anticipated that approximately 210 subjects with moderately to severely active CD 
who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized at approximately 165 study centers worldwide.


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A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria specified in Section 5.2.1 and none of the exclusion criteria specified in 
Section 5.2.2 of this protocol.
5.2.1
Inclusion Criteria
A subject will be eligible for the study participation if he/she meets the following criteria:
1.
Male or female ≥ 18 and ≤ 75 years of age at Baseline.
2.
Diagnosis of ileal, colonic, or ileocolonic Crohn's disease for ≥ 3 months prior to 
Baseline confirmed by endoscopy during the Screening Period or endoscopy 
performed within 15 days of the Screening Visit.  Appropriate documentation of 
biopsy results consistent with the diagnosis of CD, in the assessment of the 
Investigator, must be available.
3.
Average daily liquid/very soft stool frequency score ≥ 2.5 or average daily 
abdominal pain score ≥ 2.0. 
4.
CDAI ≥ 220 and ≤ 450.
5.
Simplified Endoscopic Score for Crohn's disease (SES-CD) ≥ 6 (or ≥ 4 for subjects 
with disease limited to the ileum), confirmed by a central reader.
●
A video-recorded ileocolonoscopy performed within 15 days prior to 
Screening can be used for the local and central reader assessment.
6.
Subject has inadequately responded to or experienced intolerance to previous 
treatment with immunomodulators (e.g., azathioprine, 6-mercaptopurine, or 
methotrexate) and/or an anti TNF agent (e.g., infliximab, adalimumab, or 
certolizumab pegol).  The clinical measures that defined inadequate response 
should be based on the physician/investigator clinical assessment. 
Note:  Criteria for inadequate response to or experienced intolerance to previous 
treatment with an immunomodulator or anti-TNF agent defined as:
●
Signs and symptoms of persistently active disease despite a history of 
induction regimen with one of the following agents: 


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○
At least a consecutive 90-day course of azathioprine, 6-mercaptopurine or 
injectable MTX prior to Baseline, with a stable dose for at least 28 days 
prior to Baseline of azathioprine ≥ 1.5 mg/kg/day or 6-MP ≥ 1 mg/kg/day 
(rounded to the nearest available tablet or half tablet formulation or a 
documented 6-TGN level of at least 230 pmol/8 × 108 RBC or higher on 
the current dosing regimen) or MTX ≥ 15 mg/week (subcutaneous 
[SC]/Intramuscular [IM]), or a dose that is the highest tolerated by the 
subject (e.g., due to leukopenia, elevated liver enzymes, nausea) during 
that time.
○
At least one 6-week induction with Infliximab:  5 mg/kg IV, 3 doses at 
least 2 weeks apart
○
At least one 4-week induction with Adalimumab:  one 160 mg SC dose (or 
80 mg SC dose in approved countries) followed by one 80 mg SC dose (or 
40 mg SC dose in approved countries) followed by one 40 mg dose at least 
2 weeks apart
○
At least one 4-week induction with Certolizumab pegol:  400 mg SC, 
2 doses at least 2 weeks apart OR
●
Recurrence of symptoms during scheduled maintenance dosing 
following prior clinical benefit (discontinuation despite clinical benefit 
does not qualify) OR
●
History of intolerance of at least one TNF antagonist (including, but 
not limited to infusion-related reaction, demyelination, congestive heart 
failure and infection) 
7.
Subject has a negative tuberculosis (TB) Screening Assessment.  If the subject has 
evidence of a latent TB infection, the subject must initiate and complete a 
minimum of 2 weeks (or per local guidelines, whichever is longer) of an ongoing 
TB prophylaxis or have documented completion of a full course of anti-TB 
prophylaxis, prior to Baseline.
8.
A negative serum pregnancy test for all female subjects at the Screening Visit and a 
negative urine pregnancy test for all female subjects of childbearing potential at 
baseline prior to the first dose of study drug.


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9.
If female, subject must be either postmenopausal, OR permanently surgically 
sterile OR for women of childbearing potential practicing at least one protocol-
specified method of birth control (refer to Section 5.2.4), that is effective from 
Study Day 1 through at least 30 days after the last dose of study drug.
10.
Male subjects who are sexually active with female partner(s) of childbearing 
potential must agree from Study Day 1 through 30 days after the last dose of study 
drug to practice the protocol-specified contraception (refer to Section 5.2.4).
11.
Subject must be able and willing to give written informed consent and to comply 
with the requirements of this study protocol.
12.
Subject is judged to be in otherwise good health as determined by the Principal 
Investigator based upon the results of medical history, laboratory profile, physical 
examination and a 12-lead electrocardiogram (ECG) performed during Screening.
5.2.2
Exclusion Criteria
1.
Subject with a current diagnosis of ulcerative colitis (UC), collagenous colitis or 
indeterminate colitis.
2.
Subject with previous exposure to JAK inhibitor (e.g., tofacitinib, baricitinib).
3.
Subjects who discontinued biologic therapy such as (Infliximab (REMICADE), 
Certolizumab (CIMZIA), Adalimumab (HUMIRA), Vedolizumab (ENTYVIO), 
Natalizumab (TYSABRI) < 8 weeks prior to Baseline.  Subjects who discontinued 
Ustekinumab (Stelara®) less than 12 weeks prior to Baseline.
4.
Subject received azathioprine or 6-mercaptopurine (6-MP) within 10 days of 
Baseline.
5.
Subject who previously or currently use oral aminosalicylates or MTX and meets 
one of the following criteria:
●
Has not been on stable doses for at least 14 days prior to Baseline; or
●
Has discontinued use of aminosalicylates or MTX within 14 days of Baseline.


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6.
Subject who previously or currently use oral corticosteroid and meets one of the 
following criteria:
●
Is receiving prednisone or prednisone equivalent > 30 mg/day within 7 days of 
Baseline;
●
Is receiving budesonide > 9 mg/day within 7 days of Baseline;
●
Has discontinued use of corticosteroid within 7 days of Baseline;
●
Has not been on stable doses of corticosteroid for at least 7 days prior to 
Baseline; or
●
Has been taking both oral budesonide and oral prednisone (or equivalent) 
simultaneously.
7.
Received intravenous corticosteroids within 14 days prior to Screening or during 
the Screening Period.
8.
Subject on probiotics who has not been on stable dose for at least 14 days prior to 
Baseline.
9.
Subject who previously or currently use Crohn's disease related antibiotics and 
meets one of the following criteria:
●
Has not been on stable doses for at least 14 days prior to Baseline;
●
Has discontinued Crohn's disease related antibiotics within 14 days of 
Baseline.
10.
Subject received cyclosporine, tacrolimus, or mycophenolate mofetil within 
30 days prior to Baseline.
11.
Subject has received therapeutic enema or suppository, other than required for 
endoscopy, within 7 days prior to Screening and/or during the Screening Period.
12.
Subject who has had surgical bowel resections within the past 6 months or is 
planning any resection while enrolled in the study.
13.
Subject with an ostomy, ileoanal pouch or symptomatic bowel stricture.
14.
Subject with an abdominal or peri-anal abscess.


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15.
Subject who has short bowel syndrome.
16.
Subject who previously received stem cell transplantation or Subject who 
previously received fecal microbial transplantation in the past 1 month.
17.
Subject who received non-steroidal anti-inflammatory drugs (NSAIDs) (except 
topical NSAIDs and the use of low dose aspirin for CV protection) within 14 days 
prior to Screening and during the Screening Visit.
18.
Infection(s) requiring treatment with intravenous (IV) anti-infectives within 
30 days prior to the Baseline Visit or oral anti-infectives within 14 days prior to the 
Baseline Visit.
19.
Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN 
at any time during the course of the study.
20.
Subject with positive Clostridium difficile (C. difficile) toxin stool assay during the 
Screening Period.
21.
Screening laboratory and other analyses show any of the following abnormal 
results:
●
Serum Aspartate Transaminase (AST) or Alanine transaminase (ALT) > 1.5 × 
upper limit of the reference range (ULN);
●
Estimated glomerular filtration rate by simplified 4-variable Modification of 
Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73 m2;
●
Total White Blood Cell (WBC) count < 3,000/µL;
●
Absolute neutrophil count (ANC) < 1,200/µL;
●
Platelet count < 100,000/µL;
●
Absolute lymphocytes count < 750/µL;
●
Hemoglobin < 9 gm/dL.
22.
Any active or recurrent viral infection that based on the investigator's clinical 
assessment makes the subject an unsuitable candidate for the study, including 
recurrent/disseminated herpes zoster or known history of human immunodeficiency 
virus (HIV).


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23.
Hepatitis B (HBs Ag positive [+] or detected sensitivity on the HBV DNA PCR 
qualitative test for HBc Ab positive subjects) or hepatitis C (HCV RNA detectable 
in any subject with anti-HCV Ab).
24.
Subject with active or chronic recurring infections or untreated latent TB.
25.
History of moderate to severe congestive heart failure (NYHA class III or IV), 
cerebrovascular accident and any other condition within 6 months, which in the 
opinion of the Investigator, would put the subject at risk by participation in the 
study.
26.
Use of known strong CYP3A inhibitors (e.g., clarithromycin, conivaptan, 
itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole, grapefruit 
juice) or strong CYP3A inducers (e.g., rifampin, carbamazepine, phenytoin, 
St. John's Wort) from Screening through the end of the study.
27.
Receipt of any live vaccine within 1 month prior to the Screening Visit, or will 
require live vaccination during study participation including up to 1 month after the 
last dose of study drug.
28.
Evidence of current colonic dysplasia, history of high grade colonic dysplasia, or 
history of malignancy (including of the gastrointestinal tract) other than a 
successfully treated non-metastatic cutaneous squamous cell or basal cell 
carcinoma or localized carcinoma in situ of the cervix.
29.
Has had any uncontrolled and/or clinically significant (per Investigator's judgment) 
illness or has had any surgical procedure within 30 days prior to Screening.
30.
Positive pregnancy test at Screening (serum) or Baseline (urine).
31.
Female subjects who are breastfeeding or considering becoming pregnant during 
the study.
32.
Subject is considered by the Investigator, for any reason, to be an unsuitable 
candidate for the study.


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33.
Subject who received any investigational agent or procedure within 30 days or 
5 half-lives prior to Baseline, whichever is longer.
34.
History of clinically significant drug or alcohol abuse in the last 12 months.
5.2.3
Prior and Concomitant Therapy
5.2.3.1
Prior Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject has received within 30 days prior to 
Baseline, is receiving at the time of enrollment, or receives during the study, must be 
recorded along with the reason for use, date(s) of administration including start and end 
dates, and dosage information including dose, route and frequency in source documents 
and the eCRFs.  The reason for use, date(s) of administration (including start and end 
dates), and dosage information (including dose and frequency) must be recorded.
The history of previous use (including the duration of therapy, the highest known dose 
taken, reason for use and reason[s] for termination of treatment) of the immunomodulator, 
anti-TNF and/or biologic agents will be recorded in the appropriate eCRF.  Subjects who 
have not been exposed to an anti-TNF will have their immunosuppressants recorded 
beyond the past 90 days.
The AbbVie study designated physician identified in Section 6.1.5 should be contacted if 
there are any questions regarding concomitant or prior therapy(ies).
5.2.3.2
Concomitant Therapy
Subjects who enter the study on aminosalicylates and/or MTX must remain on stable dose 
of this therapy for the entire study period.
Subjects who enter the study on Crohn's disease related antibiotics must remain on stable 
doses of this medication for at least 14 days prior to Baseline.  Change in dose of Crohn's 
disease related antibiotics during the study will not be allowed for the 16-week induction 


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period, except in cases of treatment related toxicity or concerns about development of 
antibiotic resistance.
Subjects who enter the study on oral corticosteroids are not allowed to change the 
corticosteroid dose during the first 2 weeks of the treatment period.  At Week 2, subjects 
who are taking corticosteroid therapy at Baseline must have their corticosteroid therapy 
tapered according to a tapering schedule specified below and in Section 5.3.1.1.
A proposed schedule to taper prednisone dose starts with a weekly decrease by 5 mg/day
prednisone (or equivalent) for doses > 10 mg/day of prednisone (or equivalent) until a 
10 mg/day (or equivalent) dose is reached, then a weekly decrease by 2.5 mg/day (or 
equivalent) until discontinuation.
A proposed schedule to taper budesonide dose starts with a weekly decrease by 3 mg 
budesonide until discontinuation.
If a subject should experience an inadequate response during the corticosteroid taper, the 
subject may have their corticosteroid dose increased per the investigator's discretion up to 
and beyond the dose used at Baseline.  Subjects in whom the maximum steroid dose 
exceeds the dose used at Baseline will be considered non-responders and will be censored 
for efficacy assessments from that point forward through the end of the study.  These 
subjects will continue to be evaluated in the safety population.
Use of inhaled or topical dermatologic corticosteroids is not restricted.
Subjects who enter the study on probiotics may continue this therapy provided doses 
remain stable from Baseline throughout the duration of the study.
Setons are authorized as concomitant therapy in subjects with perianal fistulas and should 
be documented in the CRF under concomitant medications.
The AbbVie Study Designated Physician identified in Section 6.1.5 should be contacted if 
there are any questions regarding concomitant or prior therapy(ies).


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5.2.3.3
Prohibited Therapy
The following are prohibited medications during the study:
●
All biologic therapy with a potential therapeutic impact on the disease being 
studied including but not limited to the following:
○
Etanercept (Enbrel®);
○
Abatacept (Orencia®);
○
Anakinra (Kineret®);
○
Rituximab (Rituxan®);
○
Natalizumab (Tysabri®);
○
Tocilizumab (Actemra®);
○
Efalizumab (Raptiva®);
○
Ustekinumab (Stelara®);
○
Belimumab (Benlysta®);
○
Golimumab (Simponi®);
○
Vedolizumab (Entyvio®);
○
Infliximab (Remicade®);
○
Certolizumab pegol (Cimzia®).
●
JAK inhibitors (e.g., tofacitinib [Xeljanz®])
●
NSAIDs (except topical NSAIDs and the use of low dose aspirin for CV 
protection).
●
Live vaccines are NOT allowed within 1 month prior to Screening and during 
the study.  Examples of live vaccines include but are not limited to the 
following:
○
monovalent live attenuated influenza A (H1N1) (intranasal)
○
seasonal trivalent live attenuated influenza (intranasal)
○
herpes zoster, rotavirus
○
varicella (chicken pox)
○
measles-mumps-rubella (MMR) or measles mumps rubella varicella 
(MMRV)


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○
oral polio vaccine (OPV)
○
smallpox
○
yellow fever
○
Bacille Calmette-Guérin (BCG)
○
typhoid
●
Rectal therapy with any therapeutic enemas or suppositories, with the 
exception of those required for endoscopy, is prohibited within 7 days prior to 
Screening endoscopy, during the remainder of the Screening Period and during 
the study.
●
Intravenous corticosteroid use is prohibited within 14 days prior to Screening 
or during the Screening Period and during the study.
●
Cyclosporine, tacrolimus, or mycophenolate mofetil use is prohibited within 
30 days prior to Baseline and during the study.
●
Azathioprine or 6-mercaptopurine (6-MP) use is prohibited within 10 days 
prior to Baseline and during the study.
●
Investigational drugs of a chemical or biologic nature are prohibited within 
30 days, or 5 half-lives (whichever is longer) of the drug prior to the Baseline 
and during the study. 
●
Use of strong CYP3A inhibitors (e.g., clarithromycin, conivaptan, 
itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole, 
grapefruit juice) or strong CYP3A inducers (e.g., rifampin, carbamazepine, 
phenytoin, St. John's wort) should be avoided from the Screening visit through 
the end of the study.
Note: Infliximab (Remicade®), Certolizumab (Cimzia®), Adalimumab 
(HUMIRA®), Vedolizumab (Entyvio®), Natalizumab (Tysabri®) are 
prohibited within 8 weeks prior to Baseline and during the study.  
Ustekinumab (Stelara®) is prohibited within 12 weeks prior to Baseline of 
during the study.
The AbbVie study designated physician identified in Section 6.1.5 should be contacted if 
there are any questions regarding prohibited therapy.


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5.2.4
Contraceptive Recommendations
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.
Postmenopausal is defined as:
●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause; or
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 mIU/mL.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered a woman of childbearing potential and is required to practice at least 
one of the following highly effective method of birth control, on Study Day 1 (or earlier) 
through at least 30 days after the last dose of study drug. 
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable)
associated with inhibition of ovulation, initiated at least 1 month prior to Study 
Day 1.
●
Bilateral tubal ligation.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of the 
WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence 


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[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable)
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the highly 
effective birth control methods listed above (excluding true abstinence).
It is important to note that contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapy ABT-494.  
The concomitant methotrexate (MTX) that may have been prescribed per standard of care 
prior to study entry and are allowed to be continued during the study.  Contraception 
should continue while the subject is on the concomitant MTX and that duration of 
contraception after discontinuation of the MTX should be based on the local label.
Contraception Recommendation for Males
For a male subject has a female partner who is postmenopausal or permanently sterile 
(bilateral oophorectomy, bilateral salpingectomy or hysterectomy), no contraception is 
required.
A male subject who is sexually active with female partner(s) of childbearing potential, 
must agree from Study Day 1 through 30 days after the last dose of study drug to practice 
contraception with:
●
Condom use and female partner(s) using at least one of the contraceptive 
measures as defined in the protocol for female study subjects of childbearing 
potential.
OR
●
True abstinence:  Refraining from heterosexual intercourse-when this is in line
with the preferred and usual lifestyle of the subject.  (Note: Periodic 
abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] 
and withdrawal are not acceptable).


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Additionally, male subject agrees not to donate sperm from Study Day 1 through 30 days 
after the last dose of study drug.
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and reporting any pregnancy to the Investigator.  If a pregnancy occurs, a partner 
authorization form requesting pregnancy outcome information will be requested from the 
pregnant partner.
It is important to note that contraception and sperm donation recommendations described 
above are specifically intended to prevent pregnancy during and after exposure to the 
investigational therapy ABT-494.  The concomitant methotrexate (MTX) that may have 
been prescribed per standard of care prior to study entry and are allowed to be continued 
during the study.  Contraception should continue while the subject is on the concomitant 
MTX and that duration of contraception and the requirement not to donate sperm after 
discontinuation of the MTX should be based on the local label.
5.3
Efficacy and Safety Assessments/Variables
Study procedures will be performed as summarized in Section 5.3.1.1.  All subjects must 
meet the study selection criteria outlined in Section 5.2.1 and Section 5.2.2 in order to be 
randomized in to the study.
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart


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Table 1.
Study Activities
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
Informed Consent
X
Inclusion/Exclusionb
X
X
Medical/Surgical 
Historyb
X
X
Prior and 
Concomitant 
Medicationsb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Endoscopyd
X
X
X
X
X
Biopsye
X
X
X
X
X
SES-CD
X
X
X
X
X
Vital Signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGg
X
Xv
Chest X-Rayh
X
Xv
PPD Skin Test or 
QuantiFERON TB 
Gold Testi
X
Latent TB Risk 
Factor Questionnaire
X
Blood Chemistry 
and Hematology
Xw
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
Urinalysisj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV and HCV 
Screeningl
X
ABT-494 
Concentrationm
X
X
X
X
X
X
X
X
X
X
X
Pharmacodynamic 
biomarkers
X
X
X
X
X
C. difficile toxin
X
Stool Sample (fecal 
calprotectin)n,o
X
X
X
X
X
X
Bristol Stool Chart
X
X
X
X
X
X
Corticosteroid Taperq
X
Crohn's Disease 
Activity Index (CDAI)
X
X
X
X
X
X
X
X
X
X
X
X
X
Inflammatory Bowel 
Disease Questionnaire 
(IBDQ)
X
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day
Follow-Up 
Visit
European Quality of 
Life 5 Dimensions 
(EQ-5D)
X
X
X
X
X
Work Productivity 
and Impairment 
Questionnaire (WPAI)
X
X
X
X
X
Abdominal Pain 
Rating Scale 
(0 – 10 Scale)
X
X
X
Monitor Adverse 
Eventsr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Dispensing/
Administration
X
X
X
X
X
X
X
X
X
X
Dispense Subject 
Diary
X
Subject Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
Additional Samples Collection (Optional)
Pharmacogenetics
X
Serologic markerst
X
X
mRNAt
X
X
Biopsy for gene 
expressionu
X
X
X
Wk = Week
a.
The Screening period will be a minimum of 7 days but no more than 35 days.  Baseline Visit date will serve as the reference for all subsequent visits.  A ± 3-day window is 
permitted around scheduled study visits.
b.
Update inclusion/exclusion, prior and concomitant therapy, and medical/surgical history information to assure subject eligibility.
c.
Physical examination performed at Screening, Baseline, Week 16 and Week 52/Early Termination Visits are full physical examinations which must include an assessment of 
extra-intestinal manifestations (EIMs) and a count of the number of cutaneous fistulas.  Physical examinations and those performed at all other visits are symptom based but 
must include a count of the number of cutaneous fistulas.
d.
Colonoscopy at/during the screening period or within 15 days of the Screening Visit will be used to calculate the SES-CD score at Baseline.  Subject will be randomly 
assigned at Baseline to have endoscopy performed at Week 12 or Week 16.  
e.
Biopsy may be done when performing the endoscopy.  Biopsy to confirm CD diagnosis may be done when performing the endoscopy if appropriate documentation for 
confirmation of the diagnosis does not exist.  Biopsies to rule out dysplasia and colon cancer may be taken at the investigator's discretion.
f.
Blood pressure, pulse rate, temperature, respiratory rate and weight should be performed before blood draws are performed.  Height will be measured at Screening only (with 
shoes off and then adding 1 inch or 2.5 cm).
g.
Subjects with normal ECG within 90 days of Screening would not require a repeat ECG, if documentation is available.  Subjects can have a repeat ECG at any time during the 
study as warranted based on the opinion of the Investigator.


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Table 1.
Study Activities (Continued)
h.
Chest x-ray includes posterior-anterior (PA) and lateral views.  Obtain chest x-ray for subjects with TB risk factors as identified by the TB risk factor questionnaire or for 
subjects living in areas endemic for TB or for subjects with positive PPD or QuantiFERON-TB Gold.  Subjects can have a chest x-ray anytime during the study as warranted 
based on the opinion of the Investigator.
i.
PPD skin test is to be read 48 to 72 hours after placement.
j.
Dipstick urinalysis will be completed by the sites at all required visits.  A microscopic analysis will be performed by the central laboratory, in the event the dipstick results 
show protein, ketones or blood greater than negative or glucose greater than normal.
k.
Serum pregnancy test will be performed on all women of childbearing potential at Screening and at Week 52/ET.  Urine pregnancy test will be performed locally at every visit 
for all women of childbearing potential.  If any urine pregnancy test is positive, a serum pregnancy test will be performed by the central laboratory.
If required by country regulatory authorities, monthly pregnancy tests will be performed throughout the study.
l.
Subjects will be tested for the presence of the hepatitis B Virus (HBV) and hepatitis C Virus (HCV) at Screening.  A positive result for the hepatitis B surface antigen 
(HBs Ag) or hepatitis C (HCV RNA detectable in any subject with anti-HCV Ab) will be exclusionary.  For subjects who are negative for HBs Ag but are positive for core 
antibodies (HBc Ab), HBV DNA PCR will be performed and any result that meets or exceeds detection sensitivity will be exclusionary.
m.
For all subjects, a PK sample will be collected at Week 2, within 1 to 3 hours after dosing, if possible.  At Week 4, Week 8, Week 12, Week 16, Week 20, Week 28, Week 36, 
Week 44 and Week 52/ET, a blood sample for PK will be collected at any time during the visit, and preferably within 1 to 8 hours after the last dose.  Patients can take the 
dose on visit days at their regular schedule and not necessarily at the clinic.  The date and accurate time of the PK sample collection and the last ABT-494 dose will be 
recorded in the CRF to the nearest minute.
n.
Stool sample will be collected at each time point indicated.  For the visit that endoscopy will be conducted, stool sample should be collected prior to endoscopy.
o.
A stool sample will be collected for fecal calprotectin analysis at each time point indicated.  Subjects will be asked to provide a stool sample at the visit, if possible, or 
subjects will be sent home with instructions and stool sample supplies (supplies will be provided).  
p.
Subject is mandated to begin corticosteroid taper at Week 2.
q.
Collection of SAEs begins the day the subject signs the informed consent.
r.
Only if subject provides written consent to collect the pharmacogenetic sample; if the informed consent form is not signed, no pharmacogenetic sample can be collected.  The 
sample is preferred to be collected at BL.


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Table 1.
Study Activities (Continued)
s.
Only if subject provides written consent to collect the serum biomarkers and mRNA samples; if the informed consent form is not signed, no serum biomarkers and mRNA can 
be collected.  
t.
Only if subject provides written consent to collect biopsy samples for gene expression analysis; if the informed consent form is not signed, no biopsy for gene expression can 
be collected.  Biopsies will be obtained at baseline and as the Week 12/16 endoscopy, based on the colonoscopy assignment for Week 12 or 16.
u.
Optional tests, only if determined by the investigator and based on the medical assessment.
v.
Laboratory tests performed during the Screening period can be repeated in case the abnormalities are considered to be transient by the investigator.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 1 are discussed in detail in this section, with the 
exception of drug concentration measurements (discussed in Section 5.3.2), 
pharmacogenetic and pharmacodynamic biomarkers, serologic markers, mRNA and gene 
expression samples (discussed in Section 5.3.1.2, Section 5.3.1.3, Section 5.3.1.4, 
Section 5.3.1.5, and Section 5.3.1.6, respectively), and the collection of adverse event 
(AE) information (discussed in Section 6.1.4).  All study data will be recorded in source 
documents and on the appropriate eCRFs.
Informed Consent
At the Screening Visit, the subject will sign and date a study specific, Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) approved, Informed Consent Form 
before any study procedures are performed or any medications are withheld from the 
subject in order to participate in this study.  A separate informed consent will be required 
for each subject in order to participate in the optional pharmacogenetic analysis, 
serological biomarker, mRNA analysis and gene expression.  Details regarding how 
informed consent will be obtained and documented are provided in Section 9.3. 
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and have none of the 
exclusion criteria at both Screening and Baseline Visits.
Medical and Surgical History
A complete medical and surgical history, including CD-onset date, history of CD 
medication use, and history of alcohol and tobacco use will be obtained from each subject 
at the Screening Visit.  An updated medical history will be obtained prior to study drug 
administration at Baseline, to ensure the subject is still eligible for enrollment, and 
updated as necessary.


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Prior corticosteroid, azathioprine, 6-MP, MTX and aminosalicylate use will be asked.  If 
subjects have/had ever been treated with these medications, the duration of therapy, 
maximum dose, reason for use and reason(s) for termination of treatment will be recorded 
in subjects' source document and in appropriated eCRF.  The details of dates of 
administration and dosages will be also recorded within the past 90 days.
A detailed anti-TNF therapy history will be recorded, this includes names of anti-TNF 
used, duration of therapy, doses, reason (s) for use and reason(s) for termination of 
treatment with these products (e.g., Inadequate Response, Intolerance, primary failure, 
secondary failure) must be documented in the subjects' source documents and in 
appropriated eCRF.
A detailed medical history with respect to Inadequate Response and/or Intolerance to an 
immunomodulator or anti-TNF agent must be documented in the subjects source 
documents.  A detailed medical history with respect to TB exposure will be documented.  
This information will include BCG vaccination, cohabitation with individuals who have 
had TB, and residence or work in TB endemic locations.
Physical Examination
A physical examination including evaluation of extra intestinal manifestations will be 
performed at the designated study visits as specified in Table 1.
A full physical examination will be performed at Screening, Baseline, Week 16 and 
Week 52/ET Visit and must include an assessment of extra-intestinal manifestations 
(EIMs) and a count of the number of cutaneous fistulas.  Symptom-based physical 
examinations will be performed at all other visits must include a count of the number of 
cutaneous fistulas.
The physical examination at the Baseline Visit will serve as the Baseline physical 
examination for the entire study.  A count of the number of cutaneous fistulas draining 
upon gentle compression must be performed during each physical exam.  Fistulas will be 
classified as abdominal or perianal/anal.  Physical examination abnormalities noted by the 


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Investigator at Baseline prior to the first dose of study drug (including fistulas and 
fissures) will be recorded in the subject's medical history.  Abnormalities noted after the 
Baseline Visit and first dose of study drug will be evaluated and documented by the 
Investigator as to whether or not these are adverse events.  All findings whether related to 
an adverse event or part of each subject's medical history will be captured on the 
appropriate eCRF page.
A symptom-directed physical examination will be performed when necessary.
Vital Signs
Vital sign determinations of systolic and diastolic blood pressure in sitting position, pulse 
rate, respiratory rate, body weight, and body temperature will be obtained at each visit.  
Blood pressure, pulse rate and respiratory rate should be performed before blood draws 
are performed.  Height will be measured at the Screening Visit only (with shoes off).  All 
measurements will be recorded in metric units where applicable.
Chest X-Ray (CXR)
A chest x-ray (posterior-anterior and lateral views) will be obtained for all subjects with 
TB risk factors as identified by the TB risk factor questionnaire (Appendix G) or for 
subjects living in areas endemic for TB or for subjects with a positive PPD or 
QuantiFERON-TB Gold.  The Investigator may obtain a Baseline chest x-ray if clinically 
indicated for a specific subject.  Subjects can have a chest x-ray anytime during the study 
as warranted based on the opinion of the Investigator.
The Principal Investigator will indicate the clinical significance of any findings and will 
sign and date the report.
Electrocardiogram (ECG)
A resting 12-lead ECG will be performed at the designated study visits as specified in 
Table 1.  A qualified physician will interpret the clinical significance of any abnormal 
finding, sign, and date each ECG.  Any clinically significant findings will be documented 


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in the source documents and later transcribed on to the appropriate eCRF.  Each signed 
original ECG will be monitored by the responsible CRA and kept with subject's source 
documents onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided all protocol required documentation is available.  
If there are other findings that are clinically significant, the Principal Investigator must 
contact the SDP before enrolling the subject.
Subjects can have a repeat ECG at any time during the study as warranted based on the 
opinion of the Investigator.
TB Screening
The TB screening tests are diagnostic test results to be interpreted in the context of the 
subject's epidemiology, history, exam findings, etc. and it is the responsibility of the 
investigator to determine if a subject has active or latent tuberculosis.
For all subjects, evidence of increased risk for TB will be assessed by a questionnaire 
(Appendix G) and testing (PPD skin test or QuantiFERON-TB Gold [or equivalent]).  
Subjects with a negative QuantiFERON®-TB Gold test OR negative PPD TB skin test 
AND no evidence of increased TB risk based on the questionnaire may be enrolled.  
Subjects with a positive QuantiFERON-TB Gold test OR a positive PPD skin test 
(defined as 5 mm of induration or greater) OR at increased risk of TB based on 
questionnaire/geography should have a chest x-ray.  Subjects with evidence of latent TB 
may be enrolled after at least 2 weeks of prophylactic treatment per local guidelines.
If a subject had a negative PPD test or QuantiFERON-TB Gold test (or interferon-gamma 
release assay-IGRA-equivalent such as T-SPOT TB test) test within 90 days prior to 
Screening and all protocol required documentation is available, the test does not need to 
be repeated, provided nothing has changed in the subject's medical history to warrant a 
repeat test.  These cases must be discussed with the AbbVie Study Designated Physician.


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Subjects should be screened for TB using either PPD or IGRA.  In the event both a PPD 
test and an IGRA test are performed, if either one is positive the subject will be 
considered to be positive.  If the IGRA test is indeterminate, the site should repeat the test.  
If the second IGRA test is also indeterminate, the subject is considered to be positive.
Subjects with evidence of latent TB may be enrolled after at least 2 weeks of prophylactic 
treatment per local guidelines.
Subjects with evidence of active TB infection are excluded.
The results of the TB test(s) will be retained at the site as the original source 
documentation.
QuantiFERON-TB Gold Test (or IGRA Equivalent such as T-SPOT TB Test)
QuantiFERON-TB Gold test (or IGRA equivalent such as T-SPOT TB test) will be 
performed at Screening.  The analyses will be performed by a certified laboratory.
OR
TB Skin Test
A PPD skin test (alternatively, also known as a TB Skin Test or Mantoux test) will be 
performed at Screening according to standard clinical practice.  The TB Skin Test should 
be read by a licensed healthcare professional between 48 and 72 hours after 
administration.  A subject who does not return within 72 hours will need to be 
rescheduled for another skin test.  The reaction will be measured in millimeters (mm) of 
induration and induration equal to or greater than 5 mm is considered a positive reaction.  
The absence of induration will be recorded as "0 mm" not "negative."
Pregnancy Tests
A serum pregnancy test will be performed at the Screening and Week 52/ET Visit on all 
female subjects of childbearing potential.  


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Women of childbearing potential includes all women who are not surgically sterile (both 
ovaries removed or uterus removed) or post-menopausal (defined as no menses for at least 
one year, without an alternate reason for amenorrhea).
At the Baseline Visit, subjects of childbearing potential will have a urine pregnancy test 
performed locally by designated study personnel.  If any urine pregnancy test is positive, a 
serum pregnancy test will be performed by the central laboratory.  If the serum pregnancy 
test is positive, dosing must be stopped and the subject must be discontinued from the 
study.
A lactating or pregnant female will not be eligible for participation or continuation in this 
study.
All women of childbearing potential will have a repeat urine pregnancy test at every 
Study Visit performed locally by designated study personnel.
Hepatitis B and C Testing
All subjects will be tested for the presence of the hepatitis B Virus (HBV) and hepatitis C 
Virus (HCV) at Screening.  Subjects with hepatitis B (HBs Ag positive [+] or detected 
sensitivity on the HBV DNA PCR qualitative test for core antibodies (HBc Ab) positive 
subjects) or hepatitis C (HCV RNA detectable in any subject with anti-HCV Ab) will be 
excluded.  Subjects who have been vaccinated against hepatitis B and are HBs Ab positive 
may be enrolled.
Clinical Laboratory Tests
Blood samples will be obtained for the laboratory tests listed in Table 2.  Blood draws 
should be performed after all clinical assessments and questionnaires (IBDQ, etc.) and 
vital sign determinations are obtained during a visit.
A certified central laboratory will be utilized to process and provide results for the clinical 
laboratory tests.  All abnormal laboratory tests that are considered clinically significant by 
the Investigator will be followed to a satisfactory resolution.


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The central laboratory chosen for this study will provide instructions regarding the 
collection, processing and shipping of these samples.
The blood samples for serum chemistry tests should be collected following a minimum 
8-hour fast, when possible.  If a subject is not able to fast when necessary, due to 
unforeseen circumstances, the non-fasting status will be recorded in study source 
documentation.  The fasting status will be recorded in the laboratory request, source 
document and CRF.


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Table 2.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysisa
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) 
count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not 
acceptable)
Reticulocyte count
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Albumin
Aspartate aminotransferase 
(AST)
Alanine aminotransferase 
(ALT)
Alkaline phosphatase
Creatine Phosphokinase (CPK)
Sodium
Potassium Chloride
Bicarbonate
Calcium
Inorganic phosphorus
Uric acid
Cholesterol
LDL cholesterol
HDL cholesterol
Total protein
Glucose
Triglycerides
Chloride
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Nitrite
Leukocytes
Microscopic Examination
Other Laboratory Tests
Serum pregnancy test
Urine pregnancy test
High sensitivity C-reactive protein 
(hs-CRP)
Hbs Ag
HBs Ab
HBc Ab
HBV DNA PCR reflex only 
HCV Ab
HCV RNA reflex only
PPD
QuantiFERON-TB Gold
Pharmacodynamic biomarkers 
Pharmacokinetic
Stool Samples Collected
C. difficile toxin
Fecal calprotectin
Additional Samples Collected (Optional)
Pharmacogenetic
mRNA
Serologic markers
Biopsy for gene expression
a.
Microscopic urinalysis will be analyzed when dipstick results are abnormal.
Urinalysis
Urine samples will be obtained and sent to the central laboratory for the tests listed in 
Table 2.  Microscopic urinalysis will only be performed by the central laboratory if the 


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dipstick UA results are abnormal, where abnormal is defined as leukocytes, nitrite, 
ketone, protein, blood or glucose value of greater than a trace.
Other Laboratory Assessments
hs-CRP
Blood samples for high-sensitivity C-reactive protein (hs-CRP) will be obtained.  Blood 
draws should be performed after all clinical assessments, questionnaires (IBDQ, etc.), and 
vital sign determinations are obtained.  The hs-CRP results from Week 2 through 
Week 16 will be blinded to sites/sponsor.  The hs-CRP results after Week 16 will be 
un-blinded.
hs-CRP will be performed by Central Lab.  However, for the purpose of evaluating 
Inadequate Response criteria, hs-CRP can also be done at local lab.  At Week 20, since 
the Week 16 hs-CRP will still be blinded, the hs-CRP performed by the local lab or the 
Week 20 Central Lab result will be used for the assessment of Inadequate Response.
Stool Samples Collected
Fecal Calprotectin
Fecal calprotectin will be performed for all subjects as indicated in Table 1.  Subjects will 
be asked to provide a stool sample, subjects will be sent home with instructions and a 
stool sample supplies (supplies will be provided).
The fecal calprotectin results will remain blinded to Investigator, study site personnel and 
the subject throughout the study.
All stool samples should be collected before any bowel preparation for endoscopy is 
started.  The central laboratory will be utilized to process and provide results for these 
laboratory tests.
The stool sample collected during the Screening Period will be used for the Baseline 
assessment (prior to receiving study drug).


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C. Difficile
During the Screening Period a stool sample will be collected and sent to the central 
laboratory for testing.  The sample will be assessed for the presence of C. difficile toxin.
The sample must be shipped to the central laboratory using dry ice.  Additional 
information is available in the Investigator Manual provided by the central laboratory.
Subjects who are positive for C. difficile toxin may be treated appropriately and 
re-screened.
CDAI
A CDAI will be calculated from a subject diary, physical exam, and appropriate 
laboratory values at all study visits beginning at Screening.  The Screening Period will be 
a minimum of 7 days but will not exceed 35 days.  The CDAI calculated during Screening 
will serve as the Baseline CDAI.
For calculation of CDAI scores, beginning with the Week 2 through Week 52, the CDAI 
scores must be calculated using a hematocrit value from the preceding visit laboratory 
work.
CDAI at Visit
Hematocrit Value Utilized
Week 2
Baseline
Week 4
Week 2
Week 8
Week 4
Week 12
Week 8
Week 16
Week 12
Week 20
Week 16
Week 28
Week 20
Week 36
Week 28
Week 44
Week 36
Week 52
Week 44


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For calculating CDAI, to answer questions one (1) through three (3), entries from the 
7 days prior to the day of study visit should be used as recorded by the subject from the 
diary.
Diary entries should not be included in the 7 days evaluated prior to the visit if:  (1) the 
day the subject received medication for bowel preparation prior to endoscopy, (2) the day 
the subject underwent an endoscopy, and (3) 2 days following the endoscopy.  Earlier 
diary entries will be used accordingly in order to provide the most recent data for 7 days 
prior to the respective study visit.
For the CDAI questions regarding presence of anal fistulas and other fistulas, all fistulas 
detectable on physical examination (draining and non-draining) should be captured on the 
CDAI and calculated into the CDAI score.
When completing question five (5) ("Taking Lomotil/Imodium/Loperamide/opiates for 
diarrhea, 0 = no, 1 = yes") on the CDAI, "no" should be answered if a subject is taking an 
opiate(s) solely for pain.
For question seven (7), hematocrit results from central laboratory will be used for the 
CDAI calculation.  If the hematocrit value contains more than one decimal point, the 
rounding will be allowed to the tenths decimal (e.g., Hematocrit value 33.44 will be 
captured as 33.4, Hematocrit value of 33.45 will be captured as 33.5).  The Hematocrit 
values either prior to completing the calculation or at the subtotal box 7 of the CDAI 
should not be rounded to a whole number.
The height obtained at Screening should be used when selecting the standard weight in 
Appendix E, and this standard weight should be used for calculating every CDAI 
throughout subject participation in the study.
Standard height is calculated by using the height obtained at Screening (without shoes) 
plus one inch.


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If the body weight obtained at the time of assessment is not captured in kilograms (kg), 
then when converting into kgs, rounding should occur using the second digit after the 
decimal (also known as the hundredth place) where if the number is 0 – 4 then keep the 
first digit after the decimal (also known as the tenth place) unchanged.  If the second digit 
after the decimal is 5 – 9 then round up the first digit after the decimal (e.g., 90.246 would 
be captured as 90.2, 97.687 would be captured as 97.7).
The subtotal of box 8 should not be rounded to a whole number.  The calculation of the 
CDAI score is in Appendix D.
Outcomes and Questionnaires
●
IBDQ – Inflammatory Bowel Disease Questionnaire (IBDQ) will be 
completed at the time points indicated in Table 1.
●
WPAI – Work Productivity and Activity Impairment Questionnaire (WPAI) 
will be completed at the time points indicated in Table 1.  The data in the 
subject completed questionnaire will be transferred to the appropriate eCRF 
(Electronic Case Report Form) by the site personnel at each study visit 
(Appendix C).
●
EQ-5D – European Quality of Life 5 Dimensions, a standardized questionnaire 
for use as a measure of health outcome will be completed at the time points 
indicated in Table 1.
●
Abdominal Pain Rating Scale (0 – 10 Scale) (Appendix I).
Corticosteroid Taper
At Week 2, subjects who are on prednisone or budesonide must have their corticosteroid 
dose tapered according to the following proposed schedule or based on Investigators' 
discretion:


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Dose
Rate
Prednisone (or equivalent)
> 10 mg/day
≤ 10 mg/day
5 mg/day/week
2.5 mg/day/week
Budesonide
≤ 9 mg/day
3 mg/day/week
If a subject should experience an inadequate response during the corticosteroid taper, the 
subject may have their corticosteroid dose increased, per the investigator's discretion, up 
to and beyond the dose used at Baseline.  Subjects in whom the maximum steroid dose 
exceeds the dose used at Baseline will be considered non-responders and will be censored 
for efficacy assessments from that point forward through the end of the study.  These 
subjects will continue to be evaluated in the safety population.
Subject Diary
Subjects will be dispensed an electronic diary at Screening and will be trained on how to 
complete the diary by site staff during the Screening Visit.  All subjects should complete 
their subject diary on a daily basis throughout the entire study.  The diary will be reviewed 
by site personnel with the subject at each visit and collected at the Final/ET Visit.
The dosing records will be reviewed and verified for compliance at each visit by the 
research personnel at the study center and reinforced if necessary.  All relevant dosing 
information will be retained by the study coordinator and transcribed into the eCRF.  
Additionally, any discernible departure from the protocol regarding study drug 
administration will be recorded on the source documents and in the appropriate drug 
accountability form.
Study Drug Dispensing/Administration
Study drug will be dispensed to subjects beginning at Baseline and at all study visits 
through Week 52.  No study medication will be dispensed at Week 52.
(Refer to Section 5.5 for additional information.)


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Endoscopy
An endoscopy will be performed on the following visits:
●
During Screening*
●
Week 12 or Week 16
●
Week 52/Early Termination
For those subjects who discontinue the study between Weeks 8 and 12 the endoscopy 
performed at the Early Termination Visit will be used as the Week 12 endoscopy result.  
An endoscopy will not be performed if a subject discontinues the study prior to Week 8.
In addition, for those subjects who discontinue the study during the extension phase, an 
endoscopy will not be performed if a subject discontinues the study prior to Week 28.
*  An endoscopy performed before the Screening visit, independently of the study, may be 
used as the Screening endoscopy, with the approval of the AbbVie Study Designated 
Physician, if the following conditions are met:
1.
biopsy confirmation of the diagnosis is available according to section "Biopsy 
During Endoscopy" below.
2.
the endoscopy took place within 15 days of Screening Visit.
3.
the endoscopy was recorded in a video format as the endoscopic eligibility will be 
determined by the central reviewers.  The same endoscopist, where possible, 
should perform all endoscopies.
An ileo-colonoscopy will be performed and recorded at the site in a video format and will 
be reviewed by a central reviewer who is blinded to the therapy, during the Screening 
Period (or within 15 days of the Screening Visit), Week 12 or Week 16 and the 
Week 52/ET Visit.  There will be a window of ± 7 days to conduct the ileocolonoscopy.  
This window may be extended as necessary after consultation with the AbbVie Study 
Designated Physician in case of external, not subject-related circumstances 


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(e.g., scheduling conflict).  The central reviewer will evaluate the data and provide the 
endoscopy subscore for calculating the Simplified Endoscopic Score (SES CD).  
Discrepancies between the central reviewer and the site endoscopist regarding a subject's 
score will be finally judged through adjudication by a second central reviewer.  The 
adjudicator will not provide an assessment but will select the assessment with whom 
he/she agrees.  The adjudicator's assessment will be considered final.  Endoscopic 
eligibility will be determined by the central reviewers.  If, in the opinion of the 
Investigator, the Screening endoscopy does not indicate the SES-CD criteria confirming 
study eligibility, the subject should be screen-failed and the video should not be sent for 
central review.
The same endoscopist should perform all endoscopies for an individual subject 
throughout the study.  In addition, where possible, the investigator or subinvestigator 
should be the endoscopist for the study.
The endoscopy during the Screening Period (or endoscopy performed within 15 days of 
the Screening Visit), Week 12 or Week 16 and Week 52/ET will be used to provide the 
endoscopy subscores for calculating the Simplified Endoscopic Score (SES CD) at 
Screening, Week 12 or Week 16 and Week 52/ET, respectively, refer to Appendix F.
The endoscopy subscores by segment will be noted in the subject's source documents and 
in the database but the central reviewer's endoscopy subscore will be used for the efficacy 
analyses.
For stratification at Week 16 re-randomization, the local reading (at Week 12 or Week 16) 
will be compared with the baseline central reading in order to determine response status.
Biopsy During Endoscopy
Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the 
assessment of the Investigator, must be available in order to confirm the subject's 
eligibility for the study.  If this documentation is not available a diagnostic biopsy from 
the most affected area of the colon must be performed during the Screening endoscopy 


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and read by a qualified local pathologist and the results reviewed by the Investigator.  
Biopsies to rule out dysplasia and colon cancer may be taken per the Investigator's 
discretion during any endoscopy performed during this study and evaluated by the local 
pathologist.  
If any biopsy sample(s) are obtained, it should also be recorded on the video.  
Any biopsy sample(s) will be collected from the respective bowel segment during the 
withdrawal of the endoscope and after sufficient recording for the central reader to 
calculate the SES-CD.
The signed pathology report will be monitored by the responsible Clinical Research 
Associate (CRA) and kept with the subject's source documents onsite.  Subjects should 
not be enrolled if colon dysplasia or colon cancer is discovered at Screening endoscopy or 
endoscopy performed within 15 days of the Screening Visit.
If a diagnosis of colon dysplasia or colon cancer is discovered during any subsequent 
endoscopic evaluation during the course of the study, the findings should be recorded as 
an adverse event and the subject should be discontinued from the study.
5.3.1.2
Blood Samples for Pharmacogenetic Analysis
An optional whole blood sample for DNA isolation will be collected on Baseline Visit 
from each subject who consents to provide samples for pharmacogenetic analysis.  The 
procedure for obtaining and documenting informed consent is discussed in Section 9.3.
The sample collection tubes will minimally be labeled with "PG-DNA," protocol number, 
subject number and the study day.  Samples will be shipped frozen to AbbVie or a 
designated laboratory for DNA extraction and long-term storage.  Instructions for the 
preparation and shipment of pharmacogenetic samples will be provided outside of this 
protocol.  


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Abbvie will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on ABT-494 (or 
drugs of this class) continues but no longer than 20 years after study completion (where 
allowed by local guidelines).
5.3.1.3
Collection and Handling of In Vivo Pharmacodynamic 
Biomarker Variables
Serum samples will be collected at time points specified in Table 1 to assess JAK activity 
effects on certain lymphocyte subsets including T (CD4+ and CD8+), B, NK cell subsets, 
reticulocyte and other cell types.
Instructions on preparation and shipment of pharmacodynamic (in vivo biomarkers) 
samples will be provided by a certified laboratory or the sponsor outside this protocol.  In 
vivo biomarkers will be assayed using a validated method under the supervision of the 
Bioanalysis Department at AbbVie.
5.3.1.4
Collection of Samples for Serologic Markers
Optional blood samples for serologic markers analysis will be collected at from each 
subject who consents to provide samples the time points indicated in Table 1.  Please refer 
to the laboratory manual for specific instructions.
The procedure for obtaining and documenting informed consent is discussed in 
Section 9.3.
The frozen samples for serologic marker analysis will be packed in dry ice sufficient to 
last during transport and shipped from the study site to the central laboratory.  Samples 
should not be allowed to thaw prior to arrival at AbbVie or the designated laboratory.  An 
inventory of the samples included will accompany the package.  Arrangements will be 
made with the central laboratory for the shipment of samples to AbbVie or the designated 
laboratory for serologic markers analysis and long-term storage as allowed by 
regional/local law and as defined in the approved informed consent form.


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5.3.1.5
Collection of Samples for mRNA Assays
Optional whole blood samples for mRNA will be collected from each subject who 
consents to provide samples at the time points indicated in Table 1.  Please refer to the 
laboratory manual for specific instructions.
The frozen samples for mRNA analysis will be packed in dry ice sufficient to last during
transport and shipped from the study site to the central laboratory.  Samples should not be 
allowed to thaw prior to arrival at AbbVie or the designated laboratory.  An inventory of 
the samples included will accompany the package.  Arrangements will be made with the 
central laboratory for the shipment of samples to AbbVie or the designated laboratory for 
mRNA analysis and long-term storage as allowed by regional/local law and as defined in 
the approved informed consent form.
5.3.1.6
Collection of Samples for Gene Expression
Optional gene expression samples may be evaluated in approximately 80 subjects.  A 
separate informed consent will be required for participation in this part of the protocol.  
Endoscopic biopsy samples for gene expression analysis will be obtained from segments 
of the colon and the ileum with the most significant abnormalities at the time of screening 
endoscopy.  Three biopsy samples each should be obtained from both the colon and 
ileum.  In patients with isolated active ileal disease, collect 3 biopsy samples from the 
ileum only.  The location biopsied at screening endoscopy should be recorded, and 
Week 12/16 biopsies should be obtained from the same segment.  Care should be taken to 
avoid the bed of ulcers, instead samples should be obtained from the area surrounding 
ulcers when these exist.  Sample handling instructions will be provided in the laboratory 
manual for gene expression analysis and long-term storage as allowed by regional/local 
law and as defined in the approved informed consent form.


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5.3.2
Drug Concentration Measurements
Blood samples for assay of ABT-494 will be collected as follows:
●
At Week 2 visit, a PK sample will be collected within 1 to 3 hours after dosing 
if possible.
●
At Week 4, Week 8, Week 12, Week 16, Week 20, Week 28, Week 36, 
Week 44 and Week 52/ET, a blood sample for PK will be collected at any time 
during the visit, and preferably within 1 to 8 hours after the last dose.
Patients can take the dose on visit days at their regular schedule and not necessarily at the 
clinic.  The accurate time of the PK sample collection and last ABT-494 dose will be 
recorded on the CRF to the nearest minute.
5.3.2.1
Handling/Processing of Samples
Detailed instructions for the handling and processing of samples will be provided by 
central laboratory.  The plasma samples will be shipped to Central Laboratory.  ABT-494 
plasma concentration will be determined at AbbVie.
5.3.2.2
Disposition of Samples
The frozen plasma samples for ABT-494 assays will be packed in dry ice sufficient to last 
during transportation and shipped from the study site to the Central Laboratory according 
to instructions in the central laboratory Lab Manual.  An inventory of the samples 
included will accompany the package.
5.3.2.3
Measurement Methods
Plasma concentrations of ABT-494 will be determined under the supervision of the Drug 
Analysis Department at AbbVie using validated liquid chromatography/mass 
spectrometry methods.  


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5.3.3
Efficacy Variables
The following endpoint definitions apply to the efficacy variables described below:
●
Remission:  Endoscopic remission AND Clinical remission
●
Response:  Endoscopic response AND Clinical response
●
Endoscopic remission:  SES-CD ≤ 4 and at least two point reduction versus 
Baseline and no subscore > 1 in any individual variable
●
Endoscopic response:  SES-CD at least 25% reduction from Baseline
●
Clinical remission:  average daily stool frequency ≤ 1.5 and not worse than 
Baseline AND average daily abdominal pain ≤ 1.0 and not worse than Baseline
●
Clinical response:  average daily stool frequency at least 30% reduction from 
Baseline and average daily abdominal pain not worse than Baseline OR 
average daily abdominal pain at least 30% reduction from Baseline and 
average daily stool frequency not worse than Baseline
5.3.3.1
Primary Variables
The co-primary endpoints of this study are:
1.
Proportion of subjects who achieve endoscopic remission at Week 12/16.
2.
Proportion of subjects who achieve clinical remission at Week 16.
5.3.3.2
Secondary Variables
The secondary endpoints (Double-Blind Induction Treatment Period) include:
●
Proportion of subjects who achieve CDAI < 150 at Week 16.
●
Proportion of subjects with decrease in CDAI ≥ 70 points from Baseline at 
Week 16.
●
Proportion of subjects who achieve clinical remission at Week 12.
●
Proportion of subjects who achieve remission at Week 16 (endoscopic 
remission at Week 12/16 and clinical remission at Week 16).


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●
Proportion of subjects who achieve response at Week 16 (endoscopic response 
at Week 12/16 and clinical response at Week 16).
●
Proportion of subjects with endoscopic response at Week 12/16.
●
Proportion of subjects who achieve clinical response at Week 16.
●
Proportion of subjects with an average daily SF ≥2.5 AND average daily 
AP ≥2.0 at Baseline who achieve clinical remission at Week 16.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve CDAI < 150 at Week 16.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve endoscopic remission at Week 12/16 and 
clinical remission at Week 16.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve clinical remission at Week 16.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve endoscopic remission at Week 12/16.
●
Change from Baseline in fecal calprotectin level at Week 16.
●
Change from Baseline in hs-CRP at Week 16.
●
Change in IBDQ from Baseline at Week 16.
●
Proportion of subjects with isolated ileal Crohn's disease who achieve 
remission at Week 16.
The secondary endpoints (Double-Blind Extension Phase) include:
●
Proportion of subject who achieve remission at Week 52.
●
Proportion of subjects who achieve endoscopic remission at Week 52.
●
Proportion of subjects who achieve clinical remission at Week 52.
●
Proportion of subject who achieve response at Week 52.
●
Proportion of subjects who achieve endoscopic response at Week 52.
●
Proportion of subjects who achieve clinical response at Week 52.
●
Proportion of subjects with an average daily SF ≥2.5 AND average daily 
AP ≥2.0 at Baseline who achieve clinical remission at Week 52.


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●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieved CDAI < 150 at Week 52.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve remission at Week 52.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve clinical remission at Week 52.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve endoscopic remission at Week 52.
●
Proportion of subjects who achieve CDAI < 150 at Week 52.
●
Proportion of subjects with decrease in CDAI ≥ 70 points from Baseline at 
Week 52.
●
Change from Baseline in fecal calprotectin level at Week 52.
●
Change from Baseline in hs-CRP at Week 52.
●
Change in IBDQ from Baseline at Week 52.
●
Change in EIMs from baseline at Week 52.
●
Proportion of subjects with isolated ileal Crohn's disease who achieve 
remission at Week 52.
5.3.3.3
Additional Efficacy Variables
The additional endpoints include:
●
Proportion of subject who achieve remission over time.
●
Proportion of subjects who achieve endoscopic remission over time.
●
Proportion of subjects who achieve clinical remission over time.
●
Proportion of subject who achieve response over time.
●
Proportion of subjects with endoscopic response over time.
●
Proportion of subjects who achieve clinical response over time.
●
Proportion of subjects who achieve CDAI < 150 over time.
●
Proportion of subjects with decrease in CDAI ≥ 70 points from Baseline over 
time.


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●
Change in WPAI from Baseline over time.
●
Change in EQ5D from Baseline over time.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve CDAI < 150 over time.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve remission over time.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve clinical remission over time.
●
Proportion of subjects taking corticosteroids at Baseline who discontinued 
corticosteroid use and achieve endoscopic remission over time.
●
Change from Baseline in fecal calprotectin level over time.
●
Change from Baseline in hs-CRP over time.
●
Change in IBDQ from Baseline over time.
●
SES-CD endpoints with adjustment for segments visualized.
●
The proportion of subjects in each treatment group with no draining fistulas at 
Week 16 among subjects with draining fistula at Baseline.
●
The proportion of subjects in each treatment group with ≥ 50% reduction from 
Baseline in the number of draining fistulas at Week 16 among subjects with 
draining fistula at Baseline.
●
The proportion of subjects in each treatment group with no draining fistulas at 
Week 52 among subjects with draining fistula at Baseline.
●
The proportion of subjects in each treatment group with ≥ 50% reduction from 
Baseline in the number of draining fistulas at Week 52 among subjects with 
draining fistula at Baseline.
5.3.4
Safety Variables
Safety analyses will be performed on all subjects who receive at least one dose of study 
drug.  Incidence of adverse events, changes in vital signs, electrocardiogram, physical 
examination results, and clinical laboratory data will be assessed.


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5.3.5
Pharmacokinetic Variables
Plasma ABT-494 concentrations will be obtained at the times indicated in Table 1.  A 
non-linear mixed-effects modeling approach will be used to estimate the population 
central values and the empirical Bayesian estimates of the individual values of ABT-494 
oral clearance (CL/F) and volume of distribution (Vss/F).  Additional parameters may be 
estimated if useful in the interpretation of the data. 
5.3.6
Pharmacogenetic and Serologic Variables
5.3.6.1
Pharmacogenetic Variables
For patients who consent to this optional testing, DNA samples may be analyzed for 
genetic factors contributing to the disease or to the subject's response to ABT-494, or 
other study treatment, in terms of pharmacokinetics, efficacy, tolerability and safety.  
Such genetic factors may include genes for drug metabolizing enzymes, drug transport 
proteins, genes within the target pathway, or other genes believed to be related to the 
disease or to drug response.  Some genes currently insufficiently characterized or 
unknown may be understood to be important at the time of analysis.  The samples may be 
analyzed as part of a multi-study assessment of genetic factors involved in the response to 
ABT-494 or drugs of this class.  The samples may also be used for the development of 
diagnostic tests related to ABT-494 (or drugs of this class) or the disease.  The results of 
pharmacogenetic analyses may not be reported with the study summary.  AbbVie will 
store the samples in a secure storage space with adequate measures to protect 
confidentiality.  As allowed by local guidelines, the samples will be retained for up to 
20 years after completion of the study research. A separate informed consent will be 
required for participation in this part of the protocol.
5.3.6.2
Serologic Marker and mRNA Variables
For patients who consent to this optional testing, serum and mRNA samples will be 
collected and stored for possible future exploratory analyses of non-genetic biomarkers 
related to the subject's disease and/or response to study drug or additional therapies, or 


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development of adverse events.  For example, samples may be analyzed for plasma and 
serum proteins, peptides, and non-protein soluble factors such as lipids that may help 
predict disease behavior and help determine more severe disease phenotypes and response 
to JAK inhibitors.  These samples may also be used for the development of diagnostic 
tests.  Results of these types of exploratory analyses, if any, will not be reported with the 
study summary.
To protect subjects' confidentiality, the samples will be coded with the subjects' study 
identifiers.  The key between the subjects' study identifiers and the subjects' personal 
identifiers will be held at the investigator site and will not be accessible to AbbVie 
researchers.  Unless a certain time limit is required by a site's local regulations, samples 
will be stored for up to 20 years in AbbVie's Immunology Biobank or a laboratory 
designated by AbbVie, which is a secure facility.  Abbvie will be responsible for the long 
term storage and destruction of the samples. 
A separate informed consent will be required for participation in this part of the protocol.  
The samples will only be used for the purposes described here and in the informed 
consent.  Any other uses would require additional ethical approval.
5.3.6.3
Gene Expression Variables
For patients who consent to this optional testing, gene expression may be evaluated in 
approximately 80 subjects.  A separate informed consent will be required for participation 
in this part of the protocol.  
Biopsy will be collected and stored for possible future exploratory analyses of gene 
expression.  Results of these types of exploratory analyses, if any, will not be reported 
with the study summary.
To protect subjects' confidentiality, the samples will be coded with the subjects' study 
identifiers.  The key between the subjects' study identifiers and the subjects' personal 
identifiers will be held at the investigator site and will not be accessible to AbbVie 
researchers.  Unless a certain time limit is required by a site's local regulations, samples 


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will be stored for up to 20 years in AbbVie's Immunology Biobank or a laboratory 
designated by AbbVie, which is a secure facility.  AbbVie will be responsible for the long 
term storage and destruction of the samples. 
The samples will only be used for the purposes described here and in the informed 
consent.  Any other uses would require additional ethical approval.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
A subject may withdraw from the study at any time.  The Investigator may discontinue 
any subject's participation for any reason, including an adverse event, safety concerns or 
failure to comply with the protocol.
Subjects will be withdrawn from the study immediately if any of the following occur:
●
Clinically significant abnormal laboratory results or adverse events, which rule 
out continuation of the study medication, as determined by the Investigator and 
the AbbVie SDP.
●
Serious infections (e.g., sepsis) which would put the subject at risk for 
continued participation in the trial as determined by the Investigator in 
consultation with the AbbVie SDP.
●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from the study.
●
Inclusion and exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study drug would place the subject at risk 
as determined by the AbbVie SDP.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie SDP.
●
Subject is non-compliant with TB prophylaxis (if applicable) or develops 
active TB at any time during the study.
●
The subject becomes pregnant while on study medication.


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●
Subject has known high grade dysplasia of the gastrointestinal tract or 
malignancy, except for localized non-melanoma skin cancer.  Discontinuation 
for carcinoma in situ of the cervix is at the discretion of the Investigator.
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial in consultation with 
the AbbVie SDP.
If, during the course of study drug administration, the subject prematurely discontinues 
study drug use, the procedures outlined for the Week 52/ET Visit must be completed 
within 2 weeks of the last dose of study drug, and preferably prior to the initiation of 
another therapy.  However, these procedures should not interfere with the initiation of any 
new treatments or therapeutic modalities that the Investigator feels are necessary to treat 
the subject's condition.  Following discontinuation of the study drug, the subject will be 
treated in accordance with the Investigator's best clinical judgment.
A final visit will occur for all subjects, approximately 30 days after the last dose of study 
medication to determine the status of any ongoing AEs/SAEs or the occurrence of any 
new AEs/SAEs.
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for early termination.  The information will be recorded on the appropriate 
eCRF page.
For subjects that are considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent and documented in the subject's source 
documentation. 
Subjects who discontinue the study prematurely will not be replaced.


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5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
Study drug will be taken orally twice a day for 52 weeks beginning on Baseline.  Subjects 
will be instructed to take two daily doses of 2 capsules (four capsules daily) as described 
in the tables below at approximately the same time each day.
At or after Week 20, if subject met the criteria of inadequate response, subject may be 
eligible to receive the Open-Label ABT-494 12 mg BID and would take 2 capsules daily.
If subject continues to meet the criteria of inadequate response, subject could move to 
receive the Open-Label ABT-494 24 mg BID (4 capsules daily).  The study drug can be 
taken with or without food.


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5.5.1
Treatments Administered
During the Double-Blind Induction Period (Weeks 1 – 16)
Treatment Group
ABT-494
3 mg
ABT-494
12 mg
Placebo for ABT-494
3 mg or 12 mg
ABT-494 3 mg BID
1
0
1
ABT-494 6 mg BID
2
0
0
ABT-494 12 mg BID
0
1
1
ABT-494 24 mg BID
0
2
0
ABT-494 24 mg QD (AM)
0
2
0
ABT-494 24 mg QD (PM)
0
0
2
Placebo
0
0
2
During the Double-Blind Extension Phase (Weeks 16 – 52)
Treatment Group
ABT-494
3 mg
ABT-494
12 mg
Placebo for ABT-494
3 mg or 12 mg
ABT-494 3 mg BID
1
0
1
ABT-494 6 mg BID
2
0
0
ABT-494 12 mg BID 
0
1
1
ABT-494 24 mg QD (AM)
0
2
0
ABT-494 24 mg QD (PM)
0
0
2
Study Drug for Administration During the Open-Label due to the Inadequate 
Response
Treatment Group
ABT-494
12 mg
ABT-494 24 mg BID
2
ABT-494 12 mg BID 
1


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5.5.2
Identity of Investigational Product
Investigational Product
ABT-494
Placebo for 3 mg or 12 mg
Mode of Administration
Oral
Oral
Oral
Dosage Form
Capsule
Capsule
Capsule
Strength (mg)
3
12
0
5.5.2.1
Packaging and Labeling
AbbVie will supply blinded study medication in weekly kits.  Each Kit will contain a 
blister card for 1 week of study medication plus 3 extra daily doses.  Daily doses are 
identified on each blister card as Day 1 through Day 7, respectively.  Additional study 
drug is identified on each blister card as "Extra."  Open-label study medication will be 
supplied in bottles.
Each kit will contain a unique kit number.  This kit number is assigned to a subject via 
IRT and encodes the appropriate study drug to be dispensed at the subject's corresponding 
study visit.  Each kit will be labeled as required per country requirements.
Labels must remain affixed to the blister cards, and bottles and must not be concealed by 
any over-labeling.  All blank spaces on the label will be completed by site staff prior to 
dispensing to the subjects.
5.5.2.2
Storage and Disposition of Study Drug
The study drug must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  
The controlled storage area should have a temperature recording device.  A storage 
temperature log is to be maintained to document proper storage conditions.  Malfunctions 
or any temperature excursions must be reported to the sponsor immediately.  In case of a 
temperature excursion, study medication should be quarantined and not dispensed until 
AbbVie deems the medication acceptable.  The investigational products are for 
investigational use only and are to be used only within the context of this study.  The 
study drug supplied for this study must be maintained under adequate security and stored 
under the conditions specified on the label until dispensed for subject use or destroyed on 


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site according to local procedures or regulations or returned to the destruction depot by 
the site monitor.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be centrally randomized using an Interactive Response Technology 
(IRT).  Before the study is initiated, the telephone number and call-in directions for the 
IRT will be provided to each site.
All subjects will be assigned a unique identification number by the IRT at the Screening 
Visit.  Subjects who meet the inclusion and none of the exclusion criteria defined in 
Section 5.2.1 and Section 5.2.2 will be centrally randomized 1:1:1:1:1:1 to one of 
six treatment groups at Baseline (Week 0) in a double-blind manner.  The IRT will assign 
a randomization number that will encode the subject's treatment group assignment 
according to the randomization schedule generated by the Statistics Department at 
AbbVie.
IRT will provide the appropriate medication kit number(s) to dispense to each subject.  
Study drug will be administered at the study visits as summarized in Section 5.5.  
Returned study medication should not be re-dispensed to any subject.
At Week 16, all subjects will be re-randomized in a ratio of 1:1:1 to the three double-blind 
doses of ABT-494 (3 mg BID, 6 mg BID or 12 mg BID).  The subjects who were 
re-randomized at Week 16 to ABT-494 24 mg QD prior to Protocol Amendment 2 will 
continue to receive the same double-blind dose until Week 52/PD.
The re-randomization will be stratified by the induction dose received during the 
first 16 weeks and by response status (responder versus non-responder) at Week 16.  All 
subjects will keep the same unique subject identification number throughout the study.


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5.5.4
Selection and Timing of Dose for Each Subject
Subjects will be randomly assigned to one of the six treatment groups (ABT-494 3 mg 
BID, ABT-494 6 mg BID, ABT-494 12 mg BID, ABT-494 24 mg BID, ABT-494 24 mg 
QD, placebo) at Baseline by the IRT system as described in Section 5.5.3.
Subjects should take study medication as outlined in Section 5.5.1.
Each subject's dosing schedule should be closely monitored by the site at each study visit 
by careful review of the subject's dosing diary.  This will ensure that all subjects enrolled 
into the study maintain their original dosing schedule beginning with the first dose of 
study drug (Baseline/Week 0).
If a subject should forget to take their study drug dose at their regularly scheduled dosing 
time, they should take the forgotten dose as soon as they remember the dose was missed 
as long as it is at least 6 hours before their next scheduled dose.  If a subject only 
remembers the missed dose within 6 hours before next scheduled dose, the subject should 
skip the missed dose and take the next dose at the scheduled time.  If the subject 
experiences a study drug interruption > 10 days, they should notify their study site 
physician, and the Investigator should consult with the study designated physician about 
discontinuing the subject from the study.
5.5.5
Blinding
The Investigator, study site personnel, the subject and all AbbVie personnel with direct 
oversight of the conduct and management of the trial (with the exception of AbbVie Drug 
Supply Management Team) will remain blinded to each subject's treatment throughout the 
course of the study.  The IRT will provide access to blinded subject treatment information 
in the case of a medical emergency.  In the event of medical situation that requires 
unblinding of the study drug assignment the Investigator is requested to contact the 
AbbVie Study Designated Physician (SDP) prior to breaking the blind, as long as this 
communication does not compromise subject safety.  However, if an urgent therapeutic 
intervention is necessary which warrants breaking the blind prior to contacting AbbVie 


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SDP, the Investigator can directly access the IRT system to break the blind without 
AbbVie agreement.  In the event that the blind is broken before notification to AbbVie 
SDP, it is requested that the AbbVie SDP be notified within 24 hours of the blind being 
broken.  Also, the date and reason that the blind was broken must be recorded in the 
source documentation and eCRF, as applicable.  Throughout the duration of the 
double-blind periods of the study, the Investigator, site personnel, and subjects will 
remain blinded to the subject's treatment group.  AbbVie will remain blinded to the 
induction and extension periods data until those data are locked and analyzed as part of 
the first and potentially second interim analysis, respectively.
5.5.5.1
Blinding of Investigational Product
In order to maintain the blind, the ABT-494 capsules and Placebo capsules provided for 
the study will be identical in appearance.
5.5.5.2
Blinding of Data for Independent Data Monitoring 
Committee (IDMC)
Data will be unblinded for review by the Independent Data Monitoring Committee 
(IDMC) by an unblinded statistician not involved in the planning, execution or analysis of 
the study.  The process for unblinding study data and ensuring its confidentiality will be 
described in the Independent Data Monitoring Committee Charter for this study.  The 
IDMC will advise the sponsor as to study continuation and/or modification.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subject dosing will be recorded on a subject dosing diary.  Subjects will be instructed to 
return all drug containers (even if empty) to the study site personnel at each clinic visit.  
The study site personnel will document compliance in the study source documents.


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5.5.7
Drug Accountability
In addition, an IRT will be used to document investigational product accountability 
including but not limited to date received, the lot number, kit number(s), date dispensed, 
subject number and the identification of person dispensing the drug.
All empty study drug blister cards will be inventoried by the site and verified by the site 
monitor.  Empty study drug blister cards should be returned by the subject at each visit for 
accountability and compliance purposes and new containers issued as necessary.  Empty 
blister cards will be retained until the site monitor is on site to confirm the returned 
medication.  Site monitor(s) and site staff will complete study medication accountability 
via IRT source documents, subject dosing diaries, and by visually inspecting the blister 
cards whenever possible.  After drug accountability has been completed, unused 
medication will be destroyed on site according to local procedures or regulations or 
returned to the destruction depot by the site monitor.  A copy of the destruction 
methodology should be maintained at the site's facility.
5.6
Discussion and Justification of Study Design
ABT-494 is a potent JAK1 selective inhibition that has been associated with endoscopic 
improvement and healing of the intestinal mucosa in preclinical animal models.  More 
recently, filgotinib, a JAK1 inhibitor in Phase 2 clinical development in Crohn's disease 
was associated with superior clinical remission versus placebo.33  This study included 
subjects who could have been inadequate responders or intolerant to either 
immunomodulators or anti-TNF therapies.  Of note, this treatment effect was more 
prominent in subjects who have inadequate responders to immunomodulators only.  
AbbVie proposes to include this patient population to assess the effect of ABT-494 and 
whether they would benefit the most from such therapy.
The proposed study is a 52-week, randomized, double-blind, placebo-controlled study to 
compare multiple doses of ABT-494 versus placebo in moderately to severely active CD 
patients with failure or intolerance to immunomodulators or anti-TNF biologic therapy.  
In order to assess the potential of ABT-494 to benefit patients with CD, we will enroll 


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patients with active disease (confirmed by central reading of endoscopy video) and assess 
the potential of ABT-494 to induce clinical remission and endoscopic improvement.  The 
16-week induction therapy period is generally accepted as the timeframe during which an 
effective treatment would be expected to produce clinical benefit in CD.
During the double-blind extension phase of this study, all patients will have an 
opportunity to be treated with ABT-494 in order to assess the potential of ABT-494 to 
maintain clinical remission in patients who have responded to treatment with ABT-494.
5.6.1
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All 
efficacy measurements in this study are standard for assessing disease activity in subjects 
with CD.  All clinical and laboratory procedures in this study are standard and generally 
accepted.  Central reading of endoscopy films will increase study rigor and ensure 
enrollment of patients with active inflammation.
5.6.2
Suitability of Subject Population
Adult male and female subjects with active CD who meet all inclusion criteria and none 
of the exclusion criteria are eligible for this study.  The specific subject population chosen 
was based on the unmet medical need for subjects with evidence of mucosal inflammation 
and who have had an inadequate response or intolerance to immunomodulators or 
anti-TNF biologic therapy.
5.6.3
Selection of Doses in the Study
This study is designed to evaluate the efficacy and safety/tolerability of ABT-494 in 
subjects with CD and to define the dose response profile of this compound.  The dose 
selection for ABT-494 in the present study was based on the preliminary analysis of PK, 
PD, safety and tolerability data from the single ascending dose study of ABT-494 in 
healthy subjects (single doses ranging from 1 to 48 mg), the multiple ascending dose 
study of ABT-494 in healthy subjects (multiple doses ranging from 3 to 24 mg BID for 
14 days), as well as the multiple dose study of tofacitinib 5 mg BID for 14 days in healthy 


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subjects.  Based on ex-vivo experiments conducted during the Phase 1 studies, we know 
that doses selected for this study significantly inhibit IL-6 signaling via the JAK1 
pathway.  In addition, the dose range selected has been shown to be well tolerated in 
healthy volunteers and includes exposure anticipated to result in JAK1 selective exposure 
that may produce both efficacy and favorable benefit:risk profile.  Study drug will be 
dosed for 52 weeks and will not exceed 24 mg BID.
During the extension Phase, the ability of ABT-494 to maintain patients in remission will 
be assessed, with opportunity for dose escalation to the highest induction dose planned, if 
needed for a specific patient.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events, please refer to Sections 6.1
through 6.1.7.  For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
investigator will provide an Other cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 


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response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, (meets protocol specific criteria [see Section 6.1.7 regarding toxicity 
management]) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.


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6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical intervention 
had not been taken.  This does not include an event that 
would have been fatal if it had occurred in a more severe 
form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to
an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences 
of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, 
life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any 
elective or spontaneous abortion or stillbirth is considered 
an important medical event.  Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
Adverse Event Severity
The investigator will use the following definitions to rate the severity of each adverse 
event:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life-threatening.
6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:


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Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All adverse events reported from the time of study drug administration until 30 days, 
following discontinuation of study drug administration have elapsed will be collected, 
whether solicited or spontaneously reported by the subject.  In addition, serious adverse 
events and protocol-related nonserious adverse events will be collected from the time the 
subject signed the study-specific informed consent.
Adverse event information will be collected as shown in Figure 3.


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Figure 3.
Adverse Event Collection
SAEs and 
Protocol-Related 
Nonserious AEs
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported




Consent 
Signed
Study Drug 
Start
Study Drug 
Stopped
30 Days After 
Study Drug 
Stopped
6.1.5
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the 
electronic data capture (EDC) system.  Serious adverse events that occur prior to the site 
having access to the RAVE® system or if RAVE is not operable should be documented on 
the SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 
Pharmacovigilance within 24 hours of being made aware of the serious adverse event.
Email:
FAX to:
For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team
1 North Waukegan Road
North Chicago, IL  60064
Office:
Email:
 
 
 


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For any subject safety concerns, please contact the physician listed below:
Primary Study Designated Physician:
Should in case of subject safety concerns or medical emergencies the Primary Study 
Designated Physician be unavailable, please call the following central back-up number:
Phone:  
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.
 
 


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Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
Subjects and their partners should avoid pregnancy throughout the course of the study, 
starting with the Screening Visit through 30 days after the last study drug administration.  
Male subjects should refrain from donating sperm for up to 30 days post last dose of study 
drug.  Results of a positive pregnancy test or confirmation of a pregnancy will be assessed 
starting with the Screening Visit through the final study visit.  In the event of pregnancy 
occurring in the partner of an enrolled subject, written informed consent for release of 
medical information from the partner must be obtained prior to the collection of any 
pregnancy-specific information and the pregnancy will be followed to outcome.
6.1.7
Toxicity Management
Serious Infections:  Subjects should be closely monitored for the development of signs 
and symptoms of infection during and after treatment with study drug.  Study drug should 
be interrupted if a subject develops a serious infection or an opportunistic infection.  A 
subject who develops a new infection during treatment with study drug should undergo 
prompt diagnostic testing appropriate for an immunocompromised subject.  As 
appropriate, antimicrobial therapy should be initiated, and the subject should be closely 
monitored.  Re-challenge with study drug may occur once the infection has been 
successfully treated.  If study drug administration is interrupted for more than 10 days, 
they should notify their study site physician, and the Investigator should consult with the 
study designated physician about discontinuing the subject from the study.  If the subject 
continues in the study after an interruption > 10 days during the Induction period, he/she 
will be considered a non-responder and will be censored for efficacy endpoints from that 
point forward through the end of the study.  These subjects will continue to be clinically 
monitored and will be evaluated in the safety analyses.  Subjects who develop active 
tuberculosis must be withdrawn from the study immediately.


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Serious Gastrointestinal Events:  Subjects presenting with the onset of signs or symptoms 
of a serious gastrointestinal event should be evaluated promptly for early identification of 
gastrointestinal perforation.
ECG Abnormality:  Subjects should be discontinued for an ECG change considered 
clinically significant.
Management of Select Laboratory Abnormalities:  For any given laboratory abnormality, 
the investigator should assess the subject, apply the standard of care for medical 
evaluation and treatment and follow any local guidelines.  Laboratory abnormalities and 
changes in vital signs are considered to be adverse events only if they result in 
discontinuation from the study, necessitate therapeutic medical intervention, (meets 
protocol specific criteria [see Section 6.1.7 regarding toxicity management]) and/or if the 
investigator considers them to be adverse events.  Specific toxicity management 
guidelines for abnormal laboratory values in hemoglobin, absolute neutrophil, absolute 
lymphocytes, total white blood cell, platelet, liver transaminases, and serum creatinine is 
described per the table below (confirmation by repeat testing is required).


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Hemoglobin

If confirmed < 8.0 g/dL or decrease from BL > 2.0 g/dL, interrupt 
study drug dosing until hemoglobin value returns to normal reference 
range or its Baseline value.
Absolute neutrophil count 
(ANC)

If confirmed < 1000 cells/mm3, interrupt study drug dosing until 
ANC value returns to normal reference range or its Baseline value. 

Discontinue study drug if confirmed < 500 cells/mm3.
Absolute lymphocytes 
counts

If confirmed < 500 cells/mm3, interrupt study drug dosing until 
absolute lymphocytes count returns to normal reference range or its 
Baseline value.
Total white blood cell 
count

If confirmed < 2000 cells/mm3, interrupt study drug dosing until 
white blood cell count returns to normal reference range or its 
Baseline value.
Platelet count

If confirmed < 50,000 cells/mm3 interrupt study drug dosing until 
platelet count returns to > 50,000 cells/mm3 or its Baseline value.
AST or ALT

Discontinue study drug if confirmed ALT or AST > 3 × ULN with a 
Total Bilirubin > 2 × ULN or INR > 1.5.

Discontinue study drug if confirmed ALT or AST > 8 × ULN.

Discontinue study drug if confirmed ALT or AST > 5 × ULN for 
more than 2 weeks.
Serum Creatinine (sCr)

If confirmed > ULN and change from BL > 1.5-fold, interrupt study 
drug dosing until sCr value returns to normal reference range or its 
Baseline value.
If the subject must undergo elective surgery, the study drug should be interrupted 1 week 
prior to the surgery.  If the subject must undergo emergency surgery, the study drug 
should be interrupted at the time of the surgery.  The study drug can recommence at least 
1 week after surgery once the physician has examined the surgical site and determined 
that it has healed and there is no sign of infection.
6.1.8
Cardiac Adjudication Committee
An independent committee of physician experts in cardiac adjudication will be utilized to 
assess cardiovascular adverse events in a blinded manner as defined by the Cardiac 
Adjudication Committee charter.


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6.1.9
Independent Data Monitoring Committee
An external Independent Data Monitoring Committee (DMC) comprised of persons 
independent of AbbVie and with relevant expertise in their field will review unblinded 
safety data from the ongoing studies.  The primary responsibility of the DMC will be to 
protect the safety of the subjects participating in this study.
A separate DMC charter will be prepared outside of the protocol and will descrive the 
roles and responsibilities of the DMC members, frequency of data reviews, and relevant 
safety data to be assessed. 
Communications from the DMC to the Study Teams will not contain information that 
could potentially unblind the team to subject treatment assignments.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 


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authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  The 
principal investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations.  If a protocol deviation 
occurs (or is identified) after a subject has been enrolled, the principal investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB) regulatory authorities (as applicable), and the following AbbVie Clinical 
Monitor(s):
Primary Contact:
Alternate Contact:
 


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Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
For the purposes of this protocol, reportable deviations are defined as:
●
Subject entered into the study even though she/he did not satisfy entry criteria.
●
Subject who developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject who received wrong treatment or incorrect dose.
●
Subject who received excluded or prohibited concomitant treatment.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analysis Plans
The objectives of the statistical analyses are to evaluate the efficacy and safety of 
ABT-494 versus placebo and to assess the pharmacokinetics (PK) of multiple doses of 
ABT-494 following oral administration in subjects with moderately to severely active 
Crohn's disease who have failed or are intolerant to immunomodulators or anti-TNF 
therapy.
Complete, specific details of the statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the 
database lock.
Unless otherwise specified, statistical tests will be one-sided significance level of 0.05 for 
efficacy analyses and two-sided of significance level of 0.05 for all other analyses.  A test 
will be deemed significant if the P value rounded to three decimal places is less than or 
equal to 0.050 unless otherwise specified.  The SAS System will be used to perform the 
statistical analyses.


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An interim analysis of the primary and secondary efficacy variables as well as safety and 
pharmacodynamics biomarker data collected from Baseline through Week 16 will be 
performed after the last subject randomized into Study M13-740 completes the 16-week 
double-blind, placebo-controlled induction period in this study (Section 8.1.10).  A 
second interim analysis of the secondary efficacy variables for the double-blind extension 
period, may be performed after 100% of subjects who were re-randomized at Week 16 
completes Week 36 of the double-blind extension period in Study M13-740.  
8.1.1
Datasets for Analysis
8.1.1.1
Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (MITT) analysis set includes all randomized subjects who 
have taken at least one dose of study drug in the double-blind induction period.  For the 
MITT analysis set, subjects are assigned to a treatment group based on the randomization 
schedule, regardless of the treatment actually received.  The MITT population will also be 
referred as "All Randomized and Treated Subjects."  The MITT analysis set will be used 
for all efficacy analysis for the double-blind induction period and baseline demographic 
and characteristics analyses.
8.1.1.2
Intent-to-Treat Responder and Non-Responder Analysis 
Sets
The intent-to-treat responders (ITT-R) and intent-to-treat non-responders (ITT-NR) 
analysis sets includes all re-randomized subjects in the double-blind extension phase who 
are responders and non-responders at Week 16, respectively.  The clinical responder is 
defined as:  average daily liquid/soft stool frequency at least 30% reduction from Baseline 
and average daily abdominal pain not worse than Baseline OR average daily abdominal 
pain at least 30% reduction from Baseline and average daily stool frequency not worse 
than Baseline.  The endoscopic responder is defined as:  a SES-CD at least 25% reduction 
from Baseline.


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For the ITT-R and ITT-NR analysis sets, subjects are assigned to a treatment group based 
on the re-randomization schedule, regardless of the treatment actually received.  The 
ITT-R and ITT-NR analysis sets will be used for all efficacy analysis for the double-blind 
extension phase.
8.1.1.3
Safety Analysis Set
The safety analysis set consists of all subjects who received at least one dose of study 
medication.  For the safety analysis set, subjects are assigned to a treatment group based 
on the treatment actually received, regardless the treatment randomized.
8.1.2
Subject Accountability
The number of subjects randomized, the number of subjects who received at least 
one dose of study drug, the number of subjects who completed the study, and the number 
of subjects who prematurely discontinued will be calculated overall and for each 
investigational site by treatment group, as well as for all subjects combined.
8.1.3
Definition of Missing Data Imputation
Missing data will be imputed using one or more of the following methods:
Last Observation Carried Forward (LOCF):  The LOCF analyses will use the completed 
evaluation from the previous visit for efficacy measures assessed to impute missing data 
at later visits.
Non-Responder Imputation (NRI):  In NRI analyses, subjects who prematurely
discontinue the study prior to endoscopic assessment at Week 12/16 will be considered 
non-responders with respect to endoscopic remission. 
Observed Cases (OC):  The OC analysis will not impute values for missing evaluations, 
and thus a subject who does not have an evaluation on a scheduled visit will be excluded 
from the OC analysis for that visit.


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The stool frequency and abdominal pain scores at an assessment visit (e.g., Week 12, 
Week 16) will be the average of the daily values reported during the 7 usable days 
preceding the scheduled assessment visit.
If 7 days daily values are not available, an average will be calculated based on the number 
of days with available data as follows:
●
An average for the most recent 6 days will be calculated if data for only 6 days 
are available, 
●
An average for the most recent 5 days will be calculated if data for only 5 days 
are available,
●
An average for the most recent 4 days will be calculated if data for only 4 days 
are available.
Diary entries should not be included in the 7 days evaluated prior to the visit if:  (1) the 
day the subject received medication for bowel preparation prior to endoscopy, (2) the day 
the subject underwent an endoscopy, and (3) 2 days following the endoscopy.  Earlier 
diary entries will be used accordingly in order to provide the most recent data for 7 days 
prior to the respective study visit.
If the minimum number of days of diary data (i.e., 4 days for SF and AP) are not 
available, then the subject's score for that visit will be considered missing and NRI will be 
used for any endpoints (e.g., clinical remission) relating to data for this visit.  Subjects 
who discontinue prior to Week 16 for any reason will be considered as "not-achieved" for 
clinical remission endpoint. 
Mixed Imputation:  Subjects who discontinue prior to Week 16 due to lack of efficacy or 
adverse events will be considered as "not achieved" for the clinical remission.  Subjects 
who discontinue for other reasons will be categorized according to LOCF. 
A subject will be considered a failure for the efficacy analyses at a later time points after 
the corticosteroid dose has been increased to greater than the dose at Baseline.


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8.1.4
Demographics and Baseline Characteristics
Baseline characteristics will be summarized for MITT, and ITT-R and ITT-NR analysis 
sets.
8.1.4.1
Baseline Characteristics and Treatment Group 
Comparability
Treatment groups will be compared to assess homogeneity at Baseline with respect to 
demographic variables such as age, gender, race, height, weight, BMI, race, ethnicity, 
duration of disease, vital signs (blood pressure, heart rate, and temperature), and planned 
efficacy assessments such as the CDAI score, average daily Abdominal Pain score, 
Average daily liquid/soft Stool Frequency, SES-CD and Ulcerated surface subscore, fecal 
calprotectin level, hs-CRP, fistula closure, IBDQ, WPAI and EQ5D.
Summary statistics for continuous variables will include the number of observations, 
mean, standard deviation, median, and range for each treatment group, and will be 
compared among treatment groups using analysis of variance (ANOVA) for normally 
distributed variables and Kruskal-Wallis non-parametric ANOVA for non-normally 
distributed variables.  For other categorical or discrete variables, frequencies and 
percentages will be computed in each category for each treatment group, as well as for all 
subjects combined, and will be compared among treatment groups using chi-square test or 
Fisher's exact test (if 25% of the cells have expected counts less than 5).
8.1.4.2
Medical Histories
Frequencies and relative frequencies (percentages) will also be computed for each 
treatment group for general medical history items.
8.1.4.3
Prior Therapy and Medications
Prior therapy and medications will include all therapies and medications administered 
prior to the date of the first dose of study drug.  Prior therapy and medication will be 


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summarized for all randomized subjects who received at least one dose of study drug.  No 
statistical test will be performed.
8.1.4.4
Concomitant Medications
Concomitant drugs will be summarized for all randomized subjects who received at least 
one dose of study drug.  Concomitant drugs will be summarized using the World Health 
Organization (WHO) Drug Dictionary with frequencies and percentages for each 
treatment group.  In addition, the number and percentage of subjects taking 0, 1, 2, 3, 4, 5, 
and ≥ 6 medications, as well as the number and percentage of subjects taking at least 
one medication will be calculated for each treatment group.  All medications administered 
between the date of the first dose of study drug and the date of the last dose of study drug, 
inclusive, (i.e., all medications starting or ongoing during the time interval) will be 
included.  Thus, all medications with an end date prior to the first study drug dose will be 
excluded from the summary table.  No statistical test will be performed.
A subject who reports two or more uses of the same concomitant medication will be 
counted only once within each generic name.  A subject with concomitant medications 
with more than one generic name will be counted only once in the overall total.
8.1.5
Subject Disposition and Study Drug Exposure
8.1.5.1
Subject Disposition
The number and percentage of subjects who are enrolled, randomized and received at 
least one dose of study drug, and the number of subjects who prematurely discontinued 
and the reason for early termination and the number of subjects who enter the 36-week 
double-blind extension phase will be summarized by treatment group.  Premature 
discontinuation of study drug will be summarized for each treatment group, as well as for 
all subjects combined, with frequencies and percentages overall and by reason for 
discontinuation for all randomized subjects who received at least one dose of study drug.  
Subjects may have multiple reasons for prematurely discontinuing study drug, but will be 
counted no more than once for the total ("Any Reason").


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8.1.5.2
Study Drug Exposure
Exposure to study drug will be summarized for all subjects who have received at least 
one dose of study drug.  The duration (days) of study drug treatment will be summarized 
with the mean, standard deviation, median and range for each treatment group.  The 
duration of treatment is defined as the difference between the dates of the first and last 
doses of the treatment plus 1 day.  Study drug compliance of the blinded study drug will 
be summarized for each treatment group.  Compliance is defined as the number of 
capsules taken (i.e., the difference between the number of capsules dispensed and the 
number of capsules returned) divided by the number of capsules a subject is supposed to 
take each day times the length of time that the subject was in the Treatment Phase of the 
study (i.e., Final/Discontinuation Visit date during Treatment Phase – Day 1 [Baseline] 
Visit date +1).  Subjects with missing data for the number of capsules returned will be 
excluded from the summary.
8.1.6
Efficacy Analysis
8.1.6.1
Primary Efficacy Variable
The co-primary endpoints are:
1.
Proportion of subjects who achieve endoscopic remission at Week 12/16.
2.
Proportion of subjects who achieve clinical remission at Week 16.
8.1.6.1.1
Analysis of Primary Endpoint
The comparisons between an ABT-494 treatment group and placebo on the two 
co-primary efficacy endpoints will be performed using MCPMod approach.  Subjects with 
missing primary endpoint data SES CD at Week 12/16 will be classified as "not achieved" 
(non-responder imputation [NRI] method) for the endoscopic remission endpoint.


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The stool frequency and abdominal pain scores at an assessment visit (e.g., Week 12, 
Week 16) will be the average of the daily values reported during the 7 usable days 
preceding the scheduled assessment visit.
If 7 days daily values are not available, an average will be calculated based on the number 
of days with available data as follows:
●
An average for the most recent 6 days will be calculated if data for only 6 days 
are available, 
●
An average for the most recent 5 days will be calculated if data for only 5 days 
are available,
●
An average for the most recent 4 days will be calculated if data for only 4 days 
are available.
If the minimum number of days of diary data (i.e., 4 days for SF and AP) are not 
available, then the subject's score for that visit will be considered missing and NRI will be 
used for any endpoints (e.g., clinical remission) relating to data for this visit.  Subjects 
who discontinue prior to Week 16 for any reason will be considered as "not-achieved" for 
clinical remission endpoint.  Diary entries should not be included in the 7 days evaluated 
prior to the visit if:  (1) the day the subject received medication for bowel preparation 
prior to endoscopy, (2) the day the subject underwent an endoscopy, and (3) 2 days 
following the endoscopy.  Earlier diary entries will be used accordingly in order to 
provide the most recent data for 7 days prior to the respective study visit.
The dose-response relationships among the five ABT-494 treatment groups and placebo 
group will be characterized for the primary endpoints endoscopic remission at 
Week 12/16 and clinical remission at Week 16 using MCPMod approach.  The following 
models will be considered:  linear, Emax, exponential, logistic and sigEmax.  The 
MCPMod approach for trial analysis stage consists of two main steps:  MCP and Mod 
step.  The MCP step focuses on establishing evidence for a drug effect across the doses, 
i.e., detecting a statistically significant dose response signal for the clinical endpoint and 
patient population investigated in the study.  This step will typically be performed using 


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an efficient test for trend, adjusting for the fact that multiple candidate dose response 
models are being considered.  If a statistically significant dose response signal has been 
established, one proceeds with determining a reference set of significant dose response 
models by discarding the non-significant models from the initial candidate set.
The response function will be the log odds (logit) of the proportion of subjects with 
endoscopic/clinical remission.  The fitted curve will be shown graphically with 
confidence intervals for each dose.  Estimates of the treatment differences in the response 
function and associated 95% confidences for each active dose against placebo will be 
calculated from the model.  These results will be back-transformed to give point estimates 
of the difference in proportions and associated 95% confidence intervals.
8.1.6.1.2
Sensitivity Analysis of the Primary Efficacy Variable
The following sensitivity analyses for the primary endpoint of endoscopic remission will 
be conducted:
●
A sensitivity analysis using observed cases, which excludes those subjects 
with missing post-baseline endoscopy, will also be done.
The following sensitivity analyses for the primary endpoint of clinical remission will be 
conducted:
●
An analysis of observed cases, which excludes those subjects with missing SF 
or AP data at scheduled assessment visits.
●
The primary analysis will be repeated using mixed-imputation.  Subjects who 
discontinue prior to Week 16 due to lack of efficacy or adverse events will be 
considered as "not achieved" for the clinical remission.  Subjects who 
discontinue for other reasons will be categorized according to LOCF.
Subgroup (characterized by the varying inclusion and exclusion criteria) analysis for the 
primary endpoints, clinical remission and endoscopic remission will be conducted.


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8.1.6.2
Secondary Efficacy Variables
8.1.6.2.1
Analysis of Secondary Endpoints
Secondary efficacy variables are divided into two groups.  The first group includes 
double-blind induction treatment period secondary endpoints.  Analyses for the first group 
of secondary endpoints will be performed using MITT analysis set.  The second group 
includes double-blind extension phase secondary endpoints.  Analyses for the second 
group of secondary endpoints will be performed using ITT-N and ITT-NR analysis sets.
For categorical secondary endpoints, the pairwise comparisons for the difference in 
proportions of subjects between treatment groups will be analyzed using the CMH test 
adjusted for randomization stratification variable(s), Crohn's disease severity (SES-CD 
< 15, ≥ 15) at Baseline and prior anti-TNF use (naïve, experienced).  Additionally, the 
CMH-based 95% confidence interval for the difference in proportions will be provided.  
The non-responder imputation will be used for subjects with missing data at the endpoint 
evaluated.  The last observation carried forward (LOCF) method will also be used as the 
sensitivity analyses for the secondary endpoints.
In general, continuous secondary efficacy variables with repeated measurements will be 
analyzed using a Mixed Effect Repeated Measure (MMRM) model.  Continuous 
secondary efficacy variables will also be analyzed using an Analysis of Covariance 
(ANCOVA) model including factors for treatment group and stratification variable, 
Crohn's disease severity (SES-CD < 15, ≥ 15) at Baseline and prior anti-TNF use (naïve, 
experienced).  Baseline values will be used as a covariate in the MMRM and ANCOVA 
models.  The MMRM analysis is considered primary for inferential purposes.
8.1.6.3
Additional Efficacy Endpoints
8.1.6.3.1
Analysis of Additional Endpoints
The pairwise comparisons for the difference between treatment groups for the additional 
categorical and continuous endpoints will be analyzed similarly as the secondary 
endpoints.


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8.1.6.4
Multiple Comparisons
The MCP step in MCPMod approach will typically be performed using an efficient test 
for trend, adjusting for the fact that multiple candidate dose response models are being 
considered.
8.1.7
Safety Analysis
Adverse events (AEs), laboratory data and vital signs are the primary safety parameters in 
this study.  All safety comparisons will be performed between treatment groups using the 
safety analysis set.  Treatment-emergent AEs are defined as events that begin or worsen 
either on or after the first dose of the study medication and within 30 days after the last 
dose of the study medication.  AEs will be summarized separately for:  1) double-blind 
induction period; 2) double-blind extension phase; 3) over the entire 52-week study 
duration.  An overview of treatment-emergent AEs, including AEs of special interest such 
as adverse events leading to death and adverse events leading to early termination (see 
details in the SAP), AEs by Medical Dictionary for Drug Regulatory Activities (MedDRA 
version 15.1 or later) preferred term and system organ class, AEs by maximum 
relationship to study drug, and AEs by maximum severity will be summarized by number 
and percentage.  Treatment group differences (each ABT-494 dose group versus placebo 
group, as well as ABT-494 dose groups combined versus placebo group) in the overall 
incidence of treatment-emergent AEs will be assessed with Fisher's exact test for each 
preferred term.
Changes in laboratory data will be described using statistical characteristics and compared 
between treatment groups will be performed using a one-way Analysis of Variance 
(ANOVA).  In addition, shift tables and listings will be provided for abnormal values, 
whereby the normal range of the analyzing laboratory will be used.  Vital signs will be 
analyzed similarly.


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8.1.7.1
General Considerations
Safety analyses will be carried out using the safety analysis set, which includes all 
subjects who receive at least one dose of study medication.  Incidence of adverse events, 
including those related to study drug, changes in vital signs, physical examination results, 
ECGs, and clinical laboratory values will be analyzed.
Treatment-emergent adverse events will be tabulated by system organ class (SOC) and by 
the Medical Dictionary for Regulatory Activities (MedDRA) preferred term for each 
treatment group.  Mean change from Baseline for laboratory and vital signs data will be 
summarized.
Missing safety data will not be imputed.
8.1.7.2
Analysis of Adverse Events
8.1.7.2.1
Treatment-Emergent Adverse Events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary.  Treatment-emergent adverse events, defined as AEs 
that began or worsened in severity after initiation of study drug in each period of the 
study, will be tabulated by system organ class (SOC) and MedDRA preferred term for 
each treatment group. 
Adverse events starting more than 30 days following discontinuation of study drug will 
not be included in summaries of treatment-emergent AEs.  When summarizing adverse 
events by relationship or severity, if a subject has an event with unknown severity or 
relationship then the subject will be counted in the severity/relationship category of 
"unknown" even if the subject has a second occurrence of the same event with a 
severity/relationship present.  The only exception is if the subject has a second occurrence 
of the same event with the most extreme severity (i.e., "severe") or a relationship 
categories of "reasonable possibility."  In this case, the subject will be counted under these 
most extreme severity/relationship categories.


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Subjects reporting more than one AE for a given MedDRA preferred term will be counted 
only once for that term using the most severe incident in each study period.  Subjects 
reporting more than one type of event within an SOC will be counted only once for that 
SOC.
Frequencies and percentages of subjects with treatment-emergent AEs will be 
summarized for each treatment group as follows:
●
Any event
●
By system organ class, and preferred term
●
By system organ class, preferred term and maximum relationship
●
By system organ class, preferred term and maximum severity
●
Any event and by system organ class and preferred term for events resulting in 
death
●
Any event and by system organ class and preferred term for events resulting in 
study drug discontinuation
●
Any event and by system organ class and preferred term for serious events
●
Any event and by system organ class and preferred term for adverse events 
with a relationship of "reasonable possibility"
●
Any event and by system organ class and preferred term for adverse events of 
special interest (infection, opportunistic infection, and gastrointestinal 
perforations, malignancies and drug related hepatic disorders)
All AEs leading to early termination of study drug will be presented in listing format.
Frequencies and percentages for any AE and for each preferred term will be compared 
between each of the ABT-494 dosing groups and the placebo group using a Fisher's exact 
test.
The adverse events of special interest (infection, opportunistic infection, and 
gastrointestinal perforations, malignancies and drug related hepatic disorders) will be 
specified in the SAP.


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A listing by treatment group of treatment-emergent AEs grouped by SOC and MedDRA 
preferred term with subject ID numbers will be generated.
The post-treatment AEs will be summarized in the same way as the treatment-emergent 
AEs described above.
8.1.7.2.2
Serious Adverse Events and Death
All treatment-emergent serious adverse events, adverse events leading to death, and 
adverse events leading to discontinuation will also be presented in listing format.  In 
addition, SAEs will be summarized by SOC and MedDRA preferred term.
8.1.7.3
Analysis of Laboratory and Vital Sign Data
Changes from Baseline to minimum value, maximum value and final values in continuous 
laboratory and vital sign parameters will be summarized by treatment group.  Treatment 
group differences between each of the ABT-494 dosing groups and the placebo group for 
mean changes from Baseline will be analyzed using ANOVA.
Vital signs and laboratory data will be described by statistical characteristics and 
frequency of abnormal values.  Frequencies and percentages of subjects with laboratory 
shifts from Baseline to the final values using normal ranges to define categories (low, 
normal, high, and missing) will be summarized by the respective categories.  Values 
beyond the normal values will be listed.  Low or high laboratory values will also be 
flagged in the data listings.
Analysis details will be specified in the SAP.
8.1.8
Pharmacokinetic and Exposure-Response Analyses
Individual ABT-494 plasma concentrations at each study visit will be tabulated and 
summarized with appropriate statistical methods.
Data from this study may be combined with data from other studies for the population 
pharmacokinetic and exposure-response analyses.  Population pharmacokinetic and 


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exposure-response analyses of only data from this study may not be conducted.  The 
following general methodology will be used for the population pharmacokinetic and 
exposure-response analyses.
Population pharmacokinetic analyses will be performed using the actual sampling time 
relative to dosing.  Pharmacokinetic models will be built using a non-linear mixed-effects 
modeling approach with the NONMEM software (Version 7, or a higher version).  The 
structure of the starting pharmacokinetic model will be based on the pharmacokinetic 
analysis of data from previous studies.  Apparent CL/F and apparent V/F of ABT-494 will 
be the pharmacokinetic parameters of major interest in the analyses.  If necessary, other 
parameters, including the parameters describing absorption characteristics, may be fixed if 
useful in the analysis.
The evaluation criteria described below will be used to examine the performance of 
different models.
1.
The objective function of the best model is significantly smaller than the alternative 
model(s).
2.
The observed and predicted concentrations from the preferred model are more 
randomly distributed across the line of unity (a straight line with zero intercept and 
a slope of one) than the alternative model(s).
3.
Visual inspection of model fits, standard errors of model parameters and change in 
inter-subject and intra-subject error.
Once an appropriate base pharmacokinetic model (including inter- and intra-subject error 
structure) is developed, empirical Bayesian estimates of individual model parameters will 
be calculated by the posterior conditional estimation technique using NONMEM.  The 
relationship between these conditional estimates CL/F and V/F values with only 
potentially physiologically relevant or clinically meaningful covariates (such as subject 
age, sex, body weight, concomitant medications, laboratory markers of hepatic of renal 
function, etc.) will be explored using stepwise forward selection method, or another 


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suitable regression/smoothing method at a significance level of 0.05.  After identification 
of all relevant covariates, a stepwise backward elimination of covariates from the full 
model will be employed to evaluate the significance (at P < 0.005, corresponding to a 
decrease in objective function > 7.88 for one degree of freedom) of each covariate in the 
full model.
Linear or non-linear relationships of primary pharmacokinetic parameters with various 
covariates will be explored.  
Relationships between ABT-494 exposure and clinical observations (primary efficacy 
variable) will be explored.  Exposure-response relationships for secondary efficacy 
variables and/or some safety measures of interest may also be explored.  Initially, the 
time-course of placebo response will be modeled.  Subsequently the relationship between 
exposure (e.g., population pharmacokinetic model predicted average concentrations, 
AUC, trough concentrations, the individual model-predicted pharmacokinetic profiles, or 
some other appropriate measure of exposure) and drug effect will be explored after 
accounting for the time-course of placebo response.  Several classes of models 
(e.g., linear, log-linear, exponential, Emax, sigmoid Emax, etc.) will be evaluated to 
characterize the exposure-response relationship based on the observed data.  Results of the 
pharmacokinetic and exposure-response analyses may be summarized in a separate report 
prior to regulatory filing of ABT-494 for treatment of Crohn's disease, rather than in the 
Clinical Study Report.
Additional analyses will be performed if useful and appropriate.  
8.1.9
Statistical Analysis of Biomarker Data
Summary statistics for the pharmacodynamic biomarkers and disease response biomarkers 
at Baseline and post-treatment time points, in addition to change from Baseline at each 
time will be provided; this will include mean, standard deviation, median, quartiles, and 
range for each group.  Appropriate graphical visualizations such as association of each 
biomarker to the relevant efficacy endpoints, pairwise correlations between biomarkers, 


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trellis/3D plots that condition on Baseline factors, etc., will be provided.  The 
pharmacodynamic effect of each biomarker between the placebo and ABT-494 treatment 
groups will be evaluated via a mixed-effects model with Treatment, Time and 
Treatment × Time interaction as fixed-effects, the corresponding Baseline score as a 
covariate, and "subjects nested within the treatment group" as a random-effect.  Other 
Baseline variables such as age, weight, etc., may be considered as appropriate.  For 
biomarkers identified to have significant overall treatment effect via this mixed-effects 
model analysis, dose response models with the biomarker as a continuous response will be 
explored.  In addition to the above analyses of biomarkers individually, the effect of 
certain combination of biomarkers on the treatment groups may be explored.
The association of biomarkers to the efficacy and safety endpoints will be explored for 
each biomarker one at a time, and also for combinations of biomarkers via some 
multivariate predictive modeling algorithms.  Pairwise correlations and graphical 
summaries will be provided.  Optimal multivariate combinations of biomarkers that 
associate with efficacy endpoints, subject response/non-response (with respect to 
appropriate clinical endpoints), and also with safety endpoints will be explored via a 
variety of statistical predictive modeling algorithms.  Also cut-points for individual 
biomarkers and optimal combinations of biomarkers that differentiate the subject response 
with respect to efficacy/safety endpoints will be explored.  The significance of these 
multivariate combinations of biomarkers will be assessed via at least 20 iterations of 
5-fold cross-validation.
8.1.10
Interim Analysis
An interim analysis of the primary and secondary efficacy variables for the double-blind 
induction period, as well as safety and pharmacodynamics during the double-blind 
induction period will be performed using data collected from Baseline through 
Week 16 after the last subject randomized into this study completes the double-blind 
induction period in Study M13-740.  A second interim analysis of the secondary efficacy, 
safety and pharmacodynamics variables for the double-blind extension period, may be 
performed using data collected from Baseline through Week 32 after 50% of subjects who 


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were re-randomized at Week 16 completes Week 32 of the double-blind extension period 
in Study M13-740.  A database lock will be performed and any discrepant data will be 
clarified before the lock.  The analysis will be conducted by an independent AbbVie 
statistician who is not part of the ABT-494 Study Team.  No alpha adjustment will be 
made for this Phase 2 study.
8.2
Determination of Sample Size
A total of 210 subjects will be equally allocated to five treatment groups and the placebo 
group, representing a randomization ratio of 1:1:1:1:1:1.  The sample size for this study is 
based on the expected proportion of subjects who achieve endoscopic remission at 
Week 12/16 and on the expected proportion of subjects who achieve clinical remission at 
Week 16.  Assuming an endoscopic remission (as well as clinical remission) rate of 12% 
in the placebo arm and maximum of 35% in at least one of the ABT-494 BID treatment 
arms (3 mg BID, 6 mg BID, 12 mg BID and 24 mg BID) at Week 12/16, a sample size of 
35 subjects per treatment group is sufficient to test for the presence of a dose response 
signal, to select the best dose response model for the observed data out of a prespecified 
set of candidate models, and to estimate target doses of interest (e.g., the minimum 
effective dose, MED) via modeling using MCP-Mod (Multiple comparison procedure and 
modeling) approach.  This approach provides at least 80% average power to detect a dose 
effect at 5% level of significance (one-sided) with the linear, Emax, exponential, logistic 
and sigEmax models pre-specified as likely candidates to characterize the dose-response 
for ABT-494 for the two co-primary endpoints of clinical and endoscopic remission.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 


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ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP and all other 
applicable regulatory requirements.
Serious adverse events that meet the reporting criteria, as dictated by local regulations, 
will be reported to both responsible Ethics Committees and Regulatory Agencies as 
required by local regulations.  During the conduct of the study, the investigator should 
promptly provide written reports (e.g., ICH Expedited Reports or any additional reports 
required by local regulations) to the IEC/IRB of any changes that affect the conduct of the 
study and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and ethical principles that have their origin in the Declaration of Helsinki.  
Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 


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the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent form.
A separate informed consent, approved by an IRB/IEC, must be voluntarily signed and 
dated before samples are collected for optional pharmacogenetic, serologic markers, 
mRNA and gene expression analyses.  The nature of the testing should be explained and 
the subject given an opportunity to ask questions.  The separate informed consents must 
be signed before the samples are collected and any testing is performed.  If the subject 
does not consent to provide samples for optional analysis, it will not impact their 
participation in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.  The Investigator Awareness Date (SAE CRF) may serve 
as the source for this data point.  This adverse event data point required for eCRF 
completion can be entered directly in the eCRF.
The following assessments that will be completed by subject will be considered source 
documentation:


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●
IBDQ
●
EQ-5D
●
WPAI-CD
●
Abdominal Pain Rating Scale (0 – 10 Scale)
Site staff will verify completion of these forms.  All questionnaires must be legible and 
completed in indelible ballpoint ink.  Any necessary corrections are to be made by 
drawing a single line through the incorrect entry and writing in the revision, the date of 
the correction, the reason for the correction, and the initials of the study subject who is 
making the correction.  Data are not to be obliterated by blacking out, using correction 
fluid or by erasing the original entry.
The questionnaire administrator will review the questionnaire for completeness and 
accuracy.  The subject-completed questionnaires will be transcribed into the EDC system 
by study personnel.  The completed paper questionnaire will be considered source.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.


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The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
10.3
Electronic Patient Reported Outcomes (ePRO)
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) tool called Trialmax, provided by the technology vendor CRF Health of Plymouth 
Meeting, PA, USA.  The ePRO system is in compliance with Title 21 CFR Part 11.  The 
documentation related to the system validation of the ePRO tool is available through the 
vendor, CRF Health, while the user acceptance testing of the study-specific ePRO design 
will be conducted and maintained at AbbVie.


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The subject will be entering the data into an electronic device, these data will be uploaded 
to a server.  The data on the server will be maintained and managed by CRF Health.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
trial.  This access will be available for the duration of the trial to the investigational sites, 
as well as delegated personnel.  Such access will be removed from investigational sites 
following the receipt of the study archive.  Data from the ePRO tool will be archived on 
appropriate data media (CD-ROM, etc.) and provided to the investigational site at that 
time as a durable record of the site's ePRO data.  It will be possible for the investigational 
site to create paper print-outs from that media.
The ePRO data (Bristol Stool Form scale, number of liquid or very soft stools, use of 
medications used for endoscopy preparation, dosing information, and general well-being) 
will be collected electronically via a handheld device into which the patient will record 
the required pieces of information on a daily basis.  The electronic device will be 
programmed to allow for data entry once per day.  All data entered on the device will be 
immediately stored to the device itself and manually/automatically uploaded to a central 
server administrated by CRF Health.  The investigational site staff will be able to access 
all uploaded subject entered data via a password protected website, until the generation, 
receipt and confirmation of the study archive.
10.4
Data Collection Process
AbbVie is using an Electronic Patient Reported Outcome (ePRO) tool to capture portions 
of the clinical data defined in this protocol.  The use of ePRO requires certain process 
changes compared to the use of traditional paper PROs.  Trial-Specific Guidelines 
(T-SGs) have been developed to document the changes from the traditional paper PRO 
process.  These T-SGs govern the ePRO processes in this trial.
11.0
Data Quality Assurance
Prior to the initiation of the study, a meeting will be held with AbbVie personnel, the 
Investigators and appropriate site personnel.  This meeting will include a detailed 


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discussion of the protocol, performance of study procedures, eCRF, Subject 
Questionnaires and Subject Dosing Diary completion, and specimen collection methods.
The AbbVie CRA will monitor each site throughout the study.
Source document verification will be performed.
All data entered in the database will be verified at AbbVie.  Any discrepancies will be 
reviewed.  The data will be reviewed and computer logic checks will be run to identify 
items such as inconsistent study dates.  A manual review of selected line listings also will 
be performed at the end of the study.
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
The data from the central laboratory analyses will be electronically transferred from the 
central laboratory to the study database.  A final review of all laboratory results will be 
conducted by a physician and clinical review team at AbbVie.
12.0
Use of Information
All information concerning ABT-494 and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of ABT-494.  
This information may be disclosed as deemed necessary by AbbVie to other clinical 
investigators, other pharmaceutical companies, and to governmental agencies.  To allow 
for the use of the information derived from this clinical study and to ensure complete and 
thorough analysis, the investigator is obligated to provide AbbVie with complete test 
results and all data developed in this study and to provide direct access to source 


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data/documents for study-related monitoring, audits, IEC/IRB review, and regulatory 
inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision making 
or patient management.  Hence, neither the investigator, the subject, nor the subject's 
physician (if different from the investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic researchers will have no access to 
subject identifiers.  Individual results will not be reported to anyone not directly involved 
in this research other than for regulatory purposes.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic information will be published or presented only in a way 
that does not identify any individual subject.
13.0
Completion of the Study
The end-of-study is defined as the date of the last subject's last visit or the actual date of 
follow-up contact, whichever is later.
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 


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both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must submit, maintain, and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.  If the 
investigator is not able to retain the records, he/she must notify AbbVie to arrange 
alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABT-494.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study of ABT-494 for the Induction of Symptomatic and Endoscopic 
Remission in Subjects with Moderately to Severely Active Crohn's 
Disease who have Inadequately Responded to or are Intolerant to 
Immunomodulators or Anti-TNF Therapy
Protocol Date:
07 November 2016
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Hanauer SB, Sandborn W; Practice Parameters Committee of the American 
College of Gastroenterology.  Management of Crohn's disease in adults.  Am J 
Gastroenterol.  2001;96(3):635-43.
2.
Loftus EV Jr.  Clinical epidemiology of inflammatory bowel disease:  incidence, 
prevalence, and environmental influences.  Gastroenterology.  
2004;126(6):1504-17.
3.
Probert CS, Jayanthi V, Rampton DS, et al.  Epidemiology of inflammatory bowel 
disease in different ethnic and religious groups:  limitations and aetiological clues.  
Int J Colorectal Dis.  1996;11(1):25-8.
4.
Solberg IC, Vatn MH, Hoie O, et al; IBSEN Study Group.  Clinical course in 
Crohn's disease:  results of a Norwegian population-based ten-year follow-up 
study.  Clin Gastroenterol Hepatol.  2007;5(12):1430-8.
5.
Munkholm P, Langholz E, Davidsen M, et al.  Intestinal cancer risk and mortality 
in patients with Crohn's disease.  Gastroenterology.  1993;105(6):1716-23.
6.
Lichtenstein GR, Hanauer SB, Sandborn WJ; Practice Parameters Committee of 
American College of Gastroenterology.  Management of Crohn's disease in adults.  
Am J Gastroenterol.  2009;104(2):465-83.
7.
Dignass A, Van Assche G, Lindsay JO, et al; European Crohn's and Colitis 
Organisation (ECCO).  The second European evidence-based Consensus on the 
diagnosis and management of Crohn's disease:  current management.  J Crohns 
Colitis.  2010;4(1):28-62.  Erratum in:  J Crohn's Colitis.  2010;4(3):353.
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Cosnes J, Bourrier A, Laharie D, et al.  Early administration of azathioprine vs 
conventional management of Crohn's disease:  a randomized controlled trial.  
Gastroenterology.  2013;145(4):758-65.


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9.
Reinisch W, Angelberger S, Petritsch W, et al; International AZT-2 Study Group.  
Azathioprine versus mesalazine for prevention of postoperative clinical recurrence 
in patients with Crohn's disease with endoscopic recurrence:  efficacy and safety 
results of a randomised, double-blind, double-dummy, multicentre trial.  Gut.  
2010;59(6):752-9.
10.
Irving PM, Gearry RB, Sparrow MP, et al.  Review article:  appropriate use of 
corticosteroids in Crohn's disease.  Aliment Pharmacol Ther.  2007;26(3):313-29.  
11.
Rutgeerts PJ.  Review article:  the limitations of corticosteroid therapy in Crohn's 
disease.  Aliment Pharmacol Ther.  2001;15(10):1515-25.
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Sandborn WJ.  State-of-the-art:  immunosuppression and biologic therapy.  Dig 
Dis.  2010;28(3):536-42.
13.
Targan SR, Hanauer SB, van Deventer SJ, et al.  A short-term study of chimeric 
monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease.  N 
Engl J Med.  1997;337(15):1029-35.
14.
Hanauer SB, Feagan BG, Lichtenstein GR, et al; ACCENT I Study Group.  
Maintenance infliximab for Crohn's disease:  the ACCENT I randomised trial.  
Lancet.  2002;359(9317):1541-9.
15.
Hanauer SB, Sandborn WJ, Rutgeerts P, et al.  Human anti-tumor necrosis factor 
monoclonal antibody (adalimumab) in Crohn's disease:  the CLASSIC-I trial.  
Gastroenterology.  2006;130(2):323-33.
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Colombel JF, Sandborn WJ, Rutgeerts P, et al.  Adalimumab for maintenance of 
clinical response and remission in patients with Crohn's disease:  the CHARM trial.  
Gastroenterology.  2007;132(1):52-65.
17.
Sandborn WJ, Feagan BG, Stoinov S, et al; PRECISE 1 Study Investigators.  
Certolizumab pegol for the treatment of Crohn's disease.  N Engl J Med.  
2007;357(3):228-38.


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18.
Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al; PRECISE 2 Study 
Investigators.  Maintenance therapy with certolizumab pegol for Crohn's disease.  
N Engl J Med.  2007;357(3):239-50.  Erratum in:  N Engl J Med.  
2007;357(13):1357.
19.
Sandborn WJ, Colombel JF, Enns R, et al; International Efficacy of Natalizumab as 
Active Crohn's Therapy (ENACT-1) Trial Group; Evaluation of Natalizumab as 
Continuous Therapy (ENACT-2) Trial Group.  Natalizumab induction and 
maintenance therapy for Crohn's disease.  N Engl J Med.  2005;353(18):1912-25.
20.
Van Assche G, Van Ranst M, Sciot R, et al.  Progressive multifocal 
leukoencephalopathy after natalizumab therapy for Crohn's disease.  N Engl J Med.  
2005;353(4):362-8.
21.
O'Shea JJ, Holland SM, Staudt LM.  JAKs and STATs in immunity, 
immunodeficiency, and cancer.  N Engl J Med.  2013;368(2):161-70.
22.
Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK.  Role of 
cytokines in inflammatory bowel disease.  World J Gastroenterol.  
2008;14(27):4280-8.
23.
Murray PJ.  The JAK-STAT signaling pathway:  input and output integration.  
J Immunol.  2007;178(5):2623-9.
24.
Ghoreschi K, Laurence A, O'Shea JJ.  Janus kinases in immune cell signaling.  
Immunol Rev.  2009;228(1):273-87.
25.
Guschin D, Rogers N, Briscoe J, et al.  A major role for the protein tyrosine kinase 
JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.  
EMBO J.  1995;14(7):1421-9.
26.
Hosokawa T, Kusugami K, Ina K, et al.  Interleukin-6 and soluble interleukin-6 
receptor in the colonic mucosa of inflammatory bowel disease.  J Gastroenterol 
Hepatol.  1999;14(10):987-96.
27.
Ito H, Takazoe M, Fukuda Y, et al.  A pilot randomized trial of a human 
anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease.  
Gastroenterology.  2004;126(4):989-96.


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28.
AbbVie.  ABT-494 Investigator Brochure Edition 5.  11 September 2015.
29.
Lawendy N, Krishnaswami S, Wang R, et al.  Effect of CP-690,550, an orally 
active janus kinase inhibitor, on renal function in healthy adult volunteers.  J Clin 
Pharmacol.  2009;49(4):423-9.
30.
Greenwald MW, Fidelus-Gort R, Levy R, et al.  A randomized dose-ranging, 
placebo-controlled study of INCB028050, a selective JAK1 and JAK2 inhibitor in 
subjects with active rheumatoid arthritis.  Arthritis Rheum.  
2010;2 (Suppl 10):2172.
31.
Vaddi K, Luchi M.  JAK inhibition for the treatment of rheumatoid arthritis:  a new 
era in oral DMARD therapy.  Expert Opin Investig Drugs.  2012;21(7):961-73.
32.
Fleischmann R, Kremer J, Cush J, et al; ORAL Solo Investigators.  
Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.  N Engl 
J Med.  2012;367(6):495-507.
33.
van de Stolpe O, Wigerinck P.  Galapagos:  filgotinib in Crohn's disease week 10 
results from FITZROY study.  December 08, 2015.  Available from:  
http://www.glpg.com/docs/view/5666ffc082e24-en.
34.
van Vollenhoven RF, Fleischmann R, Cohen S, et al.  Tofacitinib or adalimumab 
versus placebo in rheumatoid arthritis.  N Engl J Med.  2012;367(6):508-19.
35.
Pinheiro J, BornKamp B, Glimm E, et al.  Model-based dose finding under model 
uncertainty using general parametric models.  Stat Med.  2013;33(10):1646-61.
36.
Bretz F, Pinheiro J, Branson M.  Combining multiple comparisons and modeling 
techniques in dose-response studies.  Biometrics.  2005;61(3):738-48.
37.
Bornkamp B, Pinheiro J, Bretz F.  MCPMod:  an R package for the design and 
analysis of dose-finding studies.  J Stat Softw.  2009;29(7):1-23.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee (IEC) or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
Clinical Pharmacology and Pharmacometrics
Statistics
Clinical
Bioanalysis
Global Drug Supply Management
 


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Appendix C.
Sample Work Productivity and Activity Impairment 
Questionnaire:  Crohn's Disease V2.0 (WPAI-CD)


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Appendix D.
Crohn's Disease Activity Index (CDAI)


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Appendix E.
Standard Weights
Standard Height and Weight Tables – Use to Calculate CDAI Score
Actual Height 
cm (Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women)
kg (Pounds)
101.6 (40.0)
56.8 (125.3)
56.8 (125.3)
102.9 (40.5)
56.6 (124.8)
56.6 (124.8)
104.1 (41.0)
56.4 (124.3)
56.4 (124.3)
105.4 (41.5)
56.2 (123.8)
56.2 (123.8)
106.7 (42.0)
56.0 (123.0)
56.0 (123.0)
108.0 (42.5)
55.8 (123.0)
55.8 (123.0)
109.2 (43.0)
55.6 (122.7)
55.6 (122.7)
110.5 (43.5)
55.5 (122.4)
55.5 (122.4)
111.8 (44.0)
55.4 (122.1)
55.4 (122.1)
113.0 (44.5)
55.2 (121.8)
55.2 (121.8)
114.3 (45.0)
55.1 (121.6)
55.1 (121.6)
115.6 (45.5)
55.1 (121.4)
55.1 (121.4)
116.8 (46.0)
55.0 (121.3)
55.0 (121.3)
118.1 (46.5)
55.0 (121.2)
55.0 (121.2)
119.4 (47.0)
54.9 (121.1)
54.9 (121.1)
120.7 (47.5)
54.9 (121.1)
54.9 (121.1)
121.9 (48.0)
54.9 (121.1)
40.8 (89.9)
123.2 (48.5)
54.9 (121.1)
41.3 (91.0)
124.5 (49.0)
55.0 (121.2)
41.8 (92.1)
125.7 (49.5)
55.0 (121.3)
42.3 (93.3)
127.0 (50.0)
55.1 (121.5)
42.8 (94.4)
128.3 (50.5)
55.2 (121.7)
43.4 (95.6)
129.5 (51.0)
55.3(121.9)
43.9 (96.8)
130.8 (51.5)
55.4 (122.1)
44.4 (98.0)
132.1 (52.0)
55.5 (122.4)
45.0 (99.2)
133.4 (52.5)
55.7 (122.7)
45.5 (100.4)
134.6 (53.0)
55.8 (123.1)
46.1 (101.6)
135.9 (53.5)
56.0 (123.5)
46.6 (102.8)
137.2 (54.0)
56.2 (123.9)
47.2 (104.1)


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Actual Height 
cm (Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women)
kg (Pounds)
138.4 (54.5)
56.4 (124.4)
47.8 (105.3)
139.7 (55.0)
56.7 (124.9)
48.3 (106.6)
141.0 (55.5)
56.9 (125.5)
48.9 (107.9)
142.2 (56.0)
57.2 (126.1)
49.5 (109.1)
143.5 (56.5)
57.4 (126.7)
50.1 (110.4)
144.8 (57.0)
57.7 (127.3)
50.7 (111.7)
146.1 (57.5)
58.1 (128.0)
51.3 (113.0)
147.3 (58.0)
58.4 (128.7)
52.2 (115.0)
148.6 (58.5)
58.7 (129.5)
52.6 (116.0)
149.9 (59.0)
59.1 (130.3)
53.1 (117.0)
151.1 (59.5)
59.5 (131.1)
53.6 (118.3)
152.4 (60.0)
59.9 (132.0)
54.2 (119.5)
153.7 (60.5)
60.3 (132.9)
54.8 (120.8)
154.9 (61.0)
60.7 (133.8)
55.3 (122.0)
156.2 (61.5)
61.1 (134.8)
56.0 (123.5)
157.5 (62.0)
61.7 (136.0)
56.7 (125.0)
158.8 (62.5)
62.1 (137.0)
57.4 (126.5)
160.0 (63.0)
62.6 (138.0)
58.0 (128.0)
161.3 (63.5)
63.0 (139.0)
58.7 (129.5)
162.6 (64.0)
63.5 (140.0)
59.4 (131.0)
163.8 (64.5)
64.1 (141.3)
60.1 (132.5)
165.1 (65.0)
64.6 (142.5)
60.8 (134.0)
166.4 (65.5)
65.2 (143.8)
61.4 (135.5)
167.6 (66.0)
65.8 (145.0)
62.1 (137.0)
168.9 (66.5)
66.4 (146.5)
62.8 (138.5)
170.2 (67.0)
67.1 (148.0)
63.5 (140.0)
171.5 (67.5)
67.8 (149.5)
64.2 (141.5)
172.7 (68.0)
68.5 (151.0)
64.9 (143.0)
174.0 (68.5)
69.2 (152.5)
65.5 (144.5)
175.3 (69.0)
69.8 (154.0)
66.2 (146.0)
176.5 (69.5)
70.5 (155.5)
66.9 (147.5)


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Standard Height and Weight Tables – Use to Calculate CDAI Score
Actual Height 
cm (Inches)
Standard Weight (Men)
kg (Pounds)
Standard Weight (Women)
kg (Pounds)
177.8 (70.0)
71.2 (157.0)
67.6 (149.0)
179.1 (70.5)
71.9 (158.5)
68.3 (150.5)
180.3 (71.0)
72.6 (160.0)
68.9 (152.0)
181.6 (71.5)
73.4 (161.8)
69.6 (153.5)
182.9 (72.0)
74.1 (163.5)
70.3 (155.0)
184.2 (72.5)
75.0 (165.3)
71.2 (156.9)
185.4 (73.0)
75.7 (167.0)
71.9 (158.5)
186.7 (73.5)
76.6 (169.0)
72.6 (160.2)
188.0 (74.0)
77.5 (171.0)
73.4 (161.8)
189.2 (74.5)
78.4 (172.8)
74.1 (163.4)
190.5 (75.0)
79.1 (174.5)
74.9 (165.1)
191.8 (75.5)
80.2 (176.8)
75.6 (166.8)
193.0 (76.0)
81.2 (179.0)
76.4 (168.4)
194.3 (76.5)
82.0 (180.8)
77.2 (170.1)
195.6 (77.0)
82.9 (182.9)
77.9 (171.8)
196.9 (77.5)
83.9 (185.0)
78.7 (173.5)
198.1 (78.0)
84.9 (187.2)
79.5 (175.2)
199.4 (78.5)
85.9 (189.4)
80.3 (177.0)
200.7 (79.0)
86.9 (191.6)
81.0 (178.7)
201.9 (79.5)
87.9 (193.9)
81.8 (180.5)
203.2 (80.0)
89.0 (196.2)
82.6 (182.2)
204.5 (80.5)
90.0 (198.6)
*Height in shoes with one inch heels
205.7 (81.0)
91.1 (200.9)
*Indoor clothing weighing 5 pounds for 
men and 3 pounds for women
207.0 (81.5)
92.2 (203.3)
*Centimeters × 0.3937 = inches
208.3 (82.0)
93.3 (205.8)
*Pounds × 0.4535 = kilograms


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Appendix F.
SES-CD Scoring


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Appendix G.
Latent TB Risk Factor Questionnaire Example
1.
Have you or an immediate family member or other close contact ever been 
diagnosed or treated for tuberculosis?
2.
Have you lived in or had prolonged travels to countries in the following regions:
●
Sub-Saharan Africa
●
India
●
China
●
Mexico
●
Southeast Asia or Micronesia
●
The former Soviet Union
3.
Have you lived or worked in a prison, homeless shelter, immigration center, or 
nursing home?
4.
Have you, or an immediate family member, had any of the following problems for 
the past 3 weeks or longer:
●
Chronic cough
●
Production of sputum
●
Blood-streaked sputum
●
Unexplained weight loss
●
Fever
●
Fatigue/tiredness
●
Night sweats
●
Shortness of breath
Available from:  http://www.mayoclinic.com/health/tuberculosis/DS00372/DSECTION=risk-factors and
http://www.in.gov/fssa/files/Tuberculosis_Questionnaire.pdf


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Appendix H.
Bristol Stool Chart


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Appendix I.
Abdominal Pain Rating Scale (0 – 10 Scale)


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Appendix J.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.2  Synopsis
Subsection Methodology:
Seventeenth paragraph, last bullet previously read:
An optional biopsy for Gene expression sub-study will be collected during colonoscopy 
at/during Screening, and at Week 12/16 for approximately 70 subjects in the study.
Has been changed to read:
An optional biopsy for Gene expression sub-study will be collected during colonoscopy 
at/during Screening, and at Week 12/16 for approximately 80 subjects in the study.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Follow-Up Period
Last paragraph
Add:  new second sentence
The 10 day window for subject rollover may be extended on a case by case basis after 
consultation with the medical monitor.
Section 5.2.1  Inclusion Criteria
Criterion 9 and 10 previously read:
9.
If female, subject must be either postmenopausal, OR permanently surgically sterile 
OR for women of childbearing potential practicing at least one protocol-specified 
method of birth control (refer to Section 5.2.4), that is effective from Study Day 1 
through at least 180 days after the last dose of study drug.
10.
Male subjects who are sexually active with female partner(s) of childbearing 
potential must agree from Study Day 1 through 90 days after the last dose of study 
drug to practice the protocol-specified contraception (refer to Section 5.2.4).


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Has been changed to read:
9.
If female, subject must be either postmenopausal, OR permanently surgically sterile 
OR for women of childbearing potential practicing at least one protocol-specified 
method of birth control (refer to Section 5.2.4), that is effective from Study Day 1 
through at least 30 days after the last dose of study drug.
10.
Male subjects who are sexually active with female partner(s) of childbearing 
potential must agree from Study Day 1 through 30 days after the last dose of study 
drug to practice the protocol-specified contraception (refer to Section 5.2.4).
Section 5.2.3.1  Prior Therapy
Delete:  second paragraph
If subjects have/had ever been treated with corticosteroid, immunosuppressant or 
aminosalicylates, the duration of therapy, maximum dose, reason for use and reason(s) for 
termination of treatment will be recorded in appropriated eCRF.  The details of dates of 
administration and dosages will be also recorded within the past 90 days.
Section 5.2.3.1  Prior Therapy
Third paragraph
Add:  new last sentence
Subjects who have not been exposed to an anti-TNF will have their immunosuppressants 
recorded beyond the past 90 days.
Section 5.2.4  Contraceptive Recommendations
Subsection Contraception Recommendation for Females
Second paragraph, last bullet previously read:
Age < 55 years with no menses for 12 or more months without an alternative medical 
cause AND an FSH level > 40 IU/L.


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Has been changed to read:
Age < 55 years with no menses for 12 or more months without an alternative medical 
cause AND an FSH level > 40 mIU/mL.
Section 5.2.4  Contraceptive Recommendations
Subsection Contraception Recommendation for Females
Third paragraph previously read:
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered a woman of childbearing potential and is required to practice at least 
one of the following highly effective method of birth control, on Study Day 1 (or earlier) 
through at least 30 days (180 days for subjects taking MTX) after the last dose of study 
drug.
Has been changed to read:
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered a woman of childbearing potential and is required to practice at least 
one of the following highly effective method of birth control, on Study Day 1 (or earlier) 
through at least 30 days after the last dose of study drug.
Section 5.2.4  Contraceptive Recommendations
Subsection Contraception Recommendation for Females
Add:  new last paragraph
It is important to note that contraception requirements described above are specifically 
intended to prevent pregnancy during exposure to the investigational therapy ABT-494.  
The concomitant methotrexate (MTX) that may have been prescribed per standard of care 
prior to study entry and are allowed to be continued during the study.  Contraception 
should continue while the subject is on the concomitant MTX and that duration of 
contraception after discontinuation of the MTX should be based on the local label.


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Section 5.2.4  Contraceptive Recommendations
Subsection Contraception Recommendation for Males
Second paragraph previously read:
A male subject who is sexually active with female partner(s) of childbearing potential, 
must agree from Study Day 1 through 90 days after the last dose of study drug to practice 
contraception with:
Has been changed to read:
A male subject who is sexually active with female partner(s) of childbearing potential, 
must agree from Study Day 1 through 30 days after the last dose of study drug to practice 
contraception with:
Section 5.2.4  Contraceptive Recommendations
Subsection Contraception Recommendation for Males
Second paragraph, first bullet
Add:  new second paragraph
OR
Section 5.2.4  Contraceptive Recommendations
Subsection Contraception Recommendation for Males
Third paragraph previously read:
Additionally, male subject agrees not to donate sperm from Study Day 1 through 90 days 
after the last dose of study drug.
Has been changed to read:
Additionally, male subject agrees not to donate sperm from Study Day 1 through 30 days 
after the last dose of study drug.


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Section 5.2.4  Contraceptive Recommendations
Subsection Contraception Recommendation for Males
Add:  new last paragraph
It is important to note that contraception and sperm donation recommendations described 
above are specifically intended to prevent pregnancy during and after exposure to the 
investigational therapy ABT-494.  The concomitant methotrexate (MTX) that may have 
been prescribed per standard of care prior to study entry and are allowed to be continued 
during the study.  Contraception should continue while the subject is on the concomitant 
MTX and that duration of contraception and the requirement not to donate sperm after 
discontinuation of the MTX should be based on the local label.
Section 5.3.1.6  Collection of Samples for Gene Expression
First sentence previously read:
Optional gene expression samples may be evaluated in approximately 70 subjects.
Has been changed to read:
Optional gene expression samples may be evaluated in approximately 80 subjects.
Section 5.3.6.3  Gene Expression Variables
First paragraph, first sentence previously read:
For patients who consent to this optional testing, gene expression may be evaluated in 
approximately 70 subjects.
Has been changed to read:
For patients who consent to this optional testing, gene expression may be evaluated in 
approximately 80 subjects.


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Section 6.1.3  Relationship to Study Drug
In-text table previously read:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
Has been changed to read:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
Section 6.1.6  Pregnancy
Last paragraph, second sentence previously read:
Male subjects should refrain from donating sperm for up to 90 days post last dose of study 
drug.
Has been changed to read:
Male subjects should refrain from donating sperm for up to 30 days post last dose of study 
drug.
Section 8.1  Statistical and Analysis Plans
Last paragraph, last sentence previously read:
A second interim analysis of the secondary efficacy variables for the double-blind 
extension period, may be performed after 50% of subjects who were re-randomized at 
Week 16 completes Week 32 of the double-blind extension period in Study M13-740.  


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Has been changed to read:
A second interim analysis of the secondary efficacy variables for the double-blind 
extension period, may be performed after 100% of subjects who were re-randomized at 
Week 16 completes Week 36 of the double-blind extension period in Study M13-740.  
Section 9.1  Independent Ethics Committee (IEC) or Institutional Review Board 
(IRB)
Second paragraph, last sentence previously read:
The investigator will be required to submit, maintain and archive study essential 
documents according to ICH GCP.
Has been changed to read:
The investigator will be required to submit, maintain and archive study essential 
documents according to ICH GCP and all other applicable regulatory requirements.
Section 10.1  Source Documents
First paragraph
Add:  new fourth and fifth sentence 
The Investigator Awareness Date (SAE CRF) may serve as the source for this data point.  
This adverse event data point required for eCRF completion can be entered directly in the 
eCRF.
Section 13.0  Completion of the Study
Third paragraph, first sentence previously read:
The investigator must retain any records related to the study according to local 
requirements.
Has been changed to read:
The investigator must submit, maintain, and archive any records related to the study 
according to ICH GCP and all other applicable regulatory requirements.

SAP_001.pdf: 
ABT-494
M13-740 – Statistical Analysis Plan for Extension Phase
Version 1.0 – 14 Aug 2017
1
1.0
Title Page
Statistical Analysis Plan for Extension Phase
Study M13-740
A Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study of ABT-494 for the 
Induction of Symptomatic and Endoscopic 
Remission in Subjects with Moderately to Severely 
Active Crohn's Disease who have Inadequately 
Responded to or are Intolerant to 
Immunomodulators or Anti-TNF Therapy
Date:  14 Aug 2017
Version 1.0
NCT02365649


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M13-740 – Statistical Analysis Plan for Extension Phase
Version 1.0 – 14 Aug 2017
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................4
4.0
Study Objectives, Design and Procedures............................4
4.1
Objectives .............................................................................................. 4
4.2
Design Diagram ..................................................................................... 4
4.3
Sample Size.......................................................................................... 18
5.0
Analysis Populations ...........................................................18
5.1
Definition for Analysis Populations ...................................................... 18
5.2
Variables Used for Stratification of Randomization .............................. 19
6.0
Analysis Conventions ..........................................................20
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications..............33
7.1
Demographic and Baseline Characteristics ........................................... 33
7.2
Medical History.................................................................................... 35
7.3
Previous Treatment and Concomitant Medications ............................... 36
8.0
Patient Disposition...............................................................36
9.0
Study Drug Exposure and Compliance..............................36
10.0
Efficacy Analysis .................................................................37
10.1
General Considerations......................................................................... 37
10.2
Efficacy Analyses................................................................................. 37
10.3
Handling of Multiplicity....................................................................... 40
10.4
Efficacy Subgroup Analysis ................................................................. 40
11.0
Safety Analysis.....................................................................40
11.1
General Considerations......................................................................... 40
11.2
Analysis of Adverse Events.................................................................. 40
11.2.1
Treatment-Emergent Adverse Events.................................................... 40
11.2.2
Adverse Events of Special Interest........................................................ 43
11.3
Analysis of Laboratory Data................................................................. 45
11.3.1
Analysis of Liver Specific Laboratory Tests ......................................... 45
11.4
Analysis of Vital Signs and Weight ...................................................... 46


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12.0
Summary of Changes ..........................................................47
12.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP ................................................................................... 47
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP .................................................................. 48
13.0
Appendix..............................................................................48
14.0
References............................................................................48
List of Tables
Table 1.
Study Activities.................................................................................... 12
Table 2.
Visit Windows for Analysis of CDAI and CRP, Laboratory 
Parameters and Vital Signs for 36-Week Double-Blind Extension 
Phase.................................................................................................... 22
Table 3.
Visit Windows for Analysis of SES-CD, EIM, IBDQ, EQ5D, and 
WPAI for 36-Week Double-Blind Extension Phase .............................. 23
Table 4.
Visit Windows for Analysis of Bristol Stool Chart and Fecal 
Calprotectin for 36-Week Double-Blind Extension Phase..................... 23
Table 5.
An EQ-5D-5L Value Set for England ................................................... 32
List of Figures
Figure 1.
Study Design Schematic......................................................................... 6
Figure 2.
Study Design Schematic for Open-Label Extension Option for 
Patients Who Do Not Adequately Respond During the Extension 
Phase...................................................................................................... 7


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M13-740 – Statistical Analysis Plan for Extension Phase
Version 1.0 – 14 Aug 2017
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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis to be completed by 
the AbbVie Clinical Statistics Department for study Protocol M13-740 Amendment 5 
dated 07 November 2016.  It provides details to guide the analyses for baseline, efficacy, 
and safety variables.  This document describes the populations that will be analyzed, the 
variables that will be analyzed, and the statistical methods that will be utilized.  
This is the first version of the SAP for Protocol M13-740 Extension Phase.
This document describes the analyses of data except pharmacokinetic, microbiota 
metagenomic, pharmacogenetic and serologic data which will be analyzed separately.  It 
takes into account ICH Guidelines E3 and E9.
The statistical analysis for Study M13-740 Induction was performed separately.  The SAP 
for Induction has been signed off prior to Induction database lock in December, 2016.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The objective of this study is to determine the efficacy and safety of multiple doses of 
ABT-494 versus placebo and to assess the pharmacokinetics of ABT-494 following oral 
administration in subjects with moderately to severely active Crohn's disease with a 
history of inadequate response to or intolerance to immunomodulators or anti-TNF 
therapy.
4.2
Design Diagram
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy, safety, and pharmacokinetics of ABT-494 as induction 


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therapy in subjects with moderately to severely active Crohn's disease and evidence of 
mucosal inflammation defined by a SES-CD ≥ 6 (or ≥ 4 for subjects with disease limited 
to the ileum) and average daily soft/liquid stool frequency ≥ 2.5 or average daily 
abdominal pain score of ≥ 2.0; and CDAI ≥ 220 and ≤ 450, with a history of inadequate 
response or intolerance to immunomodulators and/or anti-TNF therapy.  The study will 
allow enrollment of up to 30% of subjects who were primary non responders to anti-TNF 
treatment.
The study is designed to enroll approximately 210 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target numbers of subjects have been enrolled, 
there is a possibility that additional subjects in screening will not be enrolled.
The study duration could be up to 60 weeks, including a Screening Period of up to 
35 days, a 16-week double-blind induction period, a 36-week double-blind extension 
phase, and a 30-day follow-up period.  Subjects who met eligibility criteria were 
randomized in a 1:1:1:1:1:1 ratio to one of the double-blinded induction treatment arms.
The schematics of the overall study design are shown in Figure 1 and Figure 2.


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Version 1.0 – 14 Aug 2017
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Figure 1.
Study Design Schematic


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Figure 2.
Study Design Schematic for Open-Label Extension Option for 
Patients Who Do Not Adequately Respond During the Extension 
Phase
Screening Period
Within 35 days prior to the Baseline Visit, subjects received a full explanation of the 
study design and study procedures, provided a written informed consent, and underwent 
the screening procedures as outlined in Table 1.
An e-diary was dispensed and training were provided to the subject at the Screening Visit.
Laboratory tests performed during the Screening period can be repeated in case the 
abnormalities are considered to be transient by the investigator.
16-Week Induction Period
This period began at the Baseline Visit (Week 0) and end at the Week 16 Visit.  At the 
Baseline Visit, subjects who met all the inclusion criteria and none of the exclusion 
criteria described in the protocol (Section 5.2.1 and Section 5.2.2) were enrolled into the 
study and randomized to double-blind induction period.  The randomization at Baseline 


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were stratified by endoscopic disease severity (SES-CD < 15 and ≥ 15), prior anti-TNF 
use (naïve and experienced), and by participation in the substudy of the gene expression in 
intestinal biopsies (Yes and No).  As part of the randomization at Baseline, subjects were 
randomly assigned (1:1) to have their follow-up ileocolonoscopy done at Week 12 or 
Week 16.  During this period of the study, subjects visited the study site at Weeks 2, 4, 8, 
12 and 16.  A ± 3-day window is permitted around scheduled study visits.  The last dose 
of study drug during this period is taken the evening prior to the Week 16 visit.
However, the stratification factor Prior anti-TNF use (naïve and experienced) was added 
under Amendment 3, and there are less than 10 anti-TNF naïve subjects enrolled under 
Amendment 3.  Therefore, the Prior anti-TNF use will not be included in all analysis as a 
stratification factor.
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects that end study participation early will have an Early Termination (ET) Visit and 
complete the procedures outlined for the ET Visit in Table 1 as soon as possible after the 
last dose of study drug and preferably prior to the administration of any new therapies.
36-Week Extension Phase
At Week 16, subjects who have completed the induction period will be re-randomized in a 
ratio of 1:1:1 to one of the three double-blinded doses of ABT-494 3 mg BID, 6 mg BID 
or 12 mg BID.  The re-randomization will be stratified by dose received during the 
first 16 weeks, and overall response (responder versus non-responder) at Week 16.  The 
subjects who were re-randomized at Week 16 to ABT-494 24 mg QD prior to Protocol 
Amendment 2 will continue to receive the same double-blind dose until Week 52/PD.
The central reader endoscopic score will be used for calculating the Endoscopic response 
for the evaluation of the efficacy endpoints.  However, for stratification at the time of 
re-randomization, the endoscopic score at BL from central reader and the endoscopic 
score at Week 12 or Week 16 from site local reader will be used in order to determine 
response status. 


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Clinical response is defined as average daily liquid/soft stool frequency reduction of at 
least 30% from Baseline and average daily abdominal pain score not worse than Baseline 
OR average daily abdominal pain score reduction at least 30% from baseline and average 
daily stool frequency not worse than Baseline.
During this period of the study, subjects will visit the study site at Weeks 20, 28, 36, 44, 
and 52/Early Termination.  A ± 3-day window is permitted around scheduled study visits.  
The last dose of study drug is taken the evening prior to the Week 52 visit.
Subjects will be expected to remain on double-blinded therapy throughout the entire 
36-week extension phase.  However, subjects who are considered by the investigator to 
have not achieved meaningful symptomatic relief and meet the criteria for inadequate
response at or after Week 20 will be eligible to receive the open-label therapy with 
ABT-494 12 mg BID, Figure 2.  Subjects who were re-randomized at Week 16 prior to
Protocol Amendment 2 and are taking open-label ABT-494 24 mg QD will be 
transitioned to ABT-494 12 mg BID.
Subjects who still continue to meet criteria for inadequate response following a 4-week 
course of open-label ABT-494 12 mg BID will be eligible to dose escalate to open-label 
ABT-494 24 mg BID.
Subjects with persistent inadequate response while on ABT-494 12 mg BID or 24 mg BID 
may be withdrawn from the study at the investigator's discretion.
Criteria for Inadequate response are as follows:
●
Average daily liquid/soft Stool Frequency > 2.2 OR average daily Abdominal 
Pain score > 1.8 AND
●
An increase level of hs-CRP of at least 1 mg/L from Baseline or a hs-CRP 
≥5 mg/L, either at the previous visit or at the current visit.
Note:  hs-CRP will be performed by Central Lab.  However, for the purpose of evaluating 
Inadequate Response criteria, hs-CRP can also be done at local lab.


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Assessment of inadequate response should include consideration by the Investigator to 
rule out symptoms caused by reasons other than Crohn's disease related inflammation.
In the open-label period, if the subject treated with 24 mg BID has an occurrence of an 
adverse event thought to be possibly related to study medication that in the opinion of the 
investigator warrants dose reduction, then the dose can be de-escalated to ABT-494 12 mg 
BID at the investigator's discretion.
Note:  Dose escalation and de-escalation are permitted only once during the study.
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects that end study participation early will have an ET Visit and complete the 
procedures outlined for the ET Visit in Table 1 as soon as possible after the last dose of 
study drug and preferably prior to the administration of any new therapies.
Subjects who are not re-randomized at Week 16 or subjects who early terminated from the 
study will have a follow-up visit approximately 30 days after the last administration of 
study drug to obtain information on any new or ongoing adverse events (AEs), and to 
collect vital signs and clinical laboratory tests.
Follow-Up Period
Subjects who have completed the Week 52 visit will have a follow-up visit approximately 
30 days after the last administration of study drug to obtain information on any new or 
ongoing adverse events (AEs), and to collect vital signs and clinical laboratory tests.
Re-Screen
Subjects that initially screen fail for the study may be permitted to re-screen following 
re-consent.  The subject must meet all the inclusion and none of the exclusion criteria at 
the time of re-screening in order to qualify for the study.  There is no minimum period of 
time a subject must wait to re-screen for the study.  If the subject had a complete initial 
screening evaluation including the assessment of a purified protein derivative (PPD) test 
(or equivalent), or Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold test 


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or T-SPOT TB test), chest x-ray, HBV, HCV and ECG, these tests will not be required to 
be repeated for re-screening provided the conditions noted in the protocol 
(Section 5.3.1.1) are met and no more than 90 days have passed.
An endoscopy with biopsy will not be required to be repeated for re-screening provided 
the conditions noted in the protocol (Section 5.3.1.1) are met and no more than 30 days 
have passed (from the previous screening endoscopy).  All other screening procedures 
will be repeated.  As appropriate, sites are encouraged to contact the AbbVie Medical 
Monitor to confirm if subjects should or should not be re-screened.
Unscheduled Visits
Unscheduled Visits are for purposes when the subject is coming in for a medical visit for 
evaluation and assessment.  During Unscheduled Visits, blood and urine samples will be 
obtained for the laboratory tests listed in the protocol (Table 2).
Visits for dispensing new study drug in case of temperature excursion, loss or damage are 
not considered an Unscheduled Visit.  In addition, visits to only retest a lab will not be 
considered an Unscheduled Visit.


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Table 1.
Study Activities
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
Informed Consent
X
Inclusion/Exclusionb
X
X
Medical/Surgical 
Historyb
X
X
Prior and 
Concomitant 
Medicationsb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Endoscopyd
X
X
X
X
X
Biopsye
X
X
X
X
X
SES-CD
X
X
X
X
X
Vital Signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGg
X
X
Chest X-Rayh
X
X
PPD Skin Test or 
QuantiFERON TB 
Gold Testi
X
Latent TB Risk 
Factor Questionnaire
X
Blood Chemistry 
and Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
Urinalysisj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV and HCV 
Screeningl
X
ABT-494 
Concentrationm
X
X
X
X
X
X
X
X
X
X
X
Pharmacodynamic 
biomarkers
X
X
X
X
X
C. difficile toxin
X
Stool Sample (fecal 
calprotectin)n,o
X
X
X
X
X
X
Bristol Stool Chartp
X
X
X
X
X
X
Corticosteroid Taperq
X
Crohn's Disease 
Activity Index (CDAI)
X
X
X
X
X
X
X
X
X
X
X
X
X
Inflammatory Bowel 
Disease Questionnaire 
(IBDQ)
X
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day
Follow-Up 
Visit
European Quality of 
Life 5 Dimensions 
(EQ-5D)
X
X
X
X
X
Work Productivity 
and Impairment 
Questionnaire (WPAI)
X
X
X
X
X
Abdominal Pain 
Rating Scale 
(0 – 10 Scale)
X
X
X
Monitor Adverse 
Eventsr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Dispensing/
Administration
X
X
X
X
X
X
X
X
X
X
Dispense Subject 
Diary
X
Subject Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
Additional Samples Collection (Optional)
Pharmacogenetics
X
Serologic markerst
X
X
mRNAt
X
X
Biopsy for gene 
expressionu
X
X
X
Wk = Week
a.
The Screening period will be a minimum of 7 days but no more than 35 days.  Baseline Visit date will serve as the reference for all subsequent visits.  A ± 3-day window is 
permitted around scheduled study visits.
b.
Update inclusion/exclusion, prior and concomitant therapy, and medical/surgical history information to assure subject eligibility.
c.
Physical examination performed at Screening, Baseline, Week 16 and Week 52/Early Termination Visits are full physical examinations which must include an assessment of 
extra-intestinal manifestations (EIMs) and a count of the number of cutaneous fistulas.  Physical examinations and those performed at all other visits are symptom based but 
must include a count of the number of cutaneous fistulas.
d.
Colonoscopy at/during the screening period or within 15 days of the Screening Visit will be used to calculate the SES-CD score at Baseline.  Subject will be randomly 
assigned at Baseline to have endoscopy performed at Week 12 or Week 16.
e.
Biopsy may be done when performing the endoscopy.  Biopsy to confirm CD diagnosis may be done when performing the endoscopy if appropriate documentation for 
confirmation of the diagnosis does not exist.  Biopsies to rule out dysplasia and colon cancer may be taken at the investigator's discretion.
f.
Blood pressure, pulse rate, temperature, respiratory rate and weight should be performed before blood draws are performed.  Height will be measured at Screening only (with 
shoes off and then adding 1 inch or 2.5 cm).
g.
Subjects with normal ECG within 90 days of Screening would not require a repeat ECG, if documentation is available.  Subjects can have a repeat ECG at any time during the 
study as warranted based on the opinion of the Investigator.


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Table 1.
Study Activities (Continued)
h.
Chest x-ray includes posterior-anterior (PA) and lateral views.  Obtain chest x-ray for subjects with TB risk factors as identified by the TB risk factor questionnaire or for 
subjects living in areas endemic for TB or for subjects with positive PPD or QuantiFERON-TB Gold.  Subjects can have a chest x-ray anytime during the study as warranted 
based on the opinion of the Investigator.
i.
PPD skin test is to be read 48 to 72 hours after placement.
j.
Dipstick urinalysis will be completed by the sites at all required visits.  A microscopic analysis will be performed by the central laboratory, in the event the dipstick results 
show protein, ketones or blood greater than negative or glucose greater than normal.
k.
Serum pregnancy test will be performed on all women of childbearing potential at Screening and at Week 52/ET.  Urine pregnancy test will be performed locally at every visit
for all women of childbearing potential.  If any urine pregnancy test is positive, a serum pregnancy test will be performed by the central laboratory.
If required by country regulatory authorities, monthly pregnancy tests will be performed throughout the study.
l.
Subjects will be tested for the presence of the hepatitis B Virus (HBV) and hepatitis C Virus (HCV) at Screening.  A positive result for the hepatitis B surface antigen 
(HBs Ag) or hepatitis C (HCV RNA detectable in any subject with anti-HCV Ab) will be exclusionary.  For subjects who are negative for HBs Ag but are positive for core 
antibodies (HBc Ab), HBV DNA PCR will be performed and any result that meets or exceeds detection sensitivity will be exclusionary.
m.
For all subjects, a PK sample will be collected at Week 2, within 1 to 3 hours after dosing, if possible.  At Week 4, Week 8, Week 12, Week 16, Week 20, Week 28, Week 36, 
Week 44 and Week 52/ET, a blood sample for PK will be collected at any time during the visit, and preferably within 1 to 8 hours after the last dose.  Patients can take the 
dose on visit days at their regular schedule and not necessarily at the clinic.  The date and accurate time of the PK sample collection and the last ABT-494 dose will be 
recorded in the CRF to the nearest minute.
n.
Stool sample will be collected at each time point indicated.  For the visit that endoscopy will be conducted, stool sample should be collected prior to endoscopy.
o.
A stool sample will be collected for fecal calprotectin analysis at each time point indicated.  Subjects will be asked to provide a stool sample at the visit, if possible, or 
subjects will be sent home with instructions and stool sample supplies (supplies will be provided).
p.
Stool samples for microbiota analysis should be assessed using the Bristol Stool Chart.
q.
Subject is mandated to begin corticosteroid taper at Week 2.
r.
Collection of SAEs begins the day the subject signs the informed consent.
s.
Only if subject provides written consent to collect the pharmacogenetic sample; if the informed consent form is not signed, no pharmacogenetic sample can be collected.  The 
sample is preferred to be collected at BL.


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Table 1.
Study Activities (Continued)
t.
Only if subject provides written consent to collect the serum biomarkers and mRNA samples; if the informed consent form is not signed, no serum biomarkers and mRNA can 
be collected.
u.
Only if subject provides written consent to collect biopsy samples for gene expression analysis; if the informed consent form is not signed, no biopsy for gene expression can 
be collected.  Biopsies will be obtained at baseline and as the Week 12/16 endoscopy, based on the colonoscopy assignment for Week 12 or 16.


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4.3
Sample Size
Approximately 210 subjects were equally allocated to five treatment groups and the 
placebo group, representing a randomization ratio of 1:1:1:1:1:1.  The sample size for this 
study was based on the expected proportion of subjects who achieve endoscopic remission 
at Week 12/16 and on the expected proportion of subjects who achieve clinical remission 
at Week 16.  Assuming an endoscopic remission (as well as clinical remission) rate of 
12% in the placebo arm and maximum of 35% in at least one of the ABT-494 BID 
treatment arms (3 mg BID, 6 mg BID, 12 mg BID and 24 mg BID) at Week 12/16, a 
sample size of 35 subjects per treatment group is sufficient to test for the presence of a 
dose response signal, to select the best dose response model for the observed data out of a 
prespecified set of candidate models, and to estimate target doses of interest (e.g., the 
minimum effective dose, MED) via modeling using MCP-Mod (Multiple comparison 
procedure and modeling) approach.  This approach provides at least 80% average power 
to detect a dose effect at 5% level of significance (one-sided) with the linear, Emax, 
exponential, logistic, and sigEmax models pre-specified as likely candidates to 
characterize the dose-response for ABT-494 for the two co-primary endpoints of clinical 
and endoscopic remission.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
The intent-to-treat responders (ITT-R) and intent-to-treat non-responders (ITT-NR) 
analysis sets includes all re-randomized subjects in the double-blind extension phase and 
are responders and non-responders at Week 16, respectively.  
For the ITT-R and ITT-NR analysis sets, subjects are assigned to a treatment group based 
on the re-randomization schedule, regardless of the treatment actually received.  The 
ITT-R and ITT-NR analysis sets will be used as primary sets for all efficacy analysis.  
Subjects who were randomized to placebo during the Induction Period will be 
summarized separately.


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The intent-to-treat clinical responders (ITT-CR) and intent-to-treat clinical non-
responders (ITT-CNR) analysis sets includes all re-randomized subjects in the double-
blind extension phase and are clinical responders and clinical non-responders at Week 16, 
respectively.  
For the ITT-CR and ITT-CNR analysis sets, subjects are assigned to a treatment group 
based on the re-randomization schedule, regardless of the treatment actually received.  
The ITT-CR and ITT-CNR analysis sets will be used for sensitivity analysis.  Subjects 
who were randomized to placebo during the Induction Period will be summarized 
separately.
The safety analysis set consists of all subjects who received at least one dose of study 
medication in the Extension Phase.  For the safety analysis sets, subjects are assigned to a 
treatment group based on the treatment actually received, regardless the treatment 
randomized.  The safety analysis set will be used for all safety analysis of Extension 
phase.
Any ABT-494 analysis set will consist of all subjects who received at least one dose of 
ABT-494 during Induction or Extension.  Any ABT-494 analysis set will be used for 
cumulative safety analysis (from Induction baseline to study end).
5.2
Variables Used for Stratification of Randomization
At Baseline, subjects were randomized in a 1:1:1:1:1:1 ratio to receive one of the 
six treatment groups (double-blind ABT-494 induction doses or matching placebo).
The following are the treatment groups:
Group 1:  ABT-494 3 mg BID
Group 2:  ABT-494 6 mg BID
Group 3:  ABT-494 12 mg BID


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Group 4:  ABT-494 24 mg BID
Group 5:  ABT-494 24 mg QD
Group 6:  Placebo
The randomization at Baseline was stratified by endoscopic disease severity (SES-CD 
< 15 and ≥ 15), prior anti-TNF use (naïve and experienced), and by participation in the 
substudy of the gene expression in intestinal biopsies (Yes and No).  As part of the
randomization at Baseline, subjects were randomly assigned (1:1) to have their follow-up 
ileocolonoscopy done at Week 12 or Week 16.
At Week 16, subjects who have completed the induction period were re-randomized in a 
ratio of 1:1:1 to one of the three double-blinded doses of ABT-494 3 mg BID, 6 mg BID 
or 12 mg BID.  The re-randomization was stratified by dose received during the 
first 16 weeks, and overall response (responder versus non-responder) at Week 16.  The 
subjects who were re-randomized at Week 16 to ABT-494 24 mg QD prior to Protocol 
Amendment 2 continued to receive the same double-blind dose until Week 52/PD.
Overall response consists of both Endoscopic response and Clinical response.  The central 
reader endoscopic score will be used for calculating the Endoscopic response for the 
evaluation of the efficacy endpoints.  However, for stratification re-randomization, the 
endoscopic score at baseline from central reader and the endoscopic score at Week 12 or 
Week 16 from site local reader will be used in order to determine response status.
6.0
Analysis Conventions
Definition of Baseline for Induction Period
The Baseline visit date for Induction Period is the date when the first dose of study drug is 
received and referred to as Day 1 or Week 0.  The Baseline value for a variable is defined 
as the last non-missing value on or before the date of the first dose of study drug for 
Induction Period.


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Definition of Baseline for Extension Phase
The Baseline visit date for Extension Phase is the date when the first dose of study drug 
for Extension Phase is received and referred to as Day 1 or Week 0 of Extension Phase.  
The Baseline value for a variable is defined as the last non-missing value on or before the 
date of the first dose of study drug for Extension Phase.
Definition of Rx Days (Days Relative to the First Dose of Study Drug)
Rx Days are calculated for each time point of interest and it provides a quantitative 
measure of days between the event and the first dose date.  That is, the Rx Day is 
calculated as the event date minus the date of first dose of study drug plus 1.  
The Rx Day will be a negative value when the time point of interest is prior to the date of 
first dose of study drug, and the Rx Day will be a positive value when the time point of 
interest is after the first dose date.  By this calculation algorithm the first dose day is Rx 
Day 1, while the day prior to the date of first dose is defined as Rx Day –1 (there is no Rx 
Day 0).  Rx Days are used to map actual study visits to the protocol specified study visits.
Dealing with Multiple Measurements Collected on the Same Day
For efficacy related analyses other than imaging endpoints, if multiple measurements for a 
particular parameter are collected on the same day for the same subject, the average of 
those measurements will be used.
For safety related analyses, if multiple measurements are made for a particular laboratory 
or vital sign parameter on the same day for the same subjects, the average of the values 
will be used in the analyses of change from Baseline.  For summaries and listings for shift 
from baseline and potentially significant values, all collected values within the pre-
specified treatment window will be used. 


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Definition of Analysis Windows
Since subjects do not always adhere to the study visit schedule, the following rules will be 
applied to assign actual visits to protocol-specified visits including early termination 
visits.  For each study visit mentioned in the protocol, a nominal or target day will be 
selected to represent the corresponding visit along with a window around the target day.  
Windows will be selected in a non-overlapping fashion so that a date collected on the 
CRF does not correspond to multiple visit windows.  Moreover, windows will not discard 
any Post-Baseline measurement recorded on the CRF.  If a subject had two or more actual 
visits in one visit window, the visit closest to the schedule visit will be used as the study 
visit for that window.  If two visits are equidistant from the target, then the later visit will 
be used for reporting.  
Table 2.
Visit Windows for Analysis of CDAI and CRP, Laboratory 
Parameters and Vital Signs for 36-Week Double-Blind Extension 
Phase
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 0 (Baseline of Extension Phase)
1a
≤ 1
Week 4 (Week 20 of the study)
29
2 – 57
Week 12 (Week 28 of the study)
85
58 – 113
Week 20 (Week 36 of the study)
141
114 – 169
Week 28 (Week 44 of the study)
197
170 – 225
Week 36 (Week 52 of the study)
253
226 – 999
Rx Day B = date of visit – date of first study drug in double-blind extension phase + 1
a.
Day of first dose of study drug in double-blind extension phase.


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Table 3.
Visit Windows for Analysis of SES-CD, EIM, IBDQ, EQ5D, and 
WPAI for 36-Week Double-Blind Extension Phase
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 0 (baseline of Extension Phase)
1a
≤ 1
Week 36 (Week 52 of the study)
253
2 – 999
Rx Day B = date of visit – date of first study drug in double-blind extension phase + 1
a.
Day of first dose of study drug in double-blind extension phase.
Table 4.
Visit Windows for Analysis of Bristol Stool Chart and Fecal 
Calprotectin for 36-Week Double-Blind Extension Phase
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 0 (baseline of Extension Phase)
1a
≤ 1
Week 12 (Week 28 of the study)
85
2 – 169
Week 36 (Week 52 of the study)
253
170 – 999
Rx Day B = date of visit – date of first study drug in double-blind extension phase + 1
a.
Day of first dose of study drug in double-blind extension phase.
CD-Related Corticosteroid Use
Subjects not on CD-related corticosteroids (systemic or rectal corticosteroids) at Induction 
Baseline which are then initiated during the study or who have dosages of these 
medications increased to greater than the dose taken at Baseline will be censored for 
efficacy assessments (i.e., will be considered non-responders for categorical endpoints and 
will have Baseline values carried forward for non-categorical assessments) from that point 
through the end of the study.  These subjects will continue to be evaluated in the safety 
population.
The equivalent steroid dose will be determined based on the table below:


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Corticosteroid
Equivalent Dose (mg)
Cortisone
25
Hydrocortisone
20
Prednisone
5
Prednisolone
5
Triamcinolone
4.0
Methylprednisolone
4.0
Betamethasone
0.75
Dexamethasone
0.75
Budesonide
1
Beclomethasone
5
Beclometasone
5
Open-Label Therapy
Subjects who are considered by the investigator to have not achieved meaningful 
symptomatic relief and have met the criteria for inadequate response at or after Week 20 
of the study (Week 4 of the Extension Phase) will be eligible to receive open-label therapy 
with ABT-494 12 mg BID.  These subjects will be censored for efficacy assessments 
(i.e., will be considered non-responders for categorical endpoints and will have the non-
missing value prior to open-label therapy carried forward for non-categorical assessments) 
from that point through the end of the study.  
Definition of Missing Data Imputation
The following imputation methods will be used to impute missing values in the efficacy 
analyses.  In addition, an observed case analysis will be performed.
Non-Responder Imputation (NRI)
The NRI approach is used for binary efficacy variables.  These variables can take values 
of 'Achieved' or 'Not Achieved' or may be missing for any reason including 
discontinuation from study.  According to the NRI imputation approach, all missing 
values will be considered as 'Not Achieved.'


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Last Observation Carried Forward (LOCF)
For all variables (categorical variables and continuous variables), the following rules will 
be used for the LOCF approach:
1.
Extension Baseline and Pre-Baseline values will not be used to impute the missing
Post-Baseline values.
2.
Missing values after Study Day 1 will be imputed using the latest non-missing 
values after Day 1 and prior to the missing value.  If there are no non-missing 
values after Baseline, then the LOCF value will be missing.
Observed Case (OC)
Observed case analysis will be performed such that missing values will not be imputed.  
However, all observed values will be replaced by Induction Baseline value once subjects 
received CD-related corticosteroid therapy, or value prior to open label therapy once 
subjects moved to open-label therapy.
Mixed-Effect Model Repeated Measure (MMRM)
The MMRM model will be used for continuous efficacy variables with longitudinal data 
as the primary analysis.  The MMRM model includes the baseline values as covariate, 
treatment, time point and treatment-by-time point interaction as fixed effects; and subjects 
within treatment as random effect.  An unstructured (co)variance structure will be used to 
model the within-subject error.  The comparison at a time point will be the contrast 
between treatments at that time point.  Satterthwaite's approximation will be used to 
estimate denominator degrees of freedom.
Imputation of Missing Dates
For Baseline, efficacy, and safety parameters, if the day and/or month are missing, the 
following conventions will be used to impute the missing dates:
●
01 for missing start day


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●
End of month for missing end day
●
January 1st for missing start month
●
December 31st for missing end month
In case of partially missing AE start and stop dates, the dates will be imputed by 
comparing to first dose date of study medication so than the corresponding AEs will be 
made treatment-emergent whenever possible.  If the start date of an AE is partially 
missing and the month is the same as the start date of a new therapy, the AE will be made 
treatment emergent to the new therapy.
In case of missing or partially missing study drug dosing dates, the dates will not be 
imputed.  Subjects will be treated as not receiving dose on that date.
Rule for CDAI Calculation
Up to 14 days of diary entries will be evaluated from the ePRO tool for the CDAI 
calculation for each visit.  The diary entries on the days the subjects receive endoscopy 
preparation medications, the day of endoscopy procedure, and 2 days after endoscopy 
procedure will be excluded.  For each CDAI subscore, the available scores from the most 
recent diary days (at least 4 days, up to 7 days) prior to actual day of the study visit will be 
summed, and then multiplied by the corresponding multiplier to get subtotal score.  If 
available diary entries are fewer than 7 days, the subtotal score will be calculated as 
(summed total available score/number of days) × 7 × corresponding multiplier.  The 
three subtotal scores that are based on ePRO (number of liquid/very soft stools, abdominal 
pain rating, and general well-being) will then be rounded to one decimal.  The final CDAI 
is rounded to a whole number.
If a subject has less than 4 days of diary data, the total CDAI score will not be calculated 
and will be considered missing.
Same rule will be applied to average daily stool frequency and average daily abdominal 
pain.


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Bristol Stool Chart
Up to 14 days of diary entries will be evaluated from the ePRO tool for the Bristol Stool 
Chart calculation.  These assessments on the day of endoscopy procedure, the day before 
endoscopy procedure (due to preparation medications), and 2 days after endoscopy 
procedure are excluded.  The 7 most recent non-missing assessments will be used for the 
analysis.  The Bristol Stool Chart is calculated as the number of days the subjects with 
Type 6 or Type 7 divided by the total number days with non-missing assessments, 
rounded to two decimal.
If a subject has less than 4 days of diary data, the Bristol Stool Chart will not be calculated 
and will be considered missing.
If a subject achieved reduction from Baseline ≥ 50%, this subject will be classified as 
Responder.
SES-CD Scoring
All colonoscopies shall be performed and recorded in video format.  To be eligible for the 
study, the screening colonoscopy may be performed during the Screening Period (or up to 
45 days before the Baseline visit if Amendment 2 is in place at the site).  Colonoscopies 
will also be performed at the Week 12/16 visit and Week 52 visit.  Investigators shall 
provide their SES-CD score assessment on the SES-CD score sheet for the baseline, 
Week 12/16 visit and Week 52 visit.  The investigator SES-CD scores are to be entered in 
the appropriate eCRF, however neither the Investigator's Baseline, nor Week 12/16, 
Week 52 SES-CD scores will be used for the study's efficacy analyses unless the 
adjudicator agree with the site reading.
All videotaped colonoscopies will undergo central review.  One primary central reviewer 
will evaluate the videotaped colonoscopies and provide the SES-CD scores to Parexel.  A 
second central reviewer will adjudicate between the investigator's and the central 
reviewer's SES-CD scores if there is discrepancy (more than 10% difference) in total 
SES-CD score.  The adjudicator will select the final SES-CD score that he/she most 


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agrees with from those provided by the investigator and the central reviewer, and this final 
SES-CD score will be entered into the study database and be used for the study's efficacy 
analyses.  If there is no discrepancy between the investigator and the central reviewer, that 
central reviewer's score will be entered into the study database and serve as the SES-CD 
score to be used for the study's efficacy analyses.
If there is a missing SES-CD individual variable in the SES-CD score for the study's 
efficacy analyses (for all variables except the "Presence of Narrowing" variable), the 
following imputation rules will be applied:
If the same individual variable is:
●
Missing at Week 52 but present at Week 12/16:  the missing Week 52 value 
will be imputed based on the value at Week 12/16.
●
Missing at Week 52 but no endoscopy performed at Week 12/16:  the missing 
Week 52 value will be imputed based on the value at Induction Baseline.
If there is a missing SES-CD "Presence of Narrowing" individual variable in the SES-CD 
score for the study's efficacy analyses, the following imputation rules will be applied:
If the Presence of Narrowing individual variable is:
●
Missing at Week 52 but present at Week 12/16:  the missing Week 52 value 
will be imputed based on score at Week 12/16.
However, if a Week 52 individual variable is scored for intestinal segments 
proximal to (above) the segment with the missing Presence of Narrowing 
variable, the maximum imputed value for the missing Presence of Narrowing 
individual variable will be 2.
●
Missing at Week 52 but no endoscopy performed at Week 12/16:  the missing 
Week 52 value will be imputed based on score at Induction Baseline.
However, if a Week 52 individual variable is scored for intestinal segments 
proximal to (above) the segment with the missing Presence of Narrowing 


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variable, the maximum imputed value for the missing Presence of Narrowing 
individual variable will be 2.
(Gastrointestinal anatomy places the ileum proximal to the right colon, which is proximal 
to the transverse colon, which is proximal to the sigmoid and left colon, which is proximal 
to the rectum.)
A sensitivity analysis (Worst Case Imputation) will be performed by imputing all missing 
Induction Baseline individual variables as '0' and all missing Week 52 variables as '3' 
except the Week 52 Presence of Narrowing individual variable.  At Week 52, the worst 
values for Presence of Narrowing individual variable will be 2 for Rectum, Sigmoid and 
Left Colon, Transverse Colon, and Right Colon, and 3 for Ileum.
Isolated Ileal Crohn's Disease at Induction Baseline
Isolated Ileal Crohn's disease at Induction Baseline is defined as all individual variables 
for Rectum, Sigmoid and Left Colon, Transverse Colon, and Right Colon are zero at 
Induction Baseline and subscore for ileal ≥ 4.  If any of the individual variables is missing 
or not zero, this subject is classified as Not Isolated Ileal Crohn's disease at Induction 
Baseline.
Definition of Endoscopic Remission
SES-CD ≤ 4 and at least two point reduction versus Induction baseline and no subscore 
> 1 in any individual variable.
Definition of Endoscopic Response
SES-CD at least 25% reduction from Induction baseline.
Definition of Enhanced Endoscopic Response
SES-CD reduction from Induction baseline > 50% (or for an Induction Baseline SES-CD 
of 4, at least a 2 point reduction from Induction Baseline).


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Definition of Endoscopic Improvement
SES-CD reduction from Induction baseline > 50% or endoscopic remission.
Definition of Endoscopic Healing
SES-CD ulcerated surface subscore of 0 in subjects with SES-CD ulcerated surface 
subscore ≥ 1 at Induction Baseline.
Definition of Clinical Remission
Average daily stool frequency ≤ 1.5 and not worse than Induction baseline AND average 
daily abdominal pain ≤ 1.0 and not worse than Induction baseline.
Definition of Clinical Response
Average daily stool frequency at least 30% reduction from Induction baseline and average 
daily abdominal pain not worse than Induction baseline OR average daily abdominal pain 
at least 30% reduction from Induction baseline and average daily stool frequency not 
worse than Induction baseline.
Definition of Modified Clinical Remission
Average daily stool frequency ≤ 2.8 and not worse than Induction baseline AND average 
daily abdominal pain ≤ 1.0 and not worse than Induction baseline.  This endpoint will 
only be analyzed among subjects with Induction baseline average daily stool frequency 
≥4 or average daily abdominal pain ≥ 2.0.
Definition of Enhanced Clinical Response
Average daily stool frequency at least 60% reduction from Induction baseline and average 
daily abdominal pain not worse than Induction baseline OR average daily abdominal pain 
at least 35% reduction from Induction baseline and average daily stool frequency not 
worse than Induction baseline or modified clinical remission.


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Definition of Remission
Remission at Week 52 is defined as both Endoscopic remission at Week 52 AND Clinical 
remission at Week 52.
Definition of Response
Response at Week 52 is defined as both Endoscopic response at Week 52 AND Clinical 
response at Week 52.
EuroQol-5D-5L (EQ-5D)
EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal.  
The EQ-5D consists of 2 pages.  The first page measures 5 dimensions of the health status 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with 
5 levels per dimension (no problems, slight problems, moderate problems, severe 
problems, and unable corresponding to Level 1 to Level 5 respectively).  The second page 
is an EQ Visual Analogue Scale (EQ VAS).  EQ-5D health states, defined by the 
EQ-5D-5L descriptive system on the first page, may be converted into a single index 
value.  The change from baseline of the index value and EQ VAS will be analyzed and 
reported.  UK scoring algorithm will be used (Table 5).


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Table 5.
An EQ-5D-5L Value Set for England
Central Estimate
Value for Health State 23245
Mobility
     No Problem
     Slight
     Moderate
     Severe
     Unable
0
0.051
0.063
0.212
0.275
0.051
Self-Care
     No Problem
     Slight
     Moderate
     Severe
     Unable
0
0.057
0.076
0.181
0.217
0.076
Usual Activities
     No Problem
     Slight
     Moderate
     Severe
     Unable
0
0.051
0.067
0.174
0.190
0.051
Pain/Discomfort
     No 
     Slight
     Moderate
     Severe
     Unable
0
0.060
0.075
0.276
0.341
0.276
Anxiety/Depression
     Not
     Slight
     Moderate
     Severe
     Unable
0
0.079
0.104
0.296
0.301
0.301
The value for health state 23245:
1 – 0.9675 × (sum of the subscores)
1 – 0.9675 × (0.051 + 0.076 + 0.051 
+ 0.276 + 0.301) = 0.270
The index value is 1 – 0.9675 × sum of 5 components based on central estimates.


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The minimum index value is – 0.281 (health state 55555), and the maximum index value 
is 1 (health state 11111).1
If one of the 5 dimensions is missing, the EQ-5D index value will be missing.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
For the subjects in ITT and safety analysis set, demographic information and Baseline 
values will be summarized by descriptive statistics.  Categorical data will be summarized 
by number and percent; and quantitative data will be presented by n, mean, standard 
deviation, minimum value, median, and maximum value.
In general, continuous variables will be analyzed using analysis of variance (using SAS 
procedure 'PROC GLM') with treatment group as factor.  Categorical variable will be 
analyzed using chi-square test or Fisher's exact test if ≥ 20% of the cells have expected 
cell count < 5.
The following demographic and Baseline values will be summarized.
Continuous Variables:
●
Age (years)
●
Body weight (kg)
●
Height (cm)
●
Body Mass Index (kg/m2)
●
Blood Pressure (systolic/diastolic) (mmHg)
●
Pulse (bpm)
●
Temperature (°C)
●
CDAI
●
Average Daily Stool Frequency


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●
Average Daily Abdominal Pain
●
Total SES-CD score
●
Crohn's Disease Duration (years)
●
hs-CRP mg/L
●
Fecal calprotectin
●
IBDQ score
●
WPAI and its components
●
EQ-5D
●
Abdominal Pain Rating Scale
●
Bristol Stool Chart Score
●
Mean dose of corticosteroids for those on baseline corticosteroid use.
Categorical Variables:
●
Sex (male, female)
●
Race
●
Ethnicity
●
Age (< 40, 40 to < 65, 65 to < 75, ≥75)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
Number of prior immunosuppressant use
●
Number of prior biologic use
●
hs-CRP at Baseline (< 10 and ≥ 10 mg/L)
●
Baseline fecal calprotectin (≤ 250 µg/g, > 250 µg/g)
●
Crohn's disease severity (CDAI ≤ 300, > 300) at Baseline
●
Baseline SES-CD (< 15, ≥ 15)
●
Disease duration (≤ 3 years, > 3 years)
●
Tobacco use (user, ex-user, never used, unknown)
●
Alcohol use (drinker, ex-drinker, non-drinker, unknown)
●
Region (US, ex-US)


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7.2
Medical History
Medical and Surgical History:  A complete medical and surgical history (which includes 
CD-onset date), history of tobacco and alcohol use, and TB history will be obtained from 
each subject during the Screening period.  Medical history will be summarized using body 
system and condition/diagnosis by treatment group.  No statistical tests will be performed.
Chest X-Ray Results:  All subjects undergo a standard X-ray of chest (including a 
posteroanterior [PA] and lateral view) at Screening period.  Number and percent of 
subjects with presence or absence of finding for the previous TB infection, calcified 
granulomas, Pleural scarring/thickening, and other findings will be presented by treatment 
group.  No statistical tests will be performed.
TB Test Results:  Results of PPD skin test, QuantiFERON-TB Gold test at screening 
visit will be summarized.  Induration will be summarized descriptively using n, mean, 
standard deviation, minimum values, median, and maximum values.  The frequency 
distribution of induration ≥ 5 and < 5 will be provided.  QuantiFERON-TB tests will be 
described as positive or negative.  Indetermiante QuantiFERON-TB test results will be 
repeated.  If the second QuantiFERON-TB test is positive or indeterminate, the final 
assessment will be considered positive.  If the second QuantiFERON-TB test is negative, 
the final assessment will be considered negative.  No statistical tests will be performed. 
TB Prophylaxis:  History of use of TB Prophylaxis or initiation of TB prophylaxis will 
be summarized.
ECG Results:  ECG results at screening will be presented as frequency distribution 
showing results as Normal, Abnormal (Not clinically significant), Abnormal (Clinically 
significant) and Unable to evaluate/missing.  No statistical tests will be performed.


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7.3
Previous Treatment and Concomitant Medications
Based on generic medication names, these categories of medications used by subjects 
before and during the study will be summarized by number and percent for ITT and safety 
analysis sets for the treatment groups.  No statistical tests will be performed.
The number and percent of subjects using Crohn's disease specific medications (including 
corticosteroids, aminosalicylates, immunosuppressants [defined as azathioprine, 
6-mercaptopurine, or methotrexate], antibiotics) within past 90 days prior to the Baseline, 
and at the Baseline will be tabulated.  In addition, the number and percent of subjects 
using Crohn's disease specific immunosuppressants, and biologic therapies at any time 
prior to Baseline will be tabulated.
8.0
Patient Disposition
Subject disposition will be presented for subjects in the ITT and safety analysis sets using 
the following information by treatment group:
●
Number and percent of subjects in various analysis sets by treatment group and 
by investigator and/or site number
●
Number and percent of subjects completing extension phase and discontinuing 
on or before Week 52 visit.
●
Subject disposition including the number and percent of subjects who 
prematurely discontinued the study) by primary reason and by any reason
Summary of protocol deviations will be provided.
9.0
Study Drug Exposure and Compliance
Study drug exposure and compliance will be summarized using the mean, standard 
deviation, minimum, median, and maximum.  Exposure to study drug will be summarized 
by separately for double-blind extension phase and open-label extension phase.


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Compliance is defined as the number of capsules taken (i.e., the difference between the 
number of capsules dispensed and the number of capsules returned) divided by the 
number of capsules a subject is supposed to take each day times the length of time that the 
subject was in the Treatment Phase of the study (i.e., Final/Discontinuation Visit date 
during Treatment Phase – Day 1 [Baseline] Visit date + 1).  Subjects with missing data for 
the number of capsules returned will be excluded from the summary.
10.0
Efficacy Analysis
10.1
General Considerations
All statistical tests will be two-sided with the significance level of 0.100.  Descriptive 
statistics will be provided.  These include the number of observations, mean, standard 
deviation, minimum, median, and maximum for continuous variables; and number and 
percent for discrete variables.  The analysis will be performed using SAS® (SAS Institute 
Inc., Cary, NC, USA).
10.2
Efficacy Analyses
The endpoints (Double-Blind Extension Phase) include:
●
Proportion of subject who achieve remission at Week 52.
●
Proportion of subjects who achieve endoscopic remission at Week 52.
●
Proportion of subjects who achieve both endoscopic remission and modified 
clinical remission at Week 52.
●
Proportion of subjects who achieve clinical remission over time.
●
Proportion of subjects who maintain clinical remission over time among 
subjects in clinical remission at Week 16.
●
Proportion of subjects who achieve modified clinical remission over time.
●
Proportion of subjects who maintain modified clinical remission over time 
among subjects in modified clinical remission at Week 16.
●
Proportion of subject who achieve response at Week 52.
●
Proportion of subjects with SES-CD ≤ 2 at Week 52.


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●
Proportion of subjects with SES-CD = 0 at Week 52.
●
Proportion of subjects who achieve endoscopic response at Week 52.
●
Proportion of subjects who achieve enhanced endoscopic response at Week 52.
●
Proportion of subjects who achieve endoscopic improvement at Week 52.
●
Proportion of subjects who achieve endoscopic healing at Week 52.
●
Proportion of subjects who achieve clinical response over time.
●
Proportion of subjects who achieve enhanced clinical response over time.
●
Proportion of subjects who maintain enhanced clinical response over time 
among subjects in enhanced clinical response at Week 16.
●
Proportion of subjects with an average daily SF ≥2.5 AND average daily 
AP ≥2.0 at Induction Baseline who achieve clinical remission over time.
●
Proportion of subjects taking corticosteroids at Induction Baseline who 
discontinued corticosteroid use and achieved CDAI < 150 over time.
●
Proportion of subjects taking corticosteroids at Induction Baseline who 
discontinued corticosteroid use and achieve remission at Week 52.
●
Proportion of subjects taking corticosteroids at Induction Baseline who 
discontinued corticosteroid use and achieve clinical remission over time.
●
Proportion of subjects taking corticosteroids at Induction Baseline who 
discontinued corticosteroid use and achieve modified clinical remission over 
time.
●
Proportion of subjects taking corticosteroids at Induction Baseline who 
discontinued corticosteroid use and achieve endoscopic remission at Week 52.
●
Proportion of subjects who achieve CDAI < 150 at over time.
●
Proportion of subjects with decrease in CDAI ≥ 70 points from Induction 
Baseline over time.
●
Change from Induction Baseline in fecal calprotectin level over time.
●
Change from Induction Baseline in hs-CRP at over time.
●
Change from Induction Baseline in IBDQ at Week 52.
●
Change from Induction Baseline in EQ-5D at Week 52.
●
Change from Induction baseline in EIMs at Week 52.


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●
Proportion of subjects with isolated ileal Crohn's disease who achieve 
remission at Week 52.
●
Proportion of subjects with isolated ileal Crohn's disease who achieve 
modified clinical remission at Week 52.
For categorical efficacy endpoints for double-blind extension phase, the pairwise 
comparisons for the difference in proportions of subjects between ABT-494 3 mg BID 
group and ABT-494 higher dose groups will be analyzed using the Chi-square test (or 
Fisher's exact test if ≥ 20% of the cells have expected cell count < 5.).  Additionally, the 
95% confidence interval based on normal approximation for the difference in proportions 
will be provided.  
The non-responder imputation will be used for subjects with missing data at the endpoint 
evaluated.  The last observation carried forward (LOCF) method will also be used as the 
sensitivity analyses.
In general, continuous efficacy variables with repeated measurements will be analyzed 
using a Mixed Effect Repeated Measure (MMRM) model.  The mixed model includes the 
categorical fixed effects of treatment, week and treatment-by-week interaction and the 
continuous fixed covariates of Induction baseline measurement.  An unstructured 
variance-covariance matrix will be used.  If convergence is not achieved, other 
variance-covariance matrix will be explored until coverage.  The parameter estimations 
will be based on assumption of data being missing at random and using the method of 
restrictive maximum likelihood (REML).
Continuous secondary efficacy variables will also be analyzed using an Analysis of 
Covariance (ANCOVA) model including factors for treatment group, and Induction 
Baseline values as a covariate.  The MMRM analysis is considered primary for inferential 
purposes.


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10.3
Handling of Multiplicity
The analyses are for extension phase endpoints only, and will not be controlled for
multiplicity.
10.4
Efficacy Subgroup Analysis
No subgroup analyses will be conducted for double-blind extension phase efficacy 
endpoints. 
11.0
Safety Analysis
11.1
General Considerations
Adverse events (AEs), laboratory data and vital signs are the primary safety parameters in 
this study.  The safety variable will be summarized by treatment according to the 
treatment a subject actually received.  
11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AE for double-blind Extension Phase is defined as any adverse event 
with an onset date on or after the first dose of double-blind maintenance dose and prior to 
the open-label dose or up to 30 days after the last dose of double-blind maintenance dose 
if subject discontinued prematurely in double-blind maintenance phase.
For subjects who entered open-label due to inadequate response, treatment-emergent AEs 
for open-label Extension Phase will also be summarized by open-label dose.  Treatment-
emergent AE for open-label Extension Phase is defined as any adverse event with an 
onset date on or after the first dose of open-label dose and up to 30 days after the last dose 
of open-label dose.
An overview of treatment-emergent AEs, including AEs of special interest such as 
adverse events leading to death and adverse events leading to early termination, AEs by 


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Medical Dictionary for Drug Regulatory Activities (MedDRA version 20.0 or later) 
preferred term and system organ class, AEs by maximum relationship to study drug, and 
AEs by maximum severity will be summarized by number and percentage.  
Changes in laboratory data will be summarized.
In addition, shift tables and listings will be provided for abnormal values, whereby the 
normal range of the analyzing laboratory will be used.  Vital signs will be analyzed 
similarly.
The number and percent of subjects experiencing treatment-emergent adverse events will 
be summarized for the following adverse event categories.
●
Any treatment-emergent adverse event.
●
Any treatment-emergent adverse event that was rated as possibly related to 
study drug by the investigator (Reasonable Possibility).
●
Any treatment-emergent severe adverse event.
●
Any treatment-emergent serious adverse event.
●
Any treatment-emergent adverse event leading to discontinuation of study 
drug.
●
Any treatment-emergent adverse event leading to death.
●
Any treatment-emergent adverse event of special interest.
Treatment-emergent adverse events will be summarized as follows:
●
Grouped by System Organ Class and Preferred Term.
●
Grouped by System Organ Class, Preferred Term and Severity.
●
Grouped by System Organ Class, Preferred Term and Relationship to Study 
Drug.
●
Grouped by System Organ Class and Preferred Term with subject numbers.


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In treatment-emergent AE tables, a subject who reports more than one treatment-emergent 
AE in different system organ classes will be counted only once in the overall total.  A 
subject who reports two or more different preferred terms which are in the same SOC will 
be counted only once in the SOC total.  A subject who reports more than one treatment 
AE with the same preferred term will be counted only once for that preferred term using 
the most extreme incident (i.e., most "severe" for the severity tables and most "related" for 
the relationship tables).
Adverse events will also be summarized by maximum severity.  If a subject has an 
adverse event with unknown severity, then the subject will be counted in the severity 
category of "unknown," even if the subject has another occurrence of the same adverse 
event with a severity present.  The only exception is if the subject has another occurrence 
of the same adverse event with the most extreme severity – "Severe."  In this case, the 
subject will be counted under the "Severe" category.
Adverse events will also be summarized by maximum relationship to study, as assessed 
by the investigator.  If a subject has an adverse event with unknown relationship, then the 
subject will be counted in the relationship category of "unknown," even if the subject has 
another occurrence of the same adverse event with a relationship present.  The only 
exception is if the subject has another occurrence of the same adverse event with a 
relationship assessment of "Reasonable Possibility."  In this case, the subject will be 
counted under the "Reasonable Possibility" category, respectively.
Incidence rates per 100 patient years of exposure to study drug will be presented for AE 
overviews and for AEs by SOC and preferred term where the number of events will be 
used as the numerator.
Years
Patient
Total
TEAEs
of
Number

100


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where total patient years is defined as the sum of the study drug exposure of all subjects, 
as defined in an earlier section, normalized by 365.25, and rounded to 1 decimal place.
Overview of treatment-emergent adverse events and treatment-emergent adverse events 
during the administration of ABT-494 grouped by System Organ Class and Preferred 
Term will also be summarized for the Any ABT-494 analysis set by quartile of average 
daily dose.
11.2.2
Adverse Events of Special Interest
The Adverse Events of Special Interests (AESI) categories will be summarized and 
presented for each treatment group using SMQ/CMQ/LMQ/Preferred Term.


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AESI
Type of
MedDRA
Query
Broad or 
Narrow 
Search
SMQ/CMQ/LMQ Search Criteria
Serious Infections
CMQ
"Infection" – Subset for SAEs
Opportunistic Infection
CMQ
"Opportunistic infection"
Herpes zoster
CMQ
"Herpes zoster"
Tuberculosis
CMQ
"Tuberculosis"
Malignancy
SMQ
Narrow
"Malignancies,"
Non-Melanoma Skin Cancer 
(NMSC)
SMQ
Broad
Skin Malignant tumours (Broad SMQ) 
removing Melanoma CMQ
Malignancy other than NMSC
SMQ
Narrow
Malignancy and removing NMSC 
output
Lymphoma
SMQ
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic disorders"
Intestinal Perforations
LMQ
Terms for/related to any part of GI 
Tract, GI Ulcers, obstruction, 
hemorrhage
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic 
anemias"
Adjudicated Cardiovascular 
Events
Output 
from CAC
Neutropenia
CMQ
"Hematological toxicity – Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia (Veliparib Product 
Specific)"
Renal dysfunction
SMQ
Narrow
"Acute renal failure"
Rhabdomyolysis/myopathy
SMQ
Narrow
"Rhabdomyolysis/Myopathy"
Creatine phosphokinase (CPK)
Elevation
Preferred 
Term
"blood creatine phosphokinase 
increased"
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.


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11.3
Analysis of Laboratory Data
Changes from Induction Baseline during Extension in continuous laboratory parameters 
will be summarized by n, mean, standard deviation, and median value value for each 
treatment group.  
Cross (Shift) tables from Induction Baseline to the final value according to the normal 
range will be provided for each hematology, clinical chemistry parameter and urinalysis 
parameter except for the microscopic examination.
For selected laboratory parameter with Common Toxicity Criteria (CTC) a listing of all 
subjects with any laboratory determinations meeting CTC Version 4.03 (or later) of 
Grade ≥ 3 will be provided.  For hemoglobin, an additional list will also be provided 
based on CTC Version 3.0 (or later) of Grade ≥ 2.  For each of these subjects, the whole 
course of the parameter will be listed.  For subjects with laboratory values with CTC ≥ 3, 
all of the laboratory parameters for those subjects will be listed.  For subjects with 
laboratory values with CTC 4, all of the laboratory parameters for those subjects will be 
listed.
For subjects who switched op open-label therapy, the above tables will also be presented 
by the open-label dose.
In addition, Cross (Shift) tables from Induction Baseline to the final value according to the 
normal range will be provided for each hematology, clinical chemistry parameter and 
urinalysis parameter except for the microscopic examination for the Any ABT-494 
analysis set by quartile of average daily dose.
11.3.1
Analysis of Liver Specific Laboratory Tests
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation" (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 


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elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by "as treated" treatment group:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
11.4
Analysis of Vital Signs and Weight
The following vital signs are measured at every visit during the study.
●
Body Weight (kg)
●
Blood Pressure (Systolic/Diastolic) (mmHg)
●
Pulse (bpm)
●
Temperature (°C)


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Changes from Induction Baseline in vital sign values will be summarized by n, mean, 
standard deviation, and median value for each treatment group.  
In additional, incidence of potential clinically significant results will be summarized.
Criteria for potentially clinically significant vital signs results:
Vital Sign
Category
Criteria for Potentially Clinically Significant Vital Sign
Systolic blood 
pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood
pressure
Low
Value ≤ 50 mmHg and decrease ≥ 15 mmHg from Baseline
High
Value ≥ 105 mmHg and increase ≥ 15 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
For subjects who switched op open-label therapy, the above tables will also be presented 
by the open-label dose.
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
The following efficacy variables are not mentioned in the protocol:
Modified Clinical Remission:  Average daily stool frequency ≤ 2.8 and not worse than 
baseline AND average daily abdominal pain ≤ 1.0 and not worse than Induction baseline.  
This endpoint will only be analyzed among subjects with baseline average daily stool 
frequency ≥ 4 or average daily abdominal pain ≥ 2.0.
Enhanced Clinical Response:  Average daily stool frequency at least 60% reduction from 
baseline and average daily abdominal pain not worse than baseline OR average daily 
abdominal pain at least 35% reduction from baseline and average daily stool frequency 
not worse than baseline.


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Enhanced Endoscopic Response:  SES-CD reduction from Induction baseline > 50% (or 
for a Baseline SES-CD of 4, at least a 2 point reduction from Baseline).
Endoscopic Improvement:  SES-CD reduction from Induction baseline > 50% or 
endoscopic remission.
Endoscopic Healing:  SES-CD ulcerated surface subscore of 0 in subjects with SES-CD 
ulcerated surface subscore ≥ 1 at Induction Baseline.
SES-CD ≤ 2
SES-CD = 0
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP
13.0
Appendix
14.0
References
1.
Devlin N, Shah K, Feng Y, et al.  Valuing health-related quality of life:  an EQ-5D-
5L value set for England, January 2016.  Available from:  
https://www.ohe.org/publications/valuing-health-related-quality-life-eq-5d-5l-
value-set-england or http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-
5d-5l-value-sets.html.


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1.0
Title Page
Statistical Analysis Plan for Induction Period
Study M13-740
A Multicenter, Randomized, Double-Blind,
Placebo-Controlled Study of ABT-494 for the 
Induction of Symptomatic and Endoscopic 
Remission in Subjects with Moderately to Severely 
Active Crohn's Disease who have Inadequately 
Responded to or are Intolerant to 
Immunomodulators or Anti-TNF Therapy
05 December 2016


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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................4
4.0
Study Objectives, Design and Procedures.............................4
4.1
Objectives ..................................................................................................4
4.2
Design Diagram .........................................................................................5
4.3
Sample Size..............................................................................................18
5.0
Analysis Populations .............................................................18
5.1
Definition for Analysis Populations.........................................................18
5.2
Variables Used for Stratification of Randomization................................19
6.0
Analysis Conventions ............................................................20
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............32
7.1
Demographic and Baseline Characteristics .............................................32
7.2
Medical History .......................................................................................34
7.3
Previous Treatment and Concomitant Medications.................................35
8.0
Patient Disposition.................................................................35
9.0
Study Drug Exposure and Compliance...............................35
10.0
Efficacy Analysis....................................................................36
10.1
General Considerations............................................................................36
10.2
Primary Efficacy Analyses.......................................................................37
10.3
Secondary Efficacy Analyses...................................................................39
10.4
Handling of Multiplicity ..........................................................................42
10.5
Efficacy Subgroup Analysis ....................................................................43
11.0
Safety Analysis.......................................................................43
11.1
General Considerations............................................................................43
11.2
Analysis of Adverse Events.....................................................................44
11.2.1
Treatment-Emergent Adverse Events ......................................................44
11.2.2
Adverse Events of Special Interest ..........................................................46
11.3
Analysis of Laboratory Data....................................................................47
11.3.1
Analysis of Liver Specific Laboratory Tests ...........................................48


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11.4
Analysis of Vital Signs and Weight.........................................................49
12.0
Summary of Changes ............................................................50
12.1
Summary of Changes Between the Latest Version of Protocol and 
the Current SAP .......................................................................................50
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP .....................................................................50
13.0
Appendix.................................................................................50
14.0
References...............................................................................50
List of Tables
Table 1.
Study Activities........................................................................................12
Table 2.
Visit Windows for Analysis of Efficacy Variables (Except 
SES-CD, IBDQ, WPAI, Abdominal Pain Rating Scale), 
Laboratory Parameters and Vital Signs for 16-Week Double-Blind 
Induction Period.......................................................................................21
Table 3.
Visit Windows for Analysis of IBDQ, EQ5D, and WPAI for 
16-Week Double-Blind Induction Period ................................................21
Table 4.
Visit Windows for Analysis of SES-CD and Abdominal Pain 
Rating Scale for 16-Week Double-Blind Induction Period .....................22
Table 5.
Visit Windows for Analysis of Fecal Calprotectin for 16-Week 
Double-Blind Induction Period................................................................22
Table 6.
An EQ-5D-5L Value Set for England......................................................31
List of Figures
Figure 1.
Study Design Schematic ............................................................................6
Figure 2.
Study Design Schematic for Open-Label Extension Option for 
Patients Who Do Not Adequately Respond During the Extension 
Phase ..........................................................................................................7


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analysis to be completed by 
the AbbVie Clinical Statistics Department for study Protocol M13-740 Amendment 4 
dated 15 April 2016.  It provides details to further elaborate statistical methods as outlined 
in the protocol and describes analysis conventions to guide the statistical programming 
work.
This is the first version of the SAP for Protocol M13-740.
This analysis plan describes the primary and secondary efficacy analyses as well as the 
safety analysis for the double-blind Induction Period.  The statistical analyses presented in 
this SAP represent the analyses for protocol Section 8.1.10 "Interim Analyses" and are the 
final analyses of the Induction Period of this study, and will be referred to as "Final 
Induction Analyses" thereafter in this SAP.
This document describes the analysis of data except pharmacokinetic, microbiota 
metagenomic, pharmacogenetic and serologic data which will be analyzed separately.  It 
takes into account ICH Guidelines E3 and E9.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The objective of this study is to determine the efficacy and safety of multiple doses of 
ABT-494 versus placebo and to assess the pharmacokinetics of ABT-494 following oral 
administration in subjects with moderately to severely active Crohn's disease with a 
history of inadequate response to or intolerance to immunomodulators or anti-TNF 
therapy.


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4.2
Design Diagram
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study 
designed to evaluate the efficacy, safety, and pharmacokinetics of ABT-494 as induction 
therapy in subjects with moderately to severely active Crohn's disease and evidence of 
mucosal inflammation defined by a SES-CD ≥ 6 (or ≥ 4 for subjects with disease limited 
to the ileum) and average daily soft/liquid stool frequency ≥ 2.5 or average daily 
abdominal pain score of ≥ 2.0; and CDAI ≥ 220 and ≤ 450, with a history of inadequate 
response or intolerance to immunomodulators and/or anti-TNF therapy.  The study will 
allow enrollment of up to 30% of subjects who were primary non responders to anti-TNF 
treatment.
The study is designed to enroll 210 subjects to meet scientific and regulatory objectives 
without enrolling an undue number of subjects in alignment with ethical considerations.  
Therefore, if the target numbers of subjects have been enrolled, there is a possibility that 
additional subjects in screening will not be enrolled.
The study duration could be up to 60 weeks, including a Screening Period of up to 
35 days, a 16-week double-blind induction period, a 36-week double-blind extension 
phase, and a 30-day follow-up period.  Subjects who meet eligibility criteria will be 
randomized in a 1:1:1:1:1:1 ratio to one of the double-blinded induction treatment arms.
The schematics of the overall study design are shown in Figure 1 and Figure 2.


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Figure 1.
Study Design Schematic


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Figure 2.
Study Design Schematic for Open-Label Extension Option for 
Patients Who Do Not Adequately Respond During the Extension 
Phase
Screening Period
Within 35 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and undergo the 
screening procedures as outlined in Table 1.
An e-diary will be dispensed and training will be provided to the subject at the Screening 
Visit.
Laboratory tests performed during the Screening period can be repeated in case the 
abnormalities are considered to be transient by the investigator.
16-Week Induction Period
This period will begin at the Baseline Visit (Week 0) and will end at the Week 16 Visit.  
At the Baseline Visit, subjects who meet all the inclusion criteria and none of the 
exclusion criteria described in the protocol (Section 5.2.1 and Section 5.2.2) will be 


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enrolled into the study and randomized to double-blind induction period.  The 
randomization at Baseline will be stratified by endoscopic disease severity (SES-CD < 15 
and ≥ 15), prior anti-TNF use (naïve and experienced), and by participation in the 
substudy of the gene expression in intestinal biopsies (Yes and No).  As part of the 
randomization at Baseline, subject will be randomly assigned (1:1) to have their follow-up 
ileocolonoscopy done at Week 12 or Week 16.  During this period of the study, subjects 
will visit the study site at Weeks 2, 4, 8, 12 and 16.  A ± 3-day window is permitted 
around scheduled study visits.  The last dose of study drug during this period is taken the 
evening prior to the Week 16 visit.
However, the stratification factor Prior anti-TNF use (naïve and experienced) was added 
under Amendment 3, and there are less than 10 anti-TNF naïve subjects enrolled under 
Amendment 3.  Therefore, the Prior anti-TNF use will not be included in all analysis as a 
stratification factor.
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects that end study participation early will have an Early Termination (ET) Visit and 
complete the procedures outlined for the ET Visit in Table 1 as soon as possible after the 
last dose of study drug and preferably prior to the administration of any new therapies.
36-Week Extension Phase
At Week 16, subjects who have completed the induction period will be re-randomized in a 
ratio of 1:1:1 to one of the three double-blinded doses of ABT-494 3 mg BID, 6 mg BID 
or 12 mg BID.  The re-randomization will be stratified by dose received during the 
first 16 weeks, and overall response (responder versus non-responder) at Week 16.  The 
subjects who were re-randomized at Week 16 to ABT-494 24 mg QD prior to Protocol 
Amendment 2 will continue to receive the same double-blind dose until Week 52/PD.
The central reader endoscopic score will be used for calculating the Endoscopic response 
for the evaluation of the efficacy endpoints.  However, for stratification at the time of 
re-randomization, the endoscopic score at BL from central reader and the endoscopic 


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score at Week 12 or Week 16 from site local reader will be used in order to determine 
response status. 
Clinical response is defined as average daily liquid/soft stool frequency reduction of at 
least 30% from Baseline and average daily abdominal pain not worse than Baseline OR 
average daily abdominal pain reduction at least 30% from baseline and average daily stool 
frequency not worse than Baseline.
During this period of the study, subjects will visit the study site at Weeks 20, 28, 36, 44, 
and 52/Early Termination.  A ± 3-day window is permitted around scheduled study visits.  
The last dose of study drug is taken the evening prior to the Week 52 visit.
Subjects will be expected to remain on double-blinded therapy throughout the entire 
36-week extension phase.  However, subjects who are considered by the investigator to 
have not achieved meaningful symptomatic relief and meet the criteria for inadequate 
response at or after Week 20 will be eligible to receive the open-label therapy with 
ABT-494 12 mg BID, Figure 2.  Subjects who were re-randomized at Week 16 prior to 
Protocol Amendment 2 and are taking open-label ABT-494 24 mg QD will be 
transitioned to ABT-494 12 mg BID.
Subjects who still continue to meet criteria for inadequate response following a 4-week 
course of open-label ABT-494 12 mg BID will be eligible to dose escalate to open-label 
ABT-494 24 mg BID.
Subjects with persistent inadequate response while on ABT-494 12 mg BID or 24 mg BID 
may be withdrawn from the study at the investigator's discretion.
Criteria for Inadequate response are as follows:
●
Average daily liquid/soft Stool Frequency > 2.2 OR average daily Abdominal 
Pain score > 1.8 AND
●
An increase level of hs-CRP of at least 1 mg/L from Baseline or a hs-CRP 
≥5 mg/L, either at the previous visit or at the current visit.


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Note:  hs-CRP will be performed by Central Lab.  However, for the purpose of evaluating 
Inadequate Response criteria, hs-CRP can also be done at local lab.
Assessment of inadequate response should include consideration by the Investigator to 
rule out symptoms caused by reasons other than Crohn's disease related inflammation.
In the open-label period, if the subject treated with 24 mg BID has an occurrence of an 
adverse event thought to be possibly related to study medication that in the opinion of the 
investigator warrants dose reduction, then the dose can be de-escalated to ABT-494 12 mg 
BID at the investigator's discretion.
Note:  Dose escalation and de-escalation are permitted only once during the study.
Subjects may discontinue study drug treatment at any time during study participation.  
Subjects that end study participation early will have an ET Visit and complete the 
procedures outlined for the ET Visit in Table 1 as soon as possible after the last dose of 
study drug and preferably prior to the administration of any new therapies.
Subjects who are not re-randomized at Week 16 or subjects who early terminated from the 
study will have a follow-up visit approximately 30 days after the last administration of 
study drug to obtain information on any new or ongoing adverse events (AEs), and to 
collect vital signs and clinical laboratory tests.
Follow-Up Period
Subjects who have completed the Week 52 visit will have a follow-up visit approximately 
30 days after the last administration of study drug to obtain information on any new or 
ongoing adverse events (AEs), and to collect vital signs and clinical laboratory tests.
Re-Screen
Subjects that initially screen fail for the study may be permitted to re-screen following 
re-consent.  The subject must meet all the inclusion and none of the exclusion criteria at 
the time of re-screening in order to qualify for the study.  There is no minimum period of 


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time a subject must wait to re-screen for the study.  If the subject had a complete initial 
screening evaluation including the assessment of a purified protein derivative (PPD) test 
(or equivalent), or Interferon-Gamma Release Assay (IGRA; QuantiFERON-TB Gold test 
or T-SPOT TB test), chest x-ray, HBV, HCV and ECG, these tests will not be required to 
be repeated for re-screening provided the conditions noted in the protocol 
(Section 5.3.1.1) are met and no more than 90 days have passed.
An endoscopy with biopsy will not be required to be repeated for re-screening provided 
the conditions noted in the protocol (Section 5.3.1.1) are met and no more than 30 days 
have passed (from the previous screening endoscopy).  All other screening procedures 
will be repeated.  As appropriate, sites are encouraged to contact the AbbVie Medical 
Monitor to confirm if subjects should or should not be re-screened.
Unscheduled Visits
Unscheduled Visits are for purposes when the subject is coming in for a medical visit for 
evaluation and assessment.  During Unscheduled Visits, blood and urine samples will be 
obtained for the laboratory tests listed in the protocol (Table 2).
Visits for dispensing new study drug in case of temperature excursion, loss or damage are 
not considered an Unscheduled Visit.  In addition, visits to only retest a lab will not be 
considered an Unscheduled Visit.


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Table 1.
Study Activities
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
Informed Consent
X
Inclusion/Exclusionb
X
X
Medical/Surgical 
Historyb
X
X
Prior and 
Concomitant 
Medicationsb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Endoscopyd
X
X
X
X
X
Biopsye
X
X
X
X
X
SES-CD
X
X
X
X
X
Vital Signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGg
X
Xv
Chest X-Rayh
X
Xv
PPD Skin Test or 
QuantiFERON TB 
Gold Testi
X
Latent TB Risk 
Factor Questionnaire
X
Blood Chemistry 
and Hematology
Xw
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
Urinalysisj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV and HCV 
Screeningl
X
ABT-494 
Concentrationm
X
X
X
X
X
X
X
X
X
X
X
Pharmacodynamic 
biomarkers
X
X
X
X
X
C. difficile toxin
X
Stool Sample (fecal 
calprotectin)n,o
X
X
X
X
X
X
Bristol Stool Chart
X
X
X
X
X
X
Corticosteroid Taperq
X
Crohn's Disease 
Activity Index (CDAI)
X
X
X
X
X
X
X
X
X
X
X
X
X
Inflammatory Bowel 
Disease Questionnaire 
(IBDQ)
X
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
European Quality of 
Life 5 Dimensions 
(EQ-5D)
X
X
X
X
X
Work Productivity 
and Impairment 
Questionnaire (WPAI)
X
X
X
X
X
Abdominal Pain 
Rating Scale 
(0 – 10 Scale)
X
X
X
Monitor Adverse 
Eventsr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Dispensing/
Administration
X
X
X
X
X
X
X
X
X
X
Dispense Subject 
Diary
X
Subject Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 1.
Study Activities (Continued)
Activity
Screeninga
Baseline 
(Week 0)
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
28
Wk 
36
Wk 
44
Wk 
52
Early 
Termination 
(ET) Visit
Unscheduled 
Visit
30-Day 
Follow-Up 
Visit
Additional Samples Collection (Optional)
Pharmacogenetics
X
Serologic markerst
X
X
mRNAt
X
X
Biopsy for gene 
expressionu
X
X
X
Wk = Week
a.
The Screening period will be a minimum of 7 days but no more than 35 days.  Baseline Visit date will serve as the reference for all subsequent visits.  A ± 3-day window is 
permitted around scheduled study visits.
b.
Update inclusion/exclusion, prior and concomitant therapy, and medical/surgical history information to assure subject eligibility.
c.
Physical examination performed at Screening, Baseline, Week 16 and Week 52/Early Termination Visits are full physical examinations which must include an assessment of 
extra-intestinal manifestations (EIMs) and a count of the number of cutaneous fistulas.  Physical examinations and those performed at all other visits are symptom based but 
must include a count of the number of cutaneous fistulas.
d.
Colonoscopy at/during the screening period or within 15 days of the Screening Visit will be used to calculate the SES-CD score at Baseline.  Subject will be randomly 
assigned at Baseline to have endoscopy performed at Week 12 or Week 16.
e.
Biopsy may be done when performing the endoscopy.  Biopsy to confirm CD diagnosis may be done when performing the endoscopy if appropriate documentation for 
confirmation of the diagnosis does not exist.  Biopsies to rule out dysplasia and colon cancer may be taken at the investigator's discretion.
f.
Blood pressure, pulse rate, temperature, respiratory rate and weight should be performed before blood draws are performed.  Height will be measured at Screening only (with 
shoes off and then adding 1 inch or 2.5 cm).
g.
Subjects with normal ECG within 90 days of Screening would not require a repeat ECG, if documentation is available.  Subjects can have a repeat ECG at any time during the 
study as warranted based on the opinion of the Investigator.


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Table 1.
Study Activities (Continued)
h.
Chest x-ray includes posterior-anterior (PA) and lateral views.  Obtain chest x-ray for subjects with TB risk factors as identified by the TB risk factor questionnaire or for 
subjects living in areas endemic for TB or for subjects with positive PPD or QuantiFERON-TB Gold.  Subjects can have a chest x-ray anytime during the study as warranted 
based on the opinion of the Investigator.
i.
PPD skin test is to be read 48 to 72 hours after placement.
j.
Dipstick urinalysis will be completed by the sites at all required visits.  A microscopic analysis will be performed by the central laboratory, in the event the dipstick results 
show protein, ketones or blood greater than negative or glucose greater than normal.
k.
Serum pregnancy test will be performed on all women of childbearing potential at Screening and at Week 52/ET.  Urine pregnancy test will be performed locally at every visit 
for all women of childbearing potential.  If any urine pregnancy test is positive, a serum pregnancy test will be performed by the central laboratory.
If required by country regulatory authorities, monthly pregnancy tests will be performed throughout the study.
l.
Subjects will be tested for the presence of the hepatitis B Virus (HBV) and hepatitis C Virus (HCV) at Screening.  A positive result for the hepatitis B surface antigen 
(HBs Ag) or hepatitis C (HCV RNA detectable in any subject with anti-HCV Ab) will be exclusionary.  For subjects who are negative for HBs Ag but are positive for core 
antibodies (HBc Ab), HBV DNA PCR will be performed and any result that meets or exceeds detection sensitivity will be exclusionary.
m.
For all subjects, a PK sample will be collected at Week 2, within 1 to 3 hours after dosing, if possible.  At Week 4, Week 8, Week 12, Week 16, Week 20, Week 28, Week 36, 
Week 44 and Week 52/ET, a blood sample for PK will be collected at any time during the visit, and preferably within 1 to 8 hours after the last dose.  Patients can take the 
dose on visit days at their regular schedule and not necessarily at the clinic.  The date and accurate time of the PK sample collection and the last ABT-494 dose will be 
recorded in the CRF to the nearest minute.
n.
Stool sample will be collected at each time point indicated.  For the visit that endoscopy will be conducted, stool sample should be collected prior to endoscopy.
o.
A stool sample will be collected for fecal calprotectin analysis at each time point indicated.  Subjects will be asked to provide a stool sample at the visit, if possible, or 
subjects will be sent home with instructions and stool sample supplies (supplies will be provided).
p.
Subject is mandated to begin corticosteroid taper at Week 2.
q.
Collection of SAEs begins the day the subject signs the informed consent.
r.
Only if subject provides written consent to collect the pharmacogenetic sample; if the informed consent form is not signed, no pharmacogenetic sample can be collected.  The 
sample is preferred to be collected at BL.


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Table 1.
Study Activities (Continued)
s.
Only if subject provides written consent to collect the serum biomarkers and mRNA samples; if the informed consent form is not signed, no serum biomarkers and mRNA can 
be collected.
t.
Only if subject provides written consent to collect biopsy samples for gene expression analysis; if the informed consent form is not signed, no biopsy for gene expression can 
be collected.  Biopsies will be obtained at baseline and as the Week 12/16 endoscopy, based on the colonoscopy assignment for Week 12 or 16.
u.
Optional tests, only if determined by the investigator and based on the medical assessment.
v.
Laboratory tests performed during the Screening period can be repeated in case the abnormalities are considered to be transient by the investigator.


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4.3
Sample Size
Approximately 210 subjects will be equally allocated to five treatment groups and the 
placebo group, representing a randomization ratio of 1:1:1:1:1:1.  The sample size for this 
study is based on the expected proportion of subjects who achieve endoscopic remission 
at Week 12/16 and on the expected proportion of subjects who achieve clinical remission 
at Week 16.  Assuming an endoscopic remission (as well as clinical remission) rate of 
12% in the placebo arm and maximum of 35% in at least one of the ABT-494 BID 
treatment arms (3 mg BID, 6 mg BID, 12 mg BID and 24 mg BID) at Week 12/16, a 
sample size of 35 subjects per treatment group is sufficient to test for the presence of a 
dose response signal, to select the best dose response model for the observed data out of a 
prespecified set of candidate models, and to estimate target doses of interest (e.g., the 
minimum effective dose, MED) via modeling using MCP-Mod (Multiple comparison 
procedure and modeling) approach.  This approach provides at least 80% average power 
to detect a dose effect at 5% level of significance (one-sided) with the linear, Emax, 
exponential, logistic, and sigEmax models pre-specified as likely candidates to 
characterize the dose-response for ABT-494 for the two co-primary endpoints of clinical 
and endoscopic remission.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
The following populations will be used for analyses in the study:
The modified intent-to-treat (MITT) analysis set includes all randomized subjects who 
have taken at least one dose of study drug in the double-blind induction period.  For the 
MITT analysis set, subjects are assigned to a treatment group based on the randomization 
schedule, regardless of the treatment actually received.  The MITT population will also be 
referred as "All Randomized and Treated Subjects."  The MITT analysis set will be used 
for all efficacy analysis for the double-blind induction period and baseline demographic 
and characteristics analyses.


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The safety analysis set consists of all subjects who received at least one dose of study 
medication.  For the safety analysis set, subjects are assigned to a treatment group based 
on the treatment actually received, regardless the treatment randomized.
5.2
Variables Used for Stratification of Randomization
At Baseline, subjects will be randomized in a 1:1:1:1:1:1 ratio to receive one of the
six treatment groups (double-blind ABT-494 induction doses or matching placebo).
The following are the treatment groups:
Group 1:  ABT-494 3 mg BID
Group 2:  ABT-494 6 mg BID
Group 3:  ABT-494 12 mg BID
Group 4:  ABT-494 24 mg BID
Group 5:  ABT-494 24 mg QD
Group 6:  Placebo
The randomization at Baseline will be stratified by endoscopic disease severity (SES-CD 
< 15 and ≥ 15), prior anti-TNF use (naïve and experienced), and by participation in the 
substudy of the gene expression in intestinal biopsies (Yes and No).  As part of the 
randomization at Baseline, subjects will be randomly assigned (1:1) to have their follow-
up ileocolonoscopy done at Week 12 or Week 16.
At Week 16, subjects who have completed the induction period will be re-randomized in a 
ratio of 1:1:1 to one of the three double-blinded doses of ABT-494 3 mg BID, 6 mg BID 
or 12 mg BID.  The re-randomization will be stratified by dose received during the 
first 16 weeks, and overall response (responder versus non-responder) at Week 16.  The 


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subjects who were re-randomized at Week 16 to ABT-494 24 mg QD prior to Protocol 
Amendment 2 will continue to receive the same double-blind dose until Week 52/PD.
Overall response consists of both Endoscopic response and Clinical response.  The central 
reader endoscopic score will be used for calculating the Endoscopic response for the 
evaluation of the efficacy endpoints.  However, for stratification re-randomization, the 
endoscopic score at baseline from central reader and the endoscopic score at Week 12 or 
Week 16 from site local reader will be used in order to determine response status.
6.0
Analysis Conventions
Definition of Baseline for Induction Period
The Baseline visit date for Induction Period is the date when the first dose of study drug is 
received and referred to as Day 1 or Week 0.  The Baseline value for a variable is defined 
as the last non-missing value on or before the date of the first dose of study drug.
Definition of Rx Days (Days Relative to the First Dose of Study Drug)
Rx Days are calculated for each time point of interest and it provides a quantitative 
measure of days between the event and the first dose date.  That is, the Rx Day is 
calculated as the event date minus the date of first dose of study drug plus 1.  The Rx Day 
will be a negative value when the time point of interest is prior to the date of first dose of 
study drug, and the Rx Day will be a positive value when the time point of interest is after 
the first dose date.  By this calculation algorithm the first dose day is Rx Day 1, while the 
day prior to the date of first dose is defined as Rx Day –1 (there is no Rx Day 0).  
Rx Days are used to map actual study visits to the protocol specified study visits.
Definition of Analysis Windows
Since subjects do not always adhere to the study visit schedule, the following rules will be 
applied to assign actual visits to protocol-specified visits including early termination 
visits.  For each study visit mentioned in the protocol, a nominal or target day will be 
selected to represent the corresponding visit along with a window around the target day.  


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Windows will be selected in a non-overlapping fashion so that a date collected on the 
CRF does not correspond to multiple visit windows.  Moreover, windows will not discard 
any Post-Baseline measurement recorded on the CRF.  If a subject had two or more actual 
visits in one visit window, the visit closest to the schedule visit will be used as the study 
visit for that window.  If two visits are equidistant from the target, then the later visit will 
be used for reporting.  If more than one assessment is collected on the same day, then the 
average of those assessments will be used in analyses.
Table 2.
Visit Windows for Analysis of Efficacy Variables (Except SES-CD, 
IBDQ, WPAI, Abdominal Pain Rating Scale), Laboratory 
Parameters and Vital Signs for 16-Week Double-Blind Induction 
Period
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 0
1a
≤ 1
Week 2
15
2 – 22
Week 4
29
23 – 43
Week 8
57
44 – 71
Week 12
85
72 – 99
Week 16
113
100 – 999b
Rx Day A = date of visit – date of first study drug in double-blind induction period + 1.
a.
Day of first dose of study drug in double-blind induction period.
b.
Rx Day 999 or first dose of extension period, whichever earlier.
Table 3.
Visit Windows for Analysis of IBDQ, EQ5D, and WPAI for 16-
Week Double-Blind Induction Period
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 0
1a
≤ 1
Week 8
57
2 – 85
Week 16
113
86 – 999b
Rx Day A = date of visit – date of first study drug in double-blind induction period + 1.
a.
Day of first dose of study drug in double-blind induction period.
b.
Rx Day 999 or first dose of extension period, whichever earlier.


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Table 4.
Visit Windows for Analysis of SES-CD and Abdominal Pain Rating 
Scale for 16-Week Double-Blind Induction Period
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 0
1a
≤ 1
Week 12
85
2 – 99
Week 16
113
100 – 999b
Rx Day A = date of visit – date of first study drug in double-blind induction period + 1.
a.
Day of first dose of study drug in double-blind induction period.
b.
Rx Day 999 or first dose of extension period, whichever earlier.
Table 5.
Visit Windows for Analysis of Fecal Calprotectin for 16-Week 
Double-Blind Induction Period
Scheduled Week
Nominal Day
Time Window
(Rx Day Range)
Week 0
1a
≤ 1
Week 4
29
2 – 71
Week 16
113
72 – 999b
Rx Day A = date of visit – date of first study drug in double-blind induction period + 1.
a.
Day of first dose of study drug in double-blind induction period.
b.
Rx Day 999 or first dose of extension period, whichever earlier.
CD-Related Corticosteroid Use
Subjects in whom the CD-related corticosteroids (systemic or rectal corticosteroids) that 
were not being taken at Baseline and are initiated during the study or who have equivalent 
dose of these medications increased to greater than the dose taken at Baseline will be 
censored for efficacy assessments (i.e., will be considered non-responders for categorical 
endpoints and will have Baseline values carried forward for non-categorical assessments) 
from that point through the end of the study.  These subjects will continue to be evaluated 
in the safety population.
The equivalent steroid dose will be determined based on the table below:


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Corticosteroid
Equivalent Dose (mg)
Cortisone
25
Hydrocortisone
20
Prednisone
5
Prednisolone
5
Triamcinolone
4.0
Methylprednisolone
4.0
Betamethasone
0.75
Dexamethasone
0.75
Budesonide
1
Beclomethasone
5
Beclometasone
5
Definition of Missing Data Imputation
The following imputation methods will be used to impute missing values in the efficacy 
analyses.  In addition, an observed case analysis will be performed.
Non-Responder Imputation (NRI)
The NRI approach is used for binary efficacy variables.  These variables can take values 
of 'Achieved' or 'Not Achieved' or may be missing for any reason including 
discontinuation from study.  According to the NRI imputation approach, all missing 
values will be considered as 'Not Achieved.'
Last Observation Carried Forward (LOCF)
For all variables (categorical variables and continuous variables), the following rules will 
be used for the LOCF approach:
1.
Baseline and Pre-Baseline values will not be used to impute the missing 
Post-Baseline values.


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2.
Missing values after Study Day 1 will be imputed using the latest non-missing 
values after Day 1 and prior to the missing value.  If there are no non-missing 
values after Baseline, then the LOCF value will be missing.
Observed Case (OC)
Observed case analysis will be performed such that missing values will not be imputed.
However, all observed values will be replaced by Baseline value once subjects received 
CD-related corticosteroid therapy.
Mixed-Effect Model Repeated Measure (MMRM)
The MMRM model will be used for continuous efficacy variables with longitudinal data 
as the primary analysis.  The MMRM model includes the baseline values as covariate; 
randomization strata, treatment, time point and treatment-by-time point interaction as 
fixed effects; and subjects within treatment as random effect.  An unstructured 
(co)variance structure will be used to model the within-subject error.  The comparison at a 
time point will be the contrast between treatments at that time point.  Satterthwaite's 
approximation will be used to estimate denominator degrees of freedom.
Imputation of Missing Dates
For Baseline, efficacy, and safety parameters, if the day and/or month are missing, the 
following conventions will be used to impute the missing dates:
●
01 for missing start day
●
End of month for missing end day
●
January 1st for missing start month
●
December 31st for missing end month
In case of partially missing AE start and stop dates, the dates will be imputed by 
comparing to first dose date of study medication so than the corresponding AEs will be 


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made treatment-emergent whenever possible.  If the start date of an AE is partially 
missing and the month is the same as the start date of a new therapy, the AE will be made 
treatment emergent to the new therapy.
In case of missing or partially missing study drug dosing dates, the dates will not be 
imputed.  Subjects will be treated as not receiving dose on that date.
Rule for CDAI Calculation
Up to 14 days of diary entries will be evaluated from the ePRO tool for the CDAI 
calculation for each visit.  The diary entries on the days the subjects receive endoscopy 
preparation medications, the day of endoscopy procedure, and 2 days after endoscopy 
procedure will be excluded.  For each CDAI subscore, the available scores from the most 
recent diary days (at least 4 days, up to 7 days) prior to actual day of the study visit will be 
summed, and then multiplied by the corresponding multiplier to get subtotal score.  If 
available diary entries are fewer than 7 days, the subtotal score will be calculated as 
(summed total available score/number of days) × 7 × corresponding multiplier.  The 
three subtotal scores that are based on ePRO (number of liquid/very soft stools, abdominal 
pain rating, and general well-being) will then be rounded to one decimal.  The final CDAI 
is rounded to a whole number.
If a subject has less than 4 days of diary data, the total CDAI score will not be calculated 
and will be considered missing.
Same rule will be applied to average daily stool frequency and average daily abdominal 
pain.
Bristol Stool Chart
Up to 14 days of diary entries will be evaluated from the ePRO tool for the Bristol Stool 
Chart calculation.  These assessments on the day of endoscopy procedure, the day before 
endoscopy procedure (due to preparation medications), and 2 days after endoscopy 
procedure are excluded.  The 7 most recent non-missing assessments will be used for the 


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analysis.  The Bristol Stool Chart is calculated as the number of days the subjects with 
Type 6 or Type 7 divided by the total number days with non-missing assessments, 
rounded to two decimal.
If a subject has less than 4 days of diary data, the Bristol Stool Chart will not be calculated 
and will be considered missing.
If a subject achieved reduction from Baseline ≥ 50%, this subject will be classified as 
Responder.
SES-CD Scoring
All colonoscopies shall be performed and recorded in video format.  To be eligible for the 
study, the screening colonoscopy may be performed during the Screening Period (or up to 
45 days before the Baseline visit if Amendment 2 is in place at the site).  Colonoscopies 
will also be performed at the Week 12 or 16 visit.  Investigators shall provide their SES-
CD score assessment on the SES-CD score sheet for the baseline and Week 12 or 16 
visits.  The investigator SES-CD scores are to be entered in the appropriate eCRF, 
however neither the Investigator's Baseline nor Week 12 or 16 SES-CD scores will be 
used for the study's efficacy analyses.
All videotaped colonoscopies will undergo central review.  One primary central reviewer 
will evaluate the videotaped colonoscopies and provide the SES-CD scores to Parexel.  A 
second central reviewer will adjudicate between the investigator's and the central 
reviewer's SES-CD scores if there is discrepancy (more than 10% difference) in total 
SES-CD score.  The adjudicator will select the final SES-CD score that he/she most 
agrees with from those provided by the investigator and the central reviewer, and this final 
SES-CD score will be entered into the study database and be used for the study's efficacy 
analyses.  If there is no discrepancy between the investigator and the central reviewer, that 
central reviewer's score will be entered into the study database and serve as the SES-CD 
score to be used for the study's efficacy analyses.


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If there is a missing SES-CD individual variable in the SES-CD score that serves as the 
SES-CD score for the study's efficacy analyses (for all variables except the "Presence of 
Narrowing" variable), the following imputation rules will be applied:
If the same individual variable is:
●
Missing at both Baseline and Week 12 or 16:  the missing value will be 
imputed as zero at both time points, and no change will be assumed.
●
Present at Week 12 or 16 but missing at Baseline:  the missing Baseline value 
will be imputed based on the value given at Week 12 or 16, and no change will 
be assumed.
●
Present at Baseline but missing at Week 12 or 16:  the missing Week 12 or 16 
value will be imputed based on the value given it at Baseline and no change 
will be assumed.
If there is a missing SES-CD "Presence of Narrowing" individual variable in the SES-CD 
score that serves as the SES-CD score for the study's efficacy analyses, the following 
imputation rules will be applied:
If the Presence of Narrowing individual variable is:
●
Missing at both Baseline and Week 12 or 16:  the missing Presence of 
Narrowing individual variable will be imputed as zero and no change will be 
assumed.
●
Present at Week 12 or 16 but missing at Baseline:  the missing Baseline value 
will be imputed based on the individual variable given at Week 12 or 16 and 
no change will be assumed.
However, if there is a Baseline individual variable (for any SES-CD subscore) 
for intestinal segments proximal to (above) the segment with the missing 
Presence of Narrowing individual variable, the maximum imputed value for 
the missing Presence of Narrowing individual variable will be 2.


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●
Present at Baseline but missing at Week 12 or 16:  the missing Week 12 or 16 
value will be imputed based on score given at Baseline and no change will be 
assumed.
However, if there is a Week 12 or 16 individual variable is present for 
intestinal segments proximal to (above) the segment with the missing Presence 
of Narrowing variable, the maximum imputed value for the missing Presence 
of Narrowing individual variable will be 2.
(Gastrointestinal anatomy places the ileum proximal to the right colon, which is proximal 
to the transverse colon, which is proximal to the sigmoid and left colon, which is proximal 
to the rectum.)
A sensitivity analysis (Worst Case Imputation) will be performed by imputing all missing 
Baseline individual variables as '0' and all missing Week 12 or 16 variables as '3' except 
the Week 12 or 16 Presence of Narrowing individual variable.  At Week 12 or 16, the 
worst values for Presence of Narrow individual variable will be 2 for Rectum, Sigmoid 
and Left Colon, Transverse Colon, and Right Colon, and 3 for Ileum.
If a subject only has Baseline SES-CD, and no post-Baseline SES-CD, all Baseline 
missing individual variables will be imputed as zero.
Isolated Ileal Crohn's Disease at Baseline
Isolated Ileal Crohn's disease at Baseline is defined as all individual variables for Rectum, 
Sigmoid and Left Colon, Transverse Colon, and Right Colon are zero at Baseline and 
subscore for ileal ≥ 4.  If any of the individual variables is missing or not zero, this subject 
is classified as Not Isolated Ileal Crohn's disease at Baseline.
Definition of Endoscopic Remission
SES-CD ≤ 4 and at least two point reduction versus Induction baseline and no subscore 
> 1 in any individual variable.


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Definition of Endoscopic Response
SES-CD at least 25% reduction from Induction baseline.
Definition of Clinical Remission
Average daily stool frequency ≤ 1.5 and not worse than baseline AND average daily 
abdominal pain ≤ 1.0 and not worse than Induction baseline.
Definition of Clinical Response
Average daily stool frequency at least 30% reduction from Induction baseline and average 
daily abdominal pain not worse than Induction baseline OR average daily abdominal pain 
at least 30% reduction from Induction baseline and average daily stool frequency not 
worse than Induction baseline.
Definition of Remission
Remission at Week 16 is defined as both Endoscopic remission at Week 12/16 AND 
Clinical remission at Week 16.
Definition of Response
Response at Week 16 is defined as both Endoscopic response at Week 12/16 AND 
Clinical response at Week 16.
Definition of Modified Clinical Remission
Average daily stool frequency ≤ 2.8 and not worse than baseline AND average daily 
abdominal pain ≤ 1.0 and not worse than Induction baseline.  This endpoint will only be 
analyzed among subjects with baseline average daily stool frequency ≥ 4 or average daily 
abdominal pain ≥ 2.0.
EuroQol-5D-5L (EQ-5D)
EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal.  


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The EQ-5D consists of 2 pages.  The first page measures 5 dimensions of the health status 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with 
5 levels per dimension (no problems, slight problems, moderate problems, severe 
problems, and unable corresponding to Level 1 to Level 5 respectively).  The second page 
is an EQ Visual Analogue Scale (EQ VAS).  EQ-5D health states, defined by the EQ-5D-
5L descriptive system on the first page, may be converted into a single index value.  The 
change from baseline of the index value and EQ VAS will be analyzed and reported.  UK 
scoring algorithm will be used (Table 6).


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Table 6.
An EQ-5D-5L Value Set for England
Central Estimate
Value for Health State 23245
Mobility
     No Problem
     Slight
     Moderate
     Severe
     Unable
0
0.051
0.063
0.212
0.275
0.051
Self-Care
     No Problem
     Slight
     Moderate
     Severe
     Unable
0
0.057
0.076
0.181
0.217
0.076
Usual Activities
     No Problem
     Slight
     Moderate
     Severe
     Unable
0
0.051
0.067
0.174
0.190
0.051
Pain/Discomfort
     No 
     Slight
     Moderate
     Severe
     Unable
0
0.060
0.075
0.276
0.341
0.276
Anxiety/Depression
     Not
     Slight
     Moderate
     Severe
     Unable
0
0.079
0.104
0.296
0.301
0.301
The value for health state 23245:
1 – 0.9675 × (sum of the subscores)
1 – 0.9675 × (0.051 + 0.076 + 0.051 
+ 0.276 + 0.301) = 0.270
The index value is 1 – 0.9675 × sum of 5 components based on central estimates.


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The minimum index value is – 0.281 (health state 55555), and the maximum index value 
is 1 (health state 11111).  (Reference:  Devlin N et al.  Valuing health-Related Quality of 
Life:  Ann EQ-5D-5L Value Set for England, January 2016 –
https://www.ohe.org/publications/valuing-health-related-quality-life-eq-5d-5l-value-set-
england or http://www.euroqol.org/about-eq-5d/valuation-of-eq-5d/eq-5d-5l-value-
sets.html).
If one of the 5 dimensions is missing, the EQ-5D index value will be missing.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
7.1
Demographic and Baseline Characteristics
For the subjects in MITT and safety analysis set, demographic information and Baseline 
values will be summarized by descriptive statistics.  Categorical data will be summarized 
by number and percent; and quantitative data will be presented by n, mean, standard 
deviation, minimum value, median, and maximum value.
In general, continuous variables will be analyzed using analysis of variance (using SAS 
procedure 'PROC GLM') with treatment group as factor.  Categorical variable will be 
analyzed using chi-square test or Fisher's exact test if ≥ 20% of the cells have expected 
cell count < 5.
The following demographic and Baseline values will be summarized.
Continuous Variables:
●
Age (years)
●
Body weight (kg)
●
Height (cm)
●
Body Mass Index (kg/m2)
●
Blood Pressure (systolic/diastolic) (mmHg)
●
Pulse (bpm)


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●
Temperature (°C)
●
CDAI
●
Average Daily Stool Frequency
●
Average Daily Abdominal Pain
●
Total SES-CD score
●
Crohn's Disease Duration (years)
●
hs-CRP mg/L
●
Fecal calprotectin
●
IBDQ score
●
WPAI and its components
●
EQ-5D
●
Abdominal Pain Rating Scale
●
Bristol Stool Chart Score
Categorical Variables:
●
Sex (male, female)
●
Race
●
Ethnicity
●
Age (< 40, 40 to < 65, 65 to < 75, ≥75)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
hs-CRP at Baseline (< 10 and ≥ 10 mg/L)
●
Baseline fecal calprotectin (≤ 250 µg/g, > 250 µg/g)
●
Crohn's disease severity (CDAI ≤ 300, > 300) at Baseline
●
Baseline SES-CD (< 15, ≥ 15)
●
Disease duration (≤ 3 years, > 3 years)
●
Tobacco use (user, ex-user, never used, unknown)
●
Alcohol use (drinker, ex-drinker, non-drinker, unknown)
●
Region (US, ex-US)


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7.2
Medical History
Medical and Surgical History:  A complete medical and surgical history (which includes 
CD-onset date), history of tobacco and alcohol use, and TB history will be obtained from 
each subject during the Screening period.  Medical history will be summarized using body 
system and condition/diagnosis by treatment group.  No statistical tests will be performed.
Chest X-Ray Results:  All subjects undergo a standard X-ray of chest (including a 
posteroanterior [PA] and lateral view) at Screening period.  Number and percent of 
subjects with presence or absence of finding for the previous TB infection, calcified 
granulomas, Pleural scarring/thickening, and other findings will be presented by treatment 
group.  No statistical tests will be performed.
TB Test Results:  Results of PPD skin test, QuantiFERON-TB Gold test at screening 
visit will be summarized.  Induration will be summarized descriptively using n, mean, 
standard deviation, minimum values, median, and maximum values.  The frequency 
distribution of induration ≥ 5 and < 5 will be provided.  QuantiFERON-TB tests will be 
described as positive or negative.  Indetermiante QuantiFERON-TB test results will be 
repeated.  If the second QuantiFERON-TB test is positive or indeterminate, the final 
assessment will be considered positive.  If the second QuantiFERON-TB test is negative, 
the final assessment will be considered negative.  No statistical tests will be performed. 
TB Prophylaxis:  History of use of TB Prophylaxis or initiation of TB prophylaxis will be 
summarized.
ECG Results:  ECG results at screening will be presented as frequency distribution 
showing results as Normal, Abnormal (Not clinically significant), Abnormal (Clinically 
significant) and Unable to evaluate/missing.  No statistical tests will be performed.


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7.3
Previous Treatment and Concomitant Medications
Based on generic medication names, these categories of medications used by subjects 
before and during the study will be summarized by number and percent for ITT and safety 
analysis sets for the treatment groups.  No statistical tests will be performed.
The number and percent of subjects using Crohn's disease specific medications (including 
corticosteroids, aminosalicylates, immunosuppressants [defined as azathioprine, 
6-mercaptopurine, or methotrexate], antibiotics) within past 90 days prior to the Baseline, 
and at the Baseline will be tabulated.  In addition, the number and percent of subjects 
using Crohn's disease specific immunosuppressants, and biologic therapies at any time 
prior to Baseline will be tabulated.
8.0
Patient Disposition
Subject disposition will be presented for subjects in the MITT and safety analysis sets 
using the following information by treatment group:
●
Number and percent of subjects in various analysis sets by treatment group and 
by investigator and/or site number
●
Number and percent of subjects completing double-blind induction period and 
discontinuing on or before Week 16 visit of induction period
●
Subject disposition including the number and percent of subjects who 
prematurely discontinued the double-blind induction period (on or before 
Week 16 of induction period) by primary reason and by any reason
Summary of protocol deviations will be provided.
9.0
Study Drug Exposure and Compliance
Study drug exposure and compliance will be summarized using the mean, standard 
deviation, minimum, median, and maximum.  Exposure to study drug will be summarized 
by treatment group.


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Compliance is defined as the number of capsules taken (i.e., the difference between the 
number of capsules dispensed and the number of capsules returned) divided by the 
number of capsules a subject is supposed to take each day times the length of time that the 
subject was in the Treatment Phase of the study (i.e., Final/Discontinuation Visit date 
during Treatment Phase – Day 1 [Baseline] Visit date +1).  Subjects with missing data for 
the number of capsules returned will be excluded from the summary.
10.0
Efficacy Analysis
10.1
General Considerations
All statistical tests will be two-sided with the significance level of 0.100.  Descriptive 
statistics will be provided.  These include the number of observations, mean, standard 
deviation, minimum, median, and maximum for continuous variables; and number and 
percent for discrete variables.  The analysis will be performed using SAS® (SAS Institute 
Inc., Cary, NC, USA).
Dose Response Modeling
Other than estimating the relative treatment effect of the investigational compound 
ABT-494 to placebo, one important goal of this Phase 2 study is to establish 
dose-response relationship to facilitate the dose selection for future Phase 3 trials.  
Multiple Comparison Procedure and dose-response Modeling (MCPMod) with a 
pre-defined group of candidates dose response curves will be tested against flat 
dose-response curve to best characterize the dose-response relationship.
Steps of MCPMod:
1.
Choose a candidate set of S models.
2.
Compute the optimum contrast for each model.
3.
Use contrast test to find the significant T models while preserving FWER 
(one-sided significant level of 0.05).


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4.
Use AIC criteria to find the most significant model from the significant T models 
found from Step 3.
5.
Use the model found from Step 4 to fit observed data from the study and make 
inference (e.g., to find Minimum Effective Dose (MED) or the dose achieving 
certain amount of maximum effect), or use all significant models to make inference 
about the weighted target dose of interest.
ADDPLAN or R will be used to evaluate different dose-response models and to make 
dose recommendation.
10.2
Primary Efficacy Analyses
This section provides the details of the primary efficacy analysis for the study.
Co-Primary Efficacy Variables:
●
Proportion of subjects who achieve endoscopic remission at Week 12/16.
●
Proportion of subjects who achieve clinical remission at Week 16.
Analysis Data Set for the Primary Efficacy Analysis:
The primary efficacy analysis will use the MITT analysis data set.
Imputation Method Used for the Primary Efficacy Analysis:
Missing average daily stool frequency or average daily abdominal pain at Week 16 or 
SES-CD at Week 12/16 will be imputed using the non-responder imputation (NRI) 
approach.
Statistical Method of the Primary Efficacy Analysis:
The dose-response relationships among the five ABT-494 treatment groups and placebo 
group will be characterized for the primary endpoints endoscopic remission at 
Week 12/16 and clinical remission at Week 16 using MCPMod approach.  The following 


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models will be considered:  linear, Emax, exponential, logistic, sigEmax, and quadratic.  
The MCPMod approach for trial analysis stage consists of two main steps:  MCP and 
Mod step.  The MCP step focuses on establishing evidence for a drug effect across the 
doses, i.e., detecting a statistically significant dose response signal for the clinical 
endpoint and patient population investigated in the study.  This step will typically be 
performed using an efficient test for trend, adjusting for the fact that multiple candidate 
dose response models are being considered.  If a statistically significant dose response 
signal has been established, one proceeds with determining a reference set of significant 
dose response models by discarding the non-significant models from the initial candidate 
set.
The response function will be the log odds (logit) of the proportion of subjects with 
endoscopic/clinical remission.  The fitted curve will be shown graphically with 
confidence intervals for each dose.  Estimates of the treatment differences in the response 
function and associated 95% confidences for each active dose against placebo will be 
calculated from the model.  These results will be back-transformed to give point estimates 
of the difference in proportions and associated 95% confidence intervals.
Sensitivity Analysis of the Primary Efficacy Variables
The following sensitivity analyses for the primary endpoint of endoscopic remission will 
be conducted:
●
A sensitivity analysis using observed cases, which excludes those subjects 
with missing post-baseline endoscopy, will also be done.
The following sensitivity analyses for the primary endpoint of clinical remission will be 
conducted:
●
An analysis of observed cases, which excludes those subjects with missing SF 
or AP data at scheduled assessment visits.
●
The primary analysis will be repeated using mixed-imputation.  Subjects who 
discontinue prior to Week 16 due to lack of efficacy or adverse events will be 


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considered as "not achieved" for the clinical remission.  Subjects who 
discontinue for other reasons will be categorized according to LOCF.
10.3
Secondary Efficacy Analyses
Secondary efficacy variables are divided into two groups.  The first group includes 
double-blind induction treatment period secondary endpoints.  Analyses for the first group 
of secondary endpoints will be performed using MITT analysis set.  The second group 
includes double-blind extension phase secondary endpoints.  Analyses for the 
second group of secondary endpoints will be performed using ITT-N and ITT-NR 
analysis sets.  This SAP is for Induction period only.
The secondary endpoints (Double-Blind Induction Treatment Period) include:
●
Proportion of subjects who achieve CDAI < 150 at Week 16.
●
Proportion of subjects with decrease in CDAI ≥ 70 points from Baseline at 
Week 16.
●
Proportion of subjects with decrease in CDAI ≥ 100 points from Baseline at 
Week 16.
●
Proportion of subjects who achieve clinical remission at Week 12.
●
Proportion of subjects who achieve remission at Week 16 (endoscopic 
remission at Week 12/16 and clinical remission at Week 16).
●
Proportion of subjects who achieve response at Week 16 (endoscopic response 
at Week 12/16 and clinical response at Week 16).
●
Proportion of subjects with endoscopic response at Week 12/16.
●
Proportion of subjects who achieve clinical response at Week 16.
●
Proportion of subjects with an average daily SF ≥2.5 AND average daily 
AP ≥2.0 at Baseline who achieve clinical remission at Week 16.
●
Proportion of subjects who steroid-free achieve CDAI < 150 at Week 16 
among subjects taking corticosteroids at Baseline.
●
Proportion of subjects who achieve steroid-free remission at Week 16 among 
subjects taking corticosteroids at Baseline.


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●
Proportion of subjects who achieve steroid-free clinical remission at Week 16 
among subjects taking corticosteroids at Baseline.
●
Proportion of subjects who achieve steroid-free endoscopic remission at 
Week 12/16 among subjects taking corticosteroids at Baseline.
●
Change from Baseline in fecal calprotectin level at Week 16.
●
Change from Baseline in fecal calprotectin level at Week 4.
●
Change from Baseline in hs-CRP at Week 16.
●
Change from Baseline in IBDQ at Week 16.
●
Change from Baseline in IBDQ at Week 8.
●
Proportion of subjects who achieve remission at Week 16 among subjects with 
isolated ileal Crohn's disease at Baseline.
●
Change from Baseline in abdominal pain rating scale at Week 12 and 
Week 16.
●
The proportion of subjects who achieve > 50% reduction from Baseline in 
SES-CD or endoscopic remission at Week 12/16.
●
The proportion of subjects who achieve modified clinical remission at 
Week 16 among subjects with an average daily SF ≥4.0 or average daily 
AP ≥2.0 at Baseline.
For categorical efficacy endpoints for Induction Period, the pairwise comparisons for the 
difference in proportions of subjects between treatment groups and placebo group will be 
analyzed using the CMH test adjusted for Crohn's disease severity (SES-CD < 15, ≥ 15) at 
Baseline.  Additionally, the CMH-based 95% confidence interval for the difference in 
proportions will be provided.  The 95% confidence interval for the difference in 
proportions within each Crohn's disease severity (SES-CD < 15, ≥ 15) at Baseline 
category will be calculated based on normal approximation.
The non-responder imputation will be used for subjects with missing data at the endpoint 
evaluated.  The last observation carried forward (LOCF) method will also be used as the 
sensitivity analyses for the secondary endpoints.


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In general, continuous secondary efficacy variables with repeated measurements will be 
analyzed using a Mixed Effect Repeated Measure (MMRM) model.  The mixed model 
includes the categorical fixed effects of treatment, Crohn's disease severity (SES-CD < 15, 
≥ 15) at Baseline, week and treatment-by-week interaction and the continuous fixed 
covariates of baseline measurement.  An unstructured variance-covariance matrix will be 
used.  If convergence is not achieved, other variance-covariance matrix will be explored 
until coverage.  The parameter estimations will be based on assumption of data being 
missing at random and using the method of restrictive maximum likelihood (REML).
Continuous secondary efficacy variables will also be analyzed using an Analysis of 
Covariance (ANCOVA) model including factors for treatment group and Crohn's disease 
severity (SES-CD < 15, ≥ 15) at Baseline, and Baseline values as a covariate.  The 
MMRM analysis is considered primary for inferential purposes.
The additional endpoints include:
●
Proportion of subjects who achieve clinical remission over time in Induction 
Period.
●
Proportion of subjects who achieve clinical response over time in Induction 
Period.
●
Proportion of subjects who achieve CDAI < 150 over time in Induction Period.
●
Proportion of subjects with decrease in CDAI ≥ 70 points from Induction 
Baseline over time in Induction Period.
●
Proportion of subjects with decrease in CDAI ≥ 100 points from Induction 
Baseline over time in Induction Period.
●
Proportion of subjects who are IBDQ responders (increase in IBDQ score ≥ 16 
points from Induction Baseline) over time in Induction Period.
●
Proportion of subjects with IBDQ score ≥ 170 over time in Induction Period.
●
Proportion of subjects who achieve steroid-free CDAI < 150 over time in 
Induction Period among subjects taking corticosteroids at Baseline.
●
Proportion of subjects who achieve steroid-free clinical remission over time in 
Induction Period among subjects taking corticosteroids at Baseline.


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●
Change from Induction Baseline in fecal calprotectin level over time in 
Induction Period.
●
Change from Induction Baseline in hs-CRP over time in Induction Period.
●
SES-CD endpoints without any missing individual variables.
●
The proportion of subjects with no anal fissures at Week 16 among subjects 
with anal fissures at Baseline.
●
The proportion of subjects with no draining fistulas at Week 16 among 
subjects with draining fistula at Baseline.
●
The proportion of subjects with no non-draining fistulas at Week 16 among 
subjects with non-draining fistula at Baseline.
●
The proportion of subjects with no any fistulas at Week 16 among subjects 
with any fistula at Baseline.
●
Change from Induction Baseline in Bristol Stool Chart at Week 4 and 
Week 16.
●
The proportion of subjects who achieve Bristol Stool Chart response at Week 4 
and Week 16.
●
Cross tabulation of Baseline and Week 16 in EIM.
●
The proportion of subjects who achieve modified clinical remission at over 
time in Induction Period among subjects with an average daily SF ≥4.0 or
average daily AP ≥2.0 at Baseline.
●
Change from Induction Baseline in EQ-5D over time in Induction Period.
●
Change from Induction Baseline in WPAI over time in Induction Period.
10.4
Handling of Multiplicity
The MCP step in MCPMod approach will typically be performed using an efficient test 
for trend, adjusting for the fact that multiple candidate dose response models are being 
considered.


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10.5
Efficacy Subgroup Analysis
The subgroups listed below will be used in subgroup analyses of the co-primary 
endpoints.
●
Sex (male, female)
●
Age (≤ median, > median)
●
Race (white, non-white)
●
Baseline fecal calprotectin (≤ median, > median)
●
Baseline fecal calprotectin (≤ 250 µg/g, > 250 µg/g)
●
Baseline corticosteroid use (yes, no)
●
Baseline immunosuppressant use (yes, no)
●
hs-CRP at Baseline (< 10 and ≥ 10 mg/L)
●
hs-CRP at Baseline (≤ median, > median)
●
Crohn's disease severity (CDAI ≤ 300, > 300) at Baseline
●
Baseline CDAI (≤ median, > median)
●
Baseline SES-CD (≤ median, > median)
●
Baseline SES-CD (< 15, ≥ 15)
●
Weight (≤ median, > median)
●
Baseline albumin (≤ median, > median)
●
Disease duration (≤ 3 years, > 3 years)
●
Disease duration (≤ median, > median)
●
Region (US, ex-US)
●
Prior anti-TNF status (prior anti-TNF, prior anti-TNF naïve)
11.0
Safety Analysis
11.1
General Considerations
Adverse events (AEs), laboratory data and vital signs are the primary safety parameters in 
this study.  All safety comparisons will be performed between treatment groups using the 


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safety analysis set.  The safety variable will be summarized by treatment according to the 
treatment a subject actually received.  The differences between treatment groups and 
placebo in safety parameters will be evaluated using two--sided tests at the significance 
level of 0.100.
11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent Adverse Events
Treatment-emergent AEs for double-blind Induction period are defined as events that 
begin or worsen either on or after the first dose of the study medication and within 
30 days after the last dose of the study medication for who subjects who discontinued 
study prior to double-blind Extension Period or up to the first dose of double-blind 
Extension Period for subjects who received at least a dose of study medication during 
double-blind extension period.  An overview of treatment-emergent AEs, including AEs 
of special interest such as adverse events leading to death and adverse events leading to 
early termination, AEs by Medical Dictionary for Drug Regulatory Activities (MedDRA 
version 18.1 or later) preferred term and system organ class, AEs by maximum 
relationship to study drug, and AEs by maximum severity will be summarized by number 
and percentage.  Treatment group differences (each ABT-494 dose group versus placebo 
group, as well as ABT-494 dose groups combined versus placebo group) in the overall 
incidence of treatment-emergent AEs will be assessed with Fisher's exact test for each 
preferred term for double-blind induction period.
Changes in laboratory data will be described using statistical characteristics and compared 
between treatment groups and placebo will be performed using a one-way Analysis of 
Variance (ANOVA).  In addition, shift tables and listings will be provided for abnormal 
values, whereby the normal range of the analyzing laboratory will be used.  Vital signs 
will be analyzed similarly.
The number and percent of subjects experiencing treatment-emergent adverse events will 
be summarized for the following adverse event categories.  Comparisons of the percent of 
subjects experiencing an adverse event between treatment groups and placebo will be 


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performed using Fisher's exact tests.  Only P values < 0.100 when rounded to three digits 
will be presented.
●
Any treatment-emergent adverse event.
●
Any treatment-emergent adverse event that was rated as possibly related to 
study drug by the investigator (Reasonable Possibility).
●
Any treatment-emergent severe adverse event.
●
Any treatment-emergent serious adverse event.
●
Any treatment-emergent adverse event leading to discontinuation of study 
drug.
●
Any treatment-emergent adverse event leading to death.
●
Any treatment-emergent adverse event of special interest.
Treatment-emergent adverse events will be summarized as follows:
●
Grouped by System Organ Class and Preferred Term.
●
A by-subject listing will be provided.
●
Grouped by System Organ Class, Preferred Term and Severity.
●
Grouped by System Organ Class, Preferred Term and Relationship to Study 
Drug.
●
Grouped by System Organ Class and Preferred Term with subject numbers.
In treatment-emergent AE tables, a subject who reports more than one treatment-emergent 
AE in different system organ classes will be counted only once in the overall total.  A 
subject who reports two or more different preferred terms which are in the same SOC will 
be counted only once in the SOC total.  A subject who reports more than one treatment 
AE with the same preferred term will be counted only once for that preferred term using 
the most extreme incident (i.e., most "severe" for the severity tables and most "related" for 
the relationship tables).
Adverse events will also be summarized by maximum severity.  If a subject has an 
adverse event with unknown severity, then the subject will be counted in the severity 


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category of "unknown," even if the subject has another occurrence of the same adverse 
event with a severity present.  The only exception is if the subject has another occurrence 
of the same adverse event with the most extreme severity – "Severe."  In this case, the 
subject will be counted under the "Severe" category.
Adverse events will also be summarized by maximum relationship to study, as assessed 
by the investigator.  If a subject has an adverse event with unknown relationship, then the 
subject will be counted in the relationship category of "unknown," even if the subject has 
another occurrence of the same adverse event with a relationship present.  The only 
exception is if the subject has another occurrence of the same adverse event with a 
relationship assessment of "Reasonable Possibility."  In this case, the subject will be 
counted under the "Reasonable Possibility" category, respectively.
Incidence rates per 100 patient years of exposure to study drug will be presented for AE 
overviews and for AEs by SOC and preferred term where the number of events will be 
used as the numerator.
11.2.2
Adverse Events of Special Interest
The Adverse Events of Special Interests (AESI) categories will be summarized and 
presented for each treatment group using SMQ/CMQ.


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AESI
Type of
MedDRA
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Infection
CMQ
"Infection"
Serious Infection
CMQ
"Infection" – Subset for SAEs
Opportunistic Infection
CMQ
"Opportunistic infection"
Herpes zoster
CMQ
"Herpes zoster"
Tuberculosis
CMQ
"Tuberculosis"
Malignancy
SMQ
Narrow
"Malignancies,"
"Malignant lymphomas"
Non-Melanoma Skin Cancer 
(NMSC)
SMQ
Narrow
"Skin neoplasms, malignant and 
unspecified"
Malignancy other than NMSC
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic disorders"
Gastrointestinal Perforations
SMQ
Narrow
"Gastrointestinal perforation"
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic 
anemias"
Adjudicated Cardiovascular 
Events
Output 
from CAC
Neutropenia
CMQ
"Hematological toxicity – Neutropenia"
Increased serum creatinine and 
renal dysfunction
SMQ
Narrow
"Acute renal failure"
Elevated creatine 
phosphokinase
SMQ
Narrow
"Rhabdomyolysis/myopathy"
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
11.3
Analysis of Laboratory Data
Changes from Baseline in continuous laboratory parameters will be summarized by n, 
mean, standard deviation, minimum value, median, and maximum value for each 
treatment group.  The mean change from Baseline will be compared between treatment 
groups at each time point using the ANOVA model with treatment as a factor.  The 
differences between treatment groups and placebo for mean changes from Baseline will 


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be summarized using the mean, standard error, 95% confidence interval, and P value for 
the between-group difference.
Cross (Shift) tables from Baseline to the final value according to the normal range will be 
provided for each hematology, clinical chemistry parameter and urinalysis parameter 
except for the microscopic examination.
For selected laboratory parameter with Common Toxicity Criteria (CTC) a listing of all 
subjects with any laboratory determinations meeting CTC Version 4.03 (or later) of 
Grade ≥ 3 will be provided.  For hemoglobin, an additional list will also be provided 
based on CTC Version 3.0 (or later) of Grade ≥ 2.  For each of these subjects, the whole 
course of the parameter will be listed.  For subjects with laboratory values with CTC ≥ 3, 
all of the laboratory parameters for those subjects will be listed.
11.3.1
Analysis of Liver Specific Laboratory Tests
The liver specific laboratory tests include the serum glutamic-pyruvic transaminase 
(ALT/SGPT), serum glutamic-oxaloacetic transaminase (AST/SGOT), alkaline 
phosphatase and total bilirubin.  Each of these laboratory values will be categorized as 
follows:
1.
< 1.5 ULN,
2.
≥ 1.5 × ULN TO < 3 × ULN,
3.
≥ 3 × ULN TO < 5 ULN,
4.
≥ 5 × ULN TO < 8 ULN, and
5.
≥ 8 × ULN,
where ULN is the upper normal limit.
Shift tables showing shift from Baseline to maximum and final values will be presented 
using these five categories.


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A listing of potentially clinically significant liver function laboratory values will be 
provided.  The listing will include all subjects who met any of the following 4 criteria:
1.
ALT ≥ 2.5 × ULN, or
2.
AST ≥ 2.5 × ULN, or
3.
Alkaline Phosphatase ≥ 2.5 × ULN, or
4.
Total Bilirubin ≥ 1.5 × ULN.
11.4
Analysis of Vital Signs and Weight
The following vital signs are measured at every visit during the study.
●
Body Weight (kg)
●
Blood Pressure (Systolic/Diastolic) (mmHg)
●
Pulse (bpm)
●
Temperature (°C)
Changes from Baseline in vital sign values will be summarized by n, mean, standard 
deviation, minimum value, median, and maximum value for each treatment group.  The 
mean change from Baseline will be compared between treatment groups at each time 
point using the ANOVA model with treatment as a factor.  Treatment group differences 
for mean changes from Baseline will be summarized using the mean, standard error, 95% 
confidence interval, and P-value for the between-group difference.
In additional, incidence of potential clinically significant results will be summarized.
Criteria for potentially clinically significant vital signs results:


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Vital Sign
Category
Criteria for Potentially Clinically Significant Vital Sign
Systolic blood 
pressure
Low
Value ≤ 90 mmHg and/or decrease ≥ 20 mmHg from Baseline
High
Value ≥ 180 mmHg and/or increase ≥ 20 mmHg from Baseline
Diastolic blood 
pressure
Low
Value ≤ 50 mmHg and/or decrease ≥ 15 mmHg from Baseline
High
Value ≥ 105 mmHg and/or increase ≥ 15 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and/or decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and/or increase ≥ 15 bpm from Baseline
12.0
Summary of Changes
12.1
Summary of Changes Between the Latest Version of 
Protocol and the Current SAP
12.2
Summary of Changes Between the Previous Version and the 
Current Version of the SAP
13.0
Appendix
14.0
References