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Clinical Trial Results:
A Double-Blind, Randomized, Placebo-Controlled, Dose Ranging Study to Evaluate the Efficacy and Safety of PF-04236921 in Subjects With Crohn’s Disease Who are Anti-TNF Inadequate Responders (ANDANTE)

Summary
EudraCT number	2010-023034-23
Trial protocol	IE HU GB GR DK DE BE IT CZ AT SE
Global end of trial date	26 Feb 2015

Results information
Results version number	v1(current)
This version publication date	10 Mar 2016
First version publication date	10 Mar 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

B0151003

ISRCTN number

US NCT number

NCT01287897

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc

Sponsor organisation address

235 E 42nd Street, New York, United States, 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer ClinicalTrials.gov Call Center, 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer ClinicalTrials.gov Call Center, 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

15 Jul 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Feb 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of this study were to demonstrate clinical activity of PF 04236921 that would induce a clinical response and remission in subjects with CD via the CDAI and to select dose(s) for future clinical studies.

Protection of trial subjects

A signed and dated informed consent was required before any protocol specific screening procedures were performed. The investigators explained the nature, purpose, and risks of the study to each subject. Each subject was informed that he/she could withdraw from the study at any time and for any reason. Each subject was given sufficient time to consider the implications of the study before deciding whether to participate. Subjects who chose to participate signed an informed consent document. An external independent data monitoring committee (DMC) consisting of external DMC physicians and statistician were established to review the safety of subjects on an ongoing basis including adverse event of special interest and to adjudicate any cases of abdominal or perineal abscess that occurred during the study

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Feb 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Scientific research, Safety

Long term follow-up duration

7 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Brazil: 9

Country: Number of subjects enrolled

Canada: 18

Country: Number of subjects enrolled

Israel: 13

Country: Number of subjects enrolled

New Zealand: 5

Country: Number of subjects enrolled

Switzerland: 7

Country: Number of subjects enrolled

United States: 80

Country: Number of subjects enrolled

United Kingdom: 6

Country: Number of subjects enrolled

Belgium: 17

Country: Number of subjects enrolled

Czech Republic: 9

Country: Number of subjects enrolled

Denmark: 14

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Hungary: 9

Country: Number of subjects enrolled

Ireland: 6

Country: Number of subjects enrolled

Italy: 23

Worldwide total number of subjects

247

EEA total number of subjects

108

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

240

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study included a 28-day screening period, an induction period (Week 0-12) and a 28-week follow-up period. Subjects who completed the induction treatment period could enter the follow-up period or an open-label extension study, B0151005. Subjects who discontinued treatment during the induction period could enter the follow-up period.

Screening details

A total of 250 subjects were randomized via Interactive Voice Response System (IVRS); of which, 247 received investigational product and 3 were randomized inadvertently and not dosed (2 did not meet entrance criteria and 1 did not consent properly and was not included in clinical database because the randomization page was not completed).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

The subjects, investigators, site personnel and sponsor personnel/designee who interacted with the investigators were blinded throughout the study (while others unblinded during follow up). An independent unblinded team performed the interim analysis.

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo administered subcutaneously (SC) in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo 0 mg was administered on Day 1 and Day 28

PF-04236921 10 milligram (mg)

Arm description

PF-04236921 10 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Arm type

Experimental

Investigational medicinal product name

PF-04236921

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PF-04236921 10 mg was administered subcutaneously (SC) on Day 1 and Day 28

PF-04236921 50 mg

Arm description

PF-04236921 50 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Arm type

Experimental

Investigational medicinal product name

PF-04236921

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PF-04236921 50 mg was administered on Day 1 and Day 28

PF-04236921 200 mg

Arm description

PF-04236921 200 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Arm type

Experimental

Investigational medicinal product name

PF-04236921

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

PF-04236921 200 mg was administered on Day 1 and Day 28

Number of subjects in period 1	Placebo	PF-04236921 10 milligram (mg)	PF-04236921 50 mg	PF-04236921 200 mg
Started	69	67	71	40
Treated	69	67	71	40
Completed treatment period	58 ^[1]	52 ^[2]	58 ^[3]	29 ^[4]
Completed follow-up period	3 ^[5]	8 ^[6]	3 ^[7]	4 ^[8]
Enrolled in B0151005	56 ^[9]	50 ^[10]	56 ^[11]	29 ^[12]
Completed	59	58	59	33
Not completed	10	9	12	7
Consent withdrawn by subject	1	5	3	2
Adverse event, non-fatal	5	3	6	4
Unspecified	1	-	1	-
Lost to follow-up	-	-	2	-
Lack of efficacy	2	-	-	-
Protocol deviation	1	1	-	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period” and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period” and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period” and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period” and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period”, and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period”, and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period”, and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period”, and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period” and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period” and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[11] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period” and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.
[12] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The number of subjects under “completed” and “not completed” adds up to the number under “treated”. The categories of “completed treatment period”, “completed follow-up period” and “enrolled in B0151005” are NOT mutually exclusive as some subjects are counted in more than 1 of these.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Placebo administered subcutaneously (SC) in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group title

PF-04236921 10 milligram (mg)

Reporting group description

PF-04236921 10 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group title

PF-04236921 50 mg

Reporting group description

PF-04236921 50 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group title

PF-04236921 200 mg

Reporting group description

PF-04236921 200 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group values	Placebo	PF-04236921 10 milligram (mg)	PF-04236921 50 mg	PF-04236921 200 mg	Total
Number of subjects	69	67	71	40	247
Age categorical
Units: Subjects
Adults (18-64 years)	68	66	69	37	240
From 65-84 years	1	1	2	3	7
Age Continuous \|
Units: Years
arithmetic mean (standard deviation)	38.4 ( 13.6 )	38.9 ( 12.9 )	38.9 ( 13.1 )	42.2 ( 13.2 )	-
Gender, Male/Female
Units: Participants
Female	38	34	44	25	141
Male	31	33	27	15	106

End points

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Reporting group title

Placebo

Reporting group description

Placebo administered subcutaneously (SC) in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group title

PF-04236921 10 milligram (mg)

Reporting group description

PF-04236921 10 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group title

PF-04236921 50 mg

Reporting group description

PF-04236921 50 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group title

PF-04236921 200 mg

Reporting group description

PF-04236921 200 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Primary: The CDAI-70 response rate at Week 8 in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

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End point title

The CDAI-70 response rate at Week 8 in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg ^[1]

End point description

Crohn’s Disease Activity Index (CDAI)-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of subjects with CDAI-70 response at Week 8 were compared between placebo and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score greater than or equal to (>=) 0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. Primary analysis: full analysis set (FAS, defined as all randomized subjects who received at least 1 dose of study treatment; 2 subjects [10 mg arm] excluded due to a quality issue) excluding 200 mg (halted prematurely before reaching the planned sample size and thus no longer powered at the planned level to test against placebo).

End point type

Primary

End point timeframe

Baseline and Week 8

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis.

End point values	Placebo	PF-04236921 10 milligram (mg)	PF-04236921 50 mg
Number of subjects analysed	69	65	71
Units: percentage of subjects
least squares mean (confidence interval 90%)	30.6 (18.7 to 45.9)	35 (21.6 to 51.1)	49.3 (34.1 to 64.7)

Comparison between 10 mg and placebo at Week 8

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

= 0.3406 ^[3]

Method

Generalized linear mixed model (GLMM)

Parameter type

Mean difference (final values)

Point estimate

4.3

Confidence interval

level

90%

sides

2-sided

lower limit

-13

upper limit

21.7

Variability estimate

Standard error of the mean

Dispersion value

10.5

Notes
[2] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.
[3] - Type I rate was controlled for the 2 time points (Week 8 and Week 12) at 0.05 (one sided).

Comparison between 50 mg and placebo at Week 8

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

= 0.0438 ^[5]

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

18.7

Confidence interval

level

90%

sides

2-sided

lower limit

0.7

upper limit

36.7

Variability estimate

Standard error of the mean

Dispersion value

Notes
[4] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.
[5] - Type I rate was controlled for the 2 time points (Week 8 and Week 12) at 0.05 (one sided).

Primary: The CDAI-70 response rate at Week 8 in subjects who received placebo and PF-04236921 200 mg

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End point title

The CDAI-70 response rate at Week 8 in subjects who received placebo and PF-04236921 200 mg ^[6]

End point description

CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of subjects with CDAI-70 response at Week 8 were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The analysis was performed on FAS subjects of the 200 mg and placebo arms, referred to as FAS 200 mg versus (vs) placebo. The 200 mg arm was halted before reaching the planned sample size of approximately 60 and was no longer powered at the planned level to test against placebo. Thus, the 200 mg vs placebo comparison is a sensitivity analysis.

End point type

Primary

End point timeframe

Baseline and Week 8

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis.

End point values	Placebo	PF-04236921 200 mg
Number of subjects analysed	58	29
Units: percentage of subjects
least squares mean (confidence interval 90%)	28.8 (15.4 to 47.4)	39 (19.3 to 63.1)

Comparison between 200 mg and placebo at Week 8

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 1, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.2258 ^[8]

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

10.2

Confidence interval

level

90%

sides

2-sided

lower limit

-12.1

upper limit

32.6

Variability estimate

Standard error of the mean

Dispersion value

13.6

Notes
[7] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.
[8] - Type I rate was controlled for the 2 time points (Week 8 and Week 12) at 0.05 (one sided).

Primary: The CDAI-70 response rate at Week 12 in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

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End point title

The CDAI-70 response rate at Week 12 in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg ^[9]

End point description

CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of subjects with CDAI-70 response at Week 12 were compared between placebo and and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. Primary analysis: FAS excluding 200 mg arm (halted prematurely before reaching the planned sample size and thus no longer powered at the planned level to test against placebo).

End point type

Primary

End point timeframe

Baseline and Week 12

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis.

End point values	Placebo	PF-04236921 10 milligram (mg)	PF-04236921 50 mg
Number of subjects analysed	69	65	71
Units: percentage of subjects
least squares mean (confidence interval 90%)	28.6 (17.1 to 43.7)	35.2 (21.8 to 51.5)	47.4 (32.1 to 63.1)

Comparison between 10 mg and placebo at Week 12

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

= 0.2627 ^[11]

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

6.7

Confidence interval

level

90%

sides

2-sided

lower limit

-10.6

upper limit

23.9

Variability estimate

Standard error of the mean

Dispersion value

10.5

Notes
[10] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.
[11] - Type I rate was controlled for the 2 time points (Week 8 and Week 12) at 0.05 (one sided).

Comparison between 50 mg and placebo at Week 12

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.0425 ^[13]

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

18.8

Confidence interval

level

90%

sides

2-sided

lower limit

0.8

upper limit

36.7

Variability estimate

Standard error of the mean

Dispersion value

10.9

Notes
[12] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.
[13] - Type I rate was controlled for the 2 time points (Week 8 and Week 12) at 0.05 (one sided).

Primary: The CDAI-70 response rate at Week 12 in subjects who received placebo and PF-04236921 200 mg

Top of page

End point title

The CDAI-70 response rate at Week 12 in subjects who received placebo and PF-04236921 200 mg ^[14]

End point description

CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of subjects with CDAI-70 response at Week 12 were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The analysis was performed on FAS 200 mg vs placebo. The 200 mg arm was halted before reaching the planned sample size of approximately 60 and was no longer powered at the planned level to test against placebo. Thus, the 200 mg vs placebo comparison is a sensitivity analysis.

End point type

Primary

End point timeframe

Baseline and Week 12

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis.

End point values	Placebo	PF-04236921 200 mg
Number of subjects analysed	69	40
Units: percentage of subjects
least squares mean (confidence interval 90%)	26.7 (14 to 44.9)	41.7 (21.2 to 65.6)

Comparison between 200 mg and placebo at Week 12

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 3, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

= 0.1362 ^[16]

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

15.1

Confidence interval

level

90%

sides

2-sided

lower limit

-7.5

upper limit

37.6

Variability estimate

Standard error of the mean

Dispersion value

13.7

Notes
[15] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.
[16] - Type I rate was controlled for the 2 time points (Week 8 and Week 12) at 0.05 (one sided).

Secondary: The CDAI-70 response rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

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End point title

The CDAI-70 response rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg ^[17]

End point description

CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of subjects with CDAI-70 response were compared between placebo and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The analysis was performed on the FAS excluding 200 mg arm (which was halted prematurely). "n" signifies the number of subjects with observed data of each arm at each time point.

End point type

Secondary

End point timeframe

Baseline and Weeks 2, 4, 6, and 10

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis.

End point values	Placebo	PF-04236921 10 milligram (mg)	PF-04236921 50 mg
Number of subjects analysed	69	65	71
Units: percentage of subjects
least squares mean (confidence interval 90%)
Week 2 (n=64, 63, 65)	12.3 (6.3 to 22.6)	19.4 (10.9 to 32.2)	18.1 (10.1 to 30.3)
Week 4 (n=66, 58, 59)	16.5 (9 to 28.2)	34.6 (21.7 to 50.3)	37 (23.8 to 52.5)
Week 6 (n=58, 53, 60)	21.1 (11.9 to 34.6)	35 (21.7 to 51.2)	46.2 (31.6 to 61.5)
Week 10 (n=54, 50, 51)	29.3 (17.5 to 44.7)	38.9 (24.4 to 55.5)	54 (37.8 to 69.3)

Comparison between 10 mg and placebo at Week 2

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.1527

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

7.1

Confidence interval

level

90%

sides

2-sided

lower limit

-4.3

upper limit

18.6

Variability estimate

Standard error of the mean

Dispersion value

Notes
[18] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 4

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[19]

P-value

= 0.0235

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

18.1

Confidence interval

level

90%

sides

2-sided

lower limit

3.1

upper limit

33.2

Variability estimate

Standard error of the mean

Dispersion value

9.1

Notes
[19] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placeboat Week 6

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

= 0.0792

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

13.9

Confidence interval

level

90%

sides

2-sided

lower limit

-2.3

upper limit

30.2

Variability estimate

Standard error of the mean

Dispersion value

9.9

Notes
[20] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 10

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

= 0.1909

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

9.6

Confidence interval

level

90%

sides

2-sided

lower limit

-8.4

upper limit

27.6

Variability estimate

Standard error of the mean

Dispersion value

Notes
[21] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 2

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

= 0.1981

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

5.8

Confidence interval

level

90%

sides

2-sided

lower limit

-5.4

upper limit

Variability estimate

Standard error of the mean

Dispersion value

6.8

Notes
[22] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 4

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.0132

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

20.6

Confidence interval

level

90%

sides

2-sided

lower limit

5.3

upper limit

35.8

Variability estimate

Standard error of the mean

Dispersion value

9.3

Notes
[23] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 6

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

= 0.0063

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

25.1

Confidence interval

level

90%

sides

2-sided

lower limit

8.6

upper limit

41.7

Variability estimate

Standard error of the mean

Dispersion value

10.1

Notes
[24] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 10

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

= 0.0138

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

24.7

Confidence interval

level

90%

sides

2-sided

lower limit

6.2

upper limit

43.1

Variability estimate

Standard error of the mean

Dispersion value

11.2

Notes
[25] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Secondary: The CDAI-70 response rate over time in subjects who received placebo and PF-04236921 200 mg

Top of page

End point title

The CDAI-70 response rate over time in subjects who received placebo and PF-04236921 200 mg ^[26]

End point description

CDAI-70 response was defined as a decrease in CDAI score of 70 or greater from baseline. The proportions of subjects with CDAI-70 response were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The analysis was performed on the FAS 200 mg vs placebo. The 200 mg arm was halted before reaching the planned sample size of approximately 60 subjects. "n" signifies the number of subjects with observed data of each arm at each time point.

End point type

Secondary

End point timeframe

Baseline and Weeks 2, 4, 6, and 10

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis.

End point values	Placebo	PF-04236921 200 mg
Number of subjects analysed	69	40
Units: percentage of subjects
least squares mean (confidence interval 90%)
Week 2 (n=64, 36)	11.2 (5 to 23.1)	26.5 (12.3 to 48.2)
Week 4 (n=66, 35)	15.2 (7.2 to 29.1)	24.6 (11.2 to 45.9)
Week 6 (n=58, 32)	19.5 (9.6 to 35.6)	27.2 (12.4 to 49.8)
Week 10 (n=54, 29)	27.2 (14.2 to 45.8)	46.3 (24.5 to 69.7)

Comparison between 200 mg and placebo at Week 2

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 5, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

= 0.0662

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

15.4

Confidence interval

level

90%

sides

2-sided

lower limit

-1.4

upper limit

32.1

Variability estimate

Standard error of the mean

Dispersion value

10.2

Notes
[27] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 4

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 5, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[28]

P-value

= 0.1708

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

9.5

Confidence interval

level

90%

sides

2-sided

lower limit

-6.9

upper limit

25.8

Variability estimate

Standard error of the mean

Dispersion value

Notes
[28] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 6

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 5, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

= 0.2416

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

7.8

Confidence interval

level

90%

sides

2-sided

lower limit

-10.5

upper limit

Variability estimate

Standard error of the mean

Dispersion value

11.1

Notes
[29] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 10

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 5, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[30]

P-value

= 0.088

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

19.1

Confidence interval

level

90%

sides

2-sided

lower limit

-4.1

upper limit

42.3

Variability estimate

Standard error of the mean

Dispersion value

14.1

Notes
[30] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Secondary: The CDAI remission rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Top of page

End point title

The CDAI remission rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg ^[31]

End point description

CDAI remission rate was defined as an absolute CDAI score less than (<) 150. The proportions of subjects with CDAI remission were compared between placebo and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The analysis was performed on the FAS excluding 200 mg arm (which was halted prematurely). "n" signifies the number of subjects with observed data of each arm at each time point.

End point type

Secondary

End point timeframe

Baseline and Weeks 2, 4, 6, 8, 10, and 12

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis.

End point values	Placebo	PF-04236921 10 milligram (mg)	PF-04236921 50 mg
Number of subjects analysed	69	65	71
Units: percentage of subjects
least squares mean (confidence interval 90%)
Week 2 (n=64, 63, 68)	1.6 (0.3 to 9.1)	3.6 (1 to 12.3)	9.6 (4.1 to 20.7)
Week 4 (n=66, 58, 62)	3.4 (0.9 to 11.6)	4.1 (1.1 to 13.6)	19.7 (10 to 35.1)
Week 6 (n=58, 53, 63)	8.5 (3.3 to 20.3)	7.3 (2.6 to 19.2)	23.4 (12.5 to 39.6)
Week 8 (n=58, 53, 58)	16.3 (7.6 to 31.7)	10.8 (4.4 to 24.4)	24.9 (13.3 to 41.7)
Week 10 (n=54, 50, 54)	13.1 (5.6 to 27.7)	19.9 (9.4 to 37.2)	30.9 (17.2 to 49.2)
Week 12 (n=57, 52, 57)	10.9 (4.5 to 24.1)	10.8 (4.4 to 24.5)	27.4 (14.9 to 44.9)

Comparison between 10 mg and placebo at Week 2

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[32]

P-value

= 0.261

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-3.2

upper limit

7.2

Variability estimate

Standard error of the mean

Dispersion value

3.2

Notes
[32] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 10 mg and placebo at Week 4

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

= 0.4291

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

0.7

Confidence interval

level

90%

sides

2-sided

lower limit

-5.6

upper limit

Variability estimate

Standard error of the mean

Dispersion value

3.8

Notes
[33] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 10 mg and placeboat Week 6

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[34]

P-value

= 0.5791

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

-1.2

Confidence interval

level

90%

sides

2-sided

lower limit

-11

upper limit

8.6

Variability estimate

Standard error of the mean

Dispersion value

Notes
[34] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 10 mg and placebo at Week 8

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.7544

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

-5.5

Confidence interval

level

90%

sides

2-sided

lower limit

-18.8

upper limit

7.7

Variability estimate

Standard error of the mean

Dispersion value

Notes
[35] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 10 mg and placebo at Week 10

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[36]

P-value

= 0.2308

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

6.8

Confidence interval

level

90%

sides

2-sided

lower limit

-8.3

upper limit

21.9

Variability estimate

Standard error of the mean

Dispersion value

9.2

Notes
[36] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 10 mg and placebo at Week 12

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

= 0.5038

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

-0.1

Confidence interval

level

90%

sides

2-sided

lower limit

-11.8

upper limit

11.7

Variability estimate

Standard error of the mean

Dispersion value

7.1

Notes
[37] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 50 mg and placebo at Week 2

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[38]

P-value

= 0.0498

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Dispersion value

4.9

Notes
[38] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 50 mg and placebo at Week 4

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

= 0.0155

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

16.3

Confidence interval

level

90%

sides

2-sided

lower limit

3.9

upper limit

28.7

Variability estimate

Standard error of the mean

Dispersion value

7.6

Notes
[39] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 50 mg and placeboat Week 6

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[40]

P-value

= 0.0399

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

14.9

Confidence interval

level

90%

sides

2-sided

lower limit

0.9

upper limit

28.9

Variability estimate

Standard error of the mean

Dispersion value

8.5

Notes
[40] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 50 mg and placebo at Week 8

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

= 0.1866

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

8.5

Confidence interval

level

90%

sides

2-sided

lower limit

-7.2

upper limit

24.3

Variability estimate

Standard error of the mean

Dispersion value

9.6

Notes
[41] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 50 mg and placebo at Week 10

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[42]

P-value

= 0.0415

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

17.8

Confidence interval

level

90%

sides

2-sided

lower limit

0.9

upper limit

34.7

Variability estimate

Standard error of the mean

Dispersion value

10.3

Notes
[42] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 50 mg and placebo at Week 12

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[43]

P-value

= 0.0408

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

16.5

Confidence interval

level

90%

sides

2-sided

lower limit

0.9

upper limit

32.1

Variability estimate

Standard error of the mean

Dispersion value

9.5

Notes
[43] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Secondary: The CDAI remission rate over time in subjects who received placebo and PF-04236921 200 mg

Top of page

End point title

The CDAI remission rate over time in subjects who received placebo and PF-04236921 200 mg ^[44]

End point description

CDAI remission rate was defined as an absolute CDAI score <150. The proportions of subjects with CDAI remission were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The analysis was performed on the FAS 200 mg vs placebo. The 200 mg arm was halted before reaching the planned sample size of approximately 60 subjects. "n" signifies the number of subjects with observed data of each arm at each time point.

End point type

Secondary

End point timeframe

Baseline and Weeks 2, 4, 6, 8, 10, and 12

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis.

End point values	Placebo	PF-04236921 200 mg
Number of subjects analysed	69	40
Units: percentage of subjects
least squares mean (confidence interval 90%)
Week 2 (n=64, 36)	1.1 (0.2 to 7.2)	6.9 (1.8 to 23.1)
Week 4 (n=66, 35)	2.4 (0.5 to 9.8)	5.1 (1.2 to 19.6)
Week 6 (n=58, 32)	6.1 (1.9 to 18.1)	8.8 (2.4 to 27.6)
Week 8 (n=58, 29)	11.9 (4.3 to 29.1)	8.8 (2.3 to 28.3)
Week 10 (n=54, 29)	9.4 (3.2 to 24.9)	14.8 (4.6 to 38.5)
Week 12 (n=57, 29)	7.8 (2.5 to 21.5)	11.8 (3.4 to 33.5)

Comparison between 200 mg and placebo at Week 2

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 7, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[45]

P-value

= 0.1342

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

5.8

Confidence interval

level

90%

sides

2-sided

lower limit

-2.8

upper limit

14.5

Variability estimate

Standard error of the mean

Dispersion value

5.3

Notes
[45] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 200 mg and placebo at Week 4

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 7, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[46]

P-value

= 0.2623

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

2.7

Confidence interval

level

90%

sides

2-sided

lower limit

-4.3

upper limit

9.8

Variability estimate

Standard error of the mean

Dispersion value

4.3

Notes
[46] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 200 mg and placeboat Week 6

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 7, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[47]

P-value

= 0.3324

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

2.7

Confidence interval

level

90%

sides

2-sided

lower limit

-7.7

upper limit

13.2

Variability estimate

Standard error of the mean

Dispersion value

6.3

Notes
[47] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 200 mg and placebo at Week 8

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 7, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[48]

P-value

= 0.6637

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

-3.2

Confidence interval

level

90%

sides

2-sided

lower limit

-15.5

upper limit

9.1

Variability estimate

Standard error of the mean

Dispersion value

7.5

Notes
[48] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 200 mg and placebo at Week 10

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 7, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

= 0.2721

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

5.4

Confidence interval

level

90%

sides

2-sided

lower limit

-9.3

upper limit

20.2

Variability estimate

Standard error of the mean

Dispersion value

Notes
[49] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Comparison between 200 mg and placebo at Week 12

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 7, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[50]

P-value

= 0.3022

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-8.8

upper limit

16.9

Variability estimate

Standard error of the mean

Dispersion value

7.8

Notes
[50] - Status of anti-TNF experience and concomitant immunosuppressant therapy were included as covariates.

Secondary: The CDAI-100 response rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Top of page

End point title

The CDAI-100 response rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg ^[51]

End point description

CDAI-100 response was defined as a decrease in CDAI score of 100 or greater from baseline. The proportions of subjects with CDAI-100 response at Week 12 were compared between placebo and PF-04236921 10 mg/50 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The analysis was performed on the FAS excluding 200 mg arm (which was halted prematurely). "n" signifies the number of subjects with observed data of each arm at each time point.

End point type

Secondary

End point timeframe

Baseline and Weeks 2, 4, 6, 8, 10, and 12

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis

End point values	Placebo	PF-04236921 10 milligram (mg)	PF-04236921 50 mg
Number of subjects analysed	69	65	71
Units: percentage of subjects
least squares mean (confidence interval 90%)
Week 2 (n=64, 63, 65)	12.4 (6.1 to 23.7)	16.7 (8.8 to 29.7)	12.6 (6.2 to 24)
Week 4 (n=66, 58, 59)	13 (6.5 to 24.4)	18.1 (9.5 to 31.9)	26.3 (15.1 to 41.8)
Week 6 (n=58, 53, 60)	14.5 (7.2 to 26.9)	28.7 (16.4 to 45.1)	32.2 (19.5 to 48.2)
Week 8 (n=58, 53, 56)	24.1 (13.4 to 39.3)	26.5 (14.9 to 42.6)	37.9 (23.7 to 54.5)
Week 10 (n=54, 50, 51)	21 (11.2 to 35.8)	29.8 (17 to 46.8)	38.2 (23.6 to 55.3)
Week 12 (n=57, 52, 54)	22.2 (12.1 to 37)	32.7 (19.2 to 49.7)	36.2 (22.2 to 52.9)

Comparison between 10 mg and placebo at Week 2

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[52]

P-value

= 0.2687

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

4.3

Confidence interval

level

90%

sides

2-sided

lower limit

-7.2

upper limit

15.8

Variability estimate

Standard error of the mean

Dispersion value

Notes
[52] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 4

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[53]

P-value

= 0.246

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

5.1

Confidence interval

level

90%

sides

2-sided

lower limit

-7.1

upper limit

17.3

Variability estimate

Standard error of the mean

Dispersion value

7.4

Notes
[53] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placeboat Week 6

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[54]

P-value

= 0.0633

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

14.2

Confidence interval

level

90%

sides

2-sided

lower limit

-1.1

upper limit

29.5

Variability estimate

Standard error of the mean

Dispersion value

9.3

Notes
[54] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 8

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[55]

P-value

= 0.4036

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

2.4

Confidence interval

level

90%

sides

2-sided

lower limit

-13.8

upper limit

18.6

Variability estimate

Standard error of the mean

Dispersion value

9.9

Notes
[55] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 10

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[56]

P-value

= 0.1921

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

8.9

Confidence interval

level

90%

sides

2-sided

lower limit

-7.9

upper limit

25.6

Variability estimate

Standard error of the mean

Dispersion value

10.2

Notes
[56] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 2

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[57]

P-value

= 0.4893

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

0.2

Confidence interval

level

90%

sides

2-sided

lower limit

-10.5

upper limit

10.9

Variability estimate

Standard error of the mean

Dispersion value

6.5

Notes
[57] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 12

Statistical analysis description

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[58]

P-value

= 0.1541

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

10.5

Confidence interval

level

90%

sides

2-sided

lower limit

-6.5

upper limit

27.5

Variability estimate

Standard error of the mean

Dispersion value

10.3

Notes
[58] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 4

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[59]

P-value

= 0.0619

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

13.2

Confidence interval

level

90%

sides

2-sided

lower limit

-0.9

upper limit

27.7

Variability estimate

Standard error of the mean

Dispersion value

8.6

Notes
[59] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placeboat Week 6

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[60]

P-value

= 0.029

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

17.7

Confidence interval

level

90%

sides

2-sided

lower limit

2.3

upper limit

33.1

Variability estimate

Standard error of the mean

Dispersion value

9.3

Notes
[60] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 8

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[61]

P-value

= 0.0988

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

13.8

Confidence interval

level

90%

sides

2-sided

lower limit

-3.8

upper limit

31.4

Variability estimate

Standard error of the mean

Dispersion value

10.7

Notes
[61] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 10

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[62]

P-value

= 0.0549

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

17.2

Confidence interval

level

90%

sides

2-sided

lower limit

-0.5

upper limit

Variability estimate

Standard error of the mean

Dispersion value

10.8

Notes
[62] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 12

Statistical analysis description

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[63]

P-value

= 0.092

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-3.3

upper limit

31.3

Variability estimate

Standard error of the mean

Dispersion value

10.5

Notes
[63] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Secondary: The CDAI-100 response rate over time in subjects who received placebo and PF-04236921 200 mg

Top of page

End point title

The CDAI-100 response rate over time in subjects who received placebo and PF-04236921 200 mg ^[64]

End point description

CDAI-100 response was defined as a decrease in CDAI score of 100 or greater from baseline. The proportions of subjects with CDAI-100 response at Week 12 were compared between placebo and PF-04236921 200 mg. CDAI is used to quantify the symptoms of patients with Crohn's Disease. CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit. Many clinical trials use the endpoint for response as a 70 or greater point decrease in CDAI and clinical remission is often defined as a CDAI score below 150. The analysis was performed on the FAS 200 mg vs placebo. The 200 mg arm was halted before reaching the planned sample size of approximately 60 subjects. "n" signifies the number of subjects with observed data of each arm at each time point.

End point type

Secondary

End point timeframe

Baseline and Weeks 2, 4, 6, 8, 10, and 12

Notes
[64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis

End point values	Placebo	PF-04236921 200 mg
Number of subjects analysed	69	40
Units: percentage of subjects
least squares mean (confidence interval 90%)
Week 2 (n=64, 36)	10.3 (4.4 to 22.6)	12 (4.5 to 28.6)
Week 4 (n=66, 35)	11 (4.7 to 23.5)	22.1 (9.5 to 43.5)
Week 6 (n=58, 32)	12.2 (5.3 to 25.8)	22.2 (9.3 to 44.2)
Week 8 (n=58, 29)	21.3 (10.3 to 39.1)	18.7 (7.3 to 40.2)
Week 10 (n=54, 29)	18.2 (8.4 to 34.9)	30.4 (13.6 to 54.8)
Week 12 (n=57, 29)	19.4 (9.2 to 36.5)	26.9 (11.6 to 50.6)

Comparison between 200 mg and placebo at Week 2

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 9, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[65]

P-value

= 0.4031

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

1.7

Confidence interval

level

90%

sides

2-sided

lower limit

-9.5

upper limit

12.9

Variability estimate

Standard error of the mean

Dispersion value

6.8

Notes
[65] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 4

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 9, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[66]

P-value

= 0.1219

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

11.1

Confidence interval

level

90%

sides

2-sided

lower limit

-4.6

upper limit

26.8

Variability estimate

Standard error of the mean

Dispersion value

9.6

Notes
[66] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placeboat Week 6

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 9, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[67]

P-value

= 0.16

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

9.9

Confidence interval

level

90%

sides

2-sided

lower limit

-6.5

upper limit

26.4

Variability estimate

Standard error of the mean

Dispersion value

Notes
[67] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 8

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 9, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[68]

P-value

= 0.6019

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

-2.7

Confidence interval

level

90%

sides

2-sided

lower limit

-19.5

upper limit

14.2

Variability estimate

Standard error of the mean

Dispersion value

10.3

Notes
[68] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 10

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 9, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[69]

P-value

= 0.1601

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

12.3

Confidence interval

level

90%

sides

2-sided

lower limit

-8

upper limit

32.5

Variability estimate

Standard error of the mean

Dispersion value

12.3

Notes
[69] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 12

Statistical analysis description

The Outcome included a Generalized linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference). Since the inputs in the model included different Analysis Population than in End Point 9, that will yield different estimates for placebo for the two different models.

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[70]

P-value

= 0.2622

Method

GLMM

Parameter type

Mean difference (final values)

Point estimate

7.4

Confidence interval

level

90%

sides

2-sided

lower limit

-11.8

upper limit

26.6

Variability estimate

Standard error of the mean

Dispersion value

11.7

Notes
[70] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Secondary: Change from baseline in CDAI score over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Top of page

End point title

Change from baseline in CDAI score over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg ^[71]

End point description

CDAI evaluates 8 Crohn's disease-related variables during a 1-week assessment period, yielding a composite score >=0 and without an upper limit, and higher score indicate more severe disease. The Outcome included a Linear mixed model analyses which incorporated longitudinal data for each subject, and the same model is used for estimate (least squares mean) and statistical analysis (mean difference).

End point type

Secondary

End point timeframe

Baseline and Weeks 2, 4, 6, 8, 10, and 12

Notes
[71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis

End point values	Placebo	PF-04236921 10 milligram (mg)	PF-04236921 50 mg
Number of subjects analysed	69	65	71
Units: points on a scale
least squares mean (confidence interval 90%)
Week 2 (n=64, 63, 65)	-18.9 (-38.3 to 0.6)	-28.4 (-47.6 to -9.3)	-16.2 (-34.5 to 2.2)
Week 4 (n=66, 58, 59)	-25.1 (-44.9 to -5.2)	-37.1 (-57 to -17.1)	-50.7 (-70 to -31.5)
Week 6 (n=58, 53, 60)	-32.6 (-55.5 to -9.6)	-48.5 (-71.7 to -25.3)	-54.9 (-77 to -32.9)
Week 8 (n=58, 53, 56)	-34.6 (-58.8 to -10.5)	-49.6 (-74.1 to -25)	-63.5 (-86.9 to -40)
Week 10 (n=54, 50, 51)	-19.8 (-45.9 to 6.4)	-50 (-76.6 to -23.4)	-64.7 (-90.3 to -39.1)
Week 12 (n=57, 52, 54)	-27.3 (-53.5 to -1.2)	-44.2 (-70.9 to -17.5)	-66.8 (-92.5 to -41.2)

Comparison between 10 mg and placebo at Week 2

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[72]

P-value

= 0.2173

Method

Linear mixed model (LMM)

Parameter type

Mean difference (final values)

Point estimate

-9.6

Confidence interval

level

90%

sides

2-sided

lower limit

-29.8

upper limit

10.6

Variability estimate

Standard error of the mean

Dispersion value

12.22

Notes
[72] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 4

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[73]

P-value

= 0.1778

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-12

Confidence interval

level

90%

sides

2-sided

lower limit

-33.4

upper limit

9.4

Variability estimate

Standard error of the mean

Dispersion value

12.95

Notes
[73] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placeboat Week 6

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[74]

P-value

= 0.1661

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-15.9

Confidence interval

level

90%

sides

2-sided

lower limit

-43

upper limit

11.2

Variability estimate

Standard error of the mean

Dispersion value

16.37

Notes
[74] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 8

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[75]

P-value

= 0.1993

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-14.9

Confidence interval

level

90%

sides

2-sided

lower limit

-44.1

upper limit

14.3

Variability estimate

Standard error of the mean

Dispersion value

17.66

Notes
[75] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 10

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[76]

P-value

= 0.0632

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-30.2

Confidence interval

level

90%

sides

2-sided

lower limit

-62.7

upper limit

2.3

Variability estimate

Standard error of the mean

Dispersion value

19.66

Notes
[76] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 10 mg and placebo at Week 12

Comparison groups

Placebo v PF-04236921 10 milligram (mg)

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other ^[77]

P-value

= 0.1975

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-16.8

Confidence interval

level

90%

sides

2-sided

lower limit

-49.4

upper limit

15.8

Variability estimate

Standard error of the mean

Dispersion value

19.71

Notes
[77] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 2

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[78]

P-value

= 0.5868

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

2.7

Confidence interval

level

90%

sides

2-sided

lower limit

-17.6

upper limit

22.9

Variability estimate

Standard error of the mean

Dispersion value

12.25

Notes
[78] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 4

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[79]

P-value

= 0.0243

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-25.7

Confidence interval

level

90%

sides

2-sided

lower limit

-47

upper limit

-4.3

Variability estimate

Standard error of the mean

Dispersion value

12.93

Notes
[79] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placeboat Week 6

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[80]

P-value

= 0.0834

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-22.4

Confidence interval

level

90%

sides

2-sided

lower limit

-49

upper limit

4.3

Variability estimate

Standard error of the mean

Dispersion value

16.12

Notes
[80] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 8

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[81]

P-value

= 0.0499

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-28.8

Confidence interval

level

90%

sides

2-sided

lower limit

-57.7

upper limit

Variability estimate

Standard error of the mean

Dispersion value

17.43

Notes
[81] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 10

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[82]

P-value

= 0.0111

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-44.9

Confidence interval

level

90%

sides

2-sided

lower limit

-77.1

upper limit

-12.7

Variability estimate

Standard error of the mean

Dispersion value

19.45

Notes
[82] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 50 mg and placebo at Week 12

Comparison groups

Placebo v PF-04236921 50 mg

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

other ^[83]

P-value

= 0.0221

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-39.5

Confidence interval

level

90%

sides

2-sided

lower limit

-71.7

upper limit

-7.3

Variability estimate

Standard error of the mean

Dispersion value

19.49

Notes
[83] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Secondary: Change from baseline in CDAI score over time in subjects who received placebo and PF-04236921 200 mg

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End point title

Change from baseline in CDAI score over time in subjects who received placebo and PF-04236921 200 mg ^[84]

End point description

End point type

Secondary

End point timeframe

Baseline and Weeks 2, 4, 6, 8, 10, and 12

Notes
[84] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As per planned analysis, for this end point, FAS population excluding the subjects in 200 mg group was used. Hence, the arm "PF-04236921 200 mg" was excluded from the analysis

End point values	Placebo	PF-04236921 200 mg
Number of subjects analysed	69	40
Units: points on a scale
least squares mean (confidence interval 90%)
Week 2 (n=64, 36)	-21.3 (-49.1 to 6.6)	-30.1 (-62.2 to 2.1)
Week 4 (n=66, 35)	-26.6 (-54.3 to 1.1)	-30.5 (-62.5 to 1.6)
Week 6 (n=58, 32)	-36.7 (-64.6 to -8.7)	-42.2 (-74.8 to -9.6)
Week 8 (n=58, 29)	-39.1 (-67.2 to -11)	-48.1 (-81.3 to -14.9)
Week 10 (n=54, 29)	-26.3 (-54.7 to 2.1)	-56.1 (-89.5 to -22.7)
Week 12 (n=57, 29)	-35.2 (-63.6 to -6.8)	-66.2 (-99.9 to -32.6)

Comparison between 200 mg and placebo at Week 2

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[85]

P-value

= 0.3157

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-8.8

Confidence interval

level

90%

sides

2-sided

lower limit

-39

upper limit

21.4

Variability estimate

Standard error of the mean

Dispersion value

18.27

Notes
[85] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 4

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[86]

P-value

= 0.4171

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-3.8

Confidence interval

level

90%

sides

2-sided

lower limit

-34

upper limit

26.4

Variability estimate

Standard error of the mean

Dispersion value

18.28

Notes
[86] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placeboat Week 6

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[87]

P-value

= 0.3837

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-5.6

Confidence interval

level

90%

sides

2-sided

lower limit

-36.6

upper limit

25.5

Variability estimate

Standard error of the mean

Dispersion value

18.79

Notes
[87] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 8

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[88]

P-value

= 0.3204

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-9

Confidence interval

level

90%

sides

2-sided

lower limit

-40.8

upper limit

22.8

Variability estimate

Standard error of the mean

Dispersion value

19.27

Notes
[88] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 10

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[89]

P-value

= 0.0649

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-29.9

Confidence interval

level

90%

sides

2-sided

lower limit

-62.3

upper limit

2.6

Variability estimate

Standard error of the mean

Dispersion value

19.64

Notes
[89] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Comparison between 200 mg and placebo at Week 12

Comparison groups

Placebo v PF-04236921 200 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other ^[90]

P-value

= 0.0598

Method

LMM

Parameter type

Mean difference (final values)

Point estimate

-31

Confidence interval

level

90%

sides

2-sided

lower limit

-63.9

upper limit

1.8

Variability estimate

Standard error of the mean

Dispersion value

19.87

Notes
[90] - Status of anti-TNF experience, concomitant immunosuppressant therapy, and baseline were included as covariates.

Secondary: Percentages of subjects with confirmed positive anti-drug antibodies (ADAs)

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End point title

Percentages of subjects with confirmed positive anti-drug antibodies (ADAs) ^[91]

End point description

The percentage of subjects with confirmed positive ADA was summarized for each treatment arm. ADA positive was defined as ADA titer (ie, the reciprocal of the highest dilution that gave a value equivalent to the cut point of the assay) >= 4.32. The SAS consisted of all subjects who received at least 1 dose of study drug. "n" signifies number of subjects with observed data at the time point of each arm. From Weeks 16 to 40, only subjects who remained in the follow-up period of this study and did not enter NCT01405196 were analyzed. "99999" signifies no subjects were analyzed at the time point in the treatment arm and therefore data was not available.

End point type

Secondary

End point timeframe

At baseline (Day 1) and at Weeks 4, 8, 12, 16, 24, 32 and 40

Notes
[91] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subjects in the placebo arm did not receive the study drug PF-04236921. Only subjects in the active treatment arms (PF-04236921) were analyzed for ADAs.

End point values	PF-04236921 10 milligram (mg)	PF-04236921 50 mg	PF-04236921 200 mg
Number of subjects analysed	67	71	40
Units: percentage of subjects
number (not applicable)
Day 1 (n=56, 66, 36)	0	0	0
Week 4 (n=58, 62, 29)	0	1.6	0
Week 8 (n=53, 53, 27)	0	0	0
Week 12 (n=46, 49, 24)	0	0	0
Week 16 (n=2, 1, 0)	0	0	99999
Week 24 (n=2, 1, 0)	0	0	99999
Week 32 (n=1, 0, 0)	0	99999	99999
Week 40 (n=2, 1, 0)	0	0	99999

No statistical analyses for this end point

Secondary: Percentages of subjects with confirmed positive neutralizing antibodies (NAbs)

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End point title

Percentages of subjects with confirmed positive neutralizing antibodies (NAbs) ^[92]

End point description

The percentage of subjects with confirmed positive NAbs was summarized for each treatment arm. Only ADA positive samples were analyzed for NAb. A multi-tiered approach was utilized to detect NAbs. NAb serum samples were screened at tier one, and those found presumptively NAb positive was further tested with the confirmatory assay (tier two). The percentage of subjects with confirmed positive NAbs was summarized for each treatment.

End point type

Secondary

End point timeframe

At baseline (Day 1) and at Weeks 4, 8, 12, 16, 24, 32 and 40

Notes
[92] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subjects in the placebo arm did not receive the study drug PF-04236921. Only subjects in the active treatment arms (PF-04236921) were analyzed for ADAs and only ADA positive samples were analyzed for NAbs.

End point values	PF-04236921 10 milligram (mg)	PF-04236921 50 mg	PF-04236921 200 mg
Number of subjects analysed	67	71	40
Units: percentage of subjects
number (not applicable)
Day 1 (n=56, 66, 36)	0	0	0
Week 4 (n=58, 62, 29)	0	1.6	0
Week 8 (n=53, 53, 27)	0	0	0
Week 12 (n=46, 49, 24)	0	0	0
Week 16 (n=2, 1, 0)	0	0	99999
Week 24 (n=2, 1, 0)	0	0	99999
Week 32 (n=1, 0, 0)	0	99999	99999
Week 40 (n=2, 1, 0)	0	0	99999

No statistical analyses for this end point

Secondary: Serum PF-04236921 concentration over time

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End point title

Serum PF-04236921 concentration over time ^[93]

End point description

The pharmacokinetic (PK) analysis set was the subset of subjects from the SAS who provided at least 1 PK concentration (2 subjects [10 mg arm] excluded due to a quality issue). "n" is the number of subjects with PK data at the visit. From Weeks 16 to 40, only subjects who remained in the follow-up period of this study were analyzed. "99999"=value not available, due to reasons including 1) arithmetic mean not available due to all samples were below the lower limit of quantification (<LLOQ) and thus no concentrations could be determined at the visit; 2) arithmetic mean was not available due to the number of subject analzyed was 0 at the visit; 3) Standard deviation was not calculable as there was only 1 subject.

End point type

Secondary

End point timeframe

Day 1 (predose), and at Weeks 2, 4 (Day 28, predose), 8, 10, 12, 16, 20, 24, 28, 32, 36, and 40

Notes
[93] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Subjects in the placebo arm did not receive the study drug PF-04236921. Only subjects in the active treatment arms (PF-04236921) were analyzed for serum PF 04236921 concentration.

End point values	PF-04236921 10 milligram (mg)	PF-04236921 50 mg	PF-04236921 200 mg
Number of subjects analysed	65	71	40
Units: nanogram per milliliter (ng/mL)
arithmetic mean (standard deviation)
Day 1 (n=54, 64, 37)	4.52 ( 33.2 )	2.05 ( 16.38 )	99999 ( 99999 )
Week 2 (n=46, 56, 30)	1060 ( 531.3 )	4580 ( 1938 )	21300 ( 9547 )
Week 4 (n=56, 63, 29)	674 ( 339.3 )	3180 ( 1555 )	14800 ( 6641 )
Week 6 (n=48, 57, 28)	1470 ( 863 )	6610 ( 2668 )	32200 ( 13240 )
Week 8 (n=51, 52, 28)	992 ( 501.7 )	4500 ( 1993 )	20200 ( 8683 )
Week 10 (n=47, 54, 29)	695 ( 428.5 )	3280 ( 1961 )	13600 ( 7350 )
Week 12 (n=43, 51, 26)	504 ( 435.5 )	2110 ( 1333 )	10900 ( 7802 )
Week 16 (n=2, 1, 0)	177 ( 250.3 )	1290 ( 99999 )	99999 ( 99999 )
Week 20 (n=2, 1, 0)	102 ( 143.5 )	425 ( 99999 )	99999 ( 99999 )
Week 24 (n=2, 1, 0)	63.5 ( 89.8 )	99999 ( 99999 )	99999 ( 99999 )
Week 28 (n=2, 0, 0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Week 32 (n=2, 0, 0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Week 36 (n=2, 1, 0)	99999 ( 99999 )	109 ( 99999 )	99999 ( 99999 )
Week 40 (n=2, 1, 0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Number of subjects who withdrew from the study due to treatment-emergent adverse events (AEs)

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End point title

Number of subjects who withdrew from the study due to treatment-emergent adverse events (AEs)

End point description

An AE was any untoward medical occurrence without regard to causality in a subject who received study drug. Treatment-emergent were events between first dose of treatment and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. The SAS consisted of all subjects who received at least 1 dose of study drug. "n" signifies number of subjects with observed data at the time point of each arm. From Weeks 16 to 40, only subjects who remained in the follow-up period of this study and did not enter NCT01405196 were analyzed.

End point type

Secondary

End point timeframe

Induction period: from Week 0 (Day 1) through Week 12; follow-up period: from Week 12 (or discontinuation from the induction period) through last subject visit (up to 28 weeks after completion of or discontinuation from the 12-week induction period)

End point values	Placebo	PF-04236921 10 milligram (mg)	PF-04236921 50 mg	PF-04236921 200 mg
Number of subjects analysed	69	67	71	40
Units: subjects
number (not applicable)
Induction period (Weeks 0 to 12)	7	6	6	8
Follow-up period (after Week 12)	0	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The reporting period was from the time of the first dose of study treatment through last subject visit up to 40 weeks post the first dose of study treatment for serious adverse events (SAEs) and non serious adverse events (AEs).

Adverse event reporting additional description

The same event may appear as both a non serious AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Placebo

Reporting group description

Placebo administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group title

PF-04236921 200 mg

Reporting group description

PF-04236921 200 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group title

PF-04236921 50 mg

Reporting group description

PF-04236921 50 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Reporting group title

PF-04236921 10 mg

Reporting group description

PF-04236921 10 mg administered SC in the anterolateral right and left thighs on Day 1 and Day 28. Each subject received 2 injections due to the double-dummy design of the study.

Serious adverse events	Placebo	PF-04236921 200 mg	PF-04236921 50 mg	PF-04236921 10 mg
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 69 (15.94%)	11 / 40 (27.50%)	12 / 71 (16.90%)	11 / 67 (16.42%)
number of deaths (all causes)	0	0	1	0
number of deaths resulting from adverse events	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	0 / 71 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Road traffic accident
subjects affected / exposed	1 / 69 (1.45%)	0 / 40 (0.00%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	0 / 71 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
VIIth nerve paralysis
subjects affected / exposed	1 / 69 (1.45%)	0 / 40 (0.00%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	0 / 71 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	0 / 71 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 69 (1.45%)	0 / 40 (0.00%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 69 (1.45%)	0 / 40 (0.00%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	0 / 71 (0.00%)	2 / 67 (2.99%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	2 / 71 (2.82%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 69 (1.45%)	0 / 40 (0.00%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Crohn’s disease
subjects affected / exposed	6 / 69 (8.70%)	4 / 40 (10.00%)	5 / 71 (7.04%)	6 / 67 (8.96%)
occurrences causally related to treatment / all	1 / 7	0 / 4	2 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileal fistula
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	0 / 71 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal stenosis
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	0 / 71 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	0 / 71 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fistula
subjects affected / exposed	1 / 69 (1.45%)	0 / 40 (0.00%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	1 / 69 (1.45%)	0 / 40 (0.00%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess intestinal
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	0 / 71 (0.00%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	2 / 71 (2.82%)	1 / 67 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal abscess
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 69 (1.45%)	0 / 40 (0.00%)	0 / 71 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Malnutrition
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	1 / 71 (1.41%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	PF-04236921 200 mg	PF-04236921 50 mg	PF-04236921 10 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	36 / 69 (52.17%)	20 / 40 (50.00%)	48 / 71 (67.61%)	38 / 67 (56.72%)
Nervous system disorders
Headache
subjects affected / exposed	6 / 69 (8.70%)	2 / 40 (5.00%)	9 / 71 (12.68%)	4 / 67 (5.97%)
occurrences all number	9	3	13	7
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 69 (5.80%)	2 / 40 (5.00%)	2 / 71 (2.82%)	1 / 67 (1.49%)
occurrences all number	4	2	2	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	4 / 71 (5.63%)	2 / 67 (2.99%)
occurrences all number	0	0	4	2
Pyrexia
subjects affected / exposed	7 / 69 (10.14%)	1 / 40 (2.50%)	5 / 71 (7.04%)	5 / 67 (7.46%)
occurrences all number	7	1	7	6
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	8 / 69 (11.59%)	6 / 40 (15.00%)	8 / 71 (11.27%)	6 / 67 (8.96%)
occurrences all number	8	7	8	6
Abdominal pain upper
subjects affected / exposed	0 / 69 (0.00%)	3 / 40 (7.50%)	1 / 71 (1.41%)	1 / 67 (1.49%)
occurrences all number	0	3	1	1
Crohn’s disease
subjects affected / exposed	4 / 69 (5.80%)	4 / 40 (10.00%)	7 / 71 (9.86%)	2 / 67 (2.99%)
occurrences all number	5	4	7	4
Nausea
subjects affected / exposed	1 / 69 (1.45%)	1 / 40 (2.50%)	7 / 71 (9.86%)	8 / 67 (11.94%)
occurrences all number	1	1	9	9
Proctalgia
subjects affected / exposed	0 / 69 (0.00%)	0 / 40 (0.00%)	5 / 71 (7.04%)	2 / 67 (2.99%)
occurrences all number	0	0	5	3
Vomiting
subjects affected / exposed	2 / 69 (2.90%)	2 / 40 (5.00%)	5 / 71 (7.04%)	4 / 67 (5.97%)
occurrences all number	2	2	6	4
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	0 / 69 (0.00%)	1 / 40 (2.50%)	5 / 71 (7.04%)	1 / 67 (1.49%)
occurrences all number	0	2	6	1
Rash
subjects affected / exposed	1 / 69 (1.45%)	1 / 40 (2.50%)	7 / 71 (9.86%)	3 / 67 (4.48%)
occurrences all number	1	1	9	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	8 / 69 (11.59%)	0 / 40 (0.00%)	5 / 71 (7.04%)	5 / 67 (7.46%)
occurrences all number	8	0	5	9
Back pain
subjects affected / exposed	4 / 69 (5.80%)	1 / 40 (2.50%)	3 / 71 (4.23%)	4 / 67 (5.97%)
occurrences all number	4	1	3	4
Pain in extremity
subjects affected / exposed	4 / 69 (5.80%)	1 / 40 (2.50%)	1 / 71 (1.41%)	2 / 67 (2.99%)
occurrences all number	4	1	1	2
Infections and infestations
Nasopharyngitis
subjects affected / exposed	3 / 69 (4.35%)	3 / 40 (7.50%)	8 / 71 (11.27%)	11 / 67 (16.42%)
occurrences all number	3	4	8	11
Upper respiratory tract infection
subjects affected / exposed	2 / 69 (2.90%)	0 / 40 (0.00%)	4 / 71 (5.63%)	0 / 67 (0.00%)
occurrences all number	2	0	4	0
Urinary tract infection
subjects affected / exposed	3 / 69 (4.35%)	5 / 40 (12.50%)	3 / 71 (4.23%)	4 / 67 (5.97%)
occurrences all number	3	8	3	4

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Were there any global substantial amendments to the protocol? Yes

03 Mar 2011

Amendment 1 occurred on 03 March 2011. Changes were made to Exclusion Criteria 3, 17, 21 and 22. Exclusion Criterion 3 was modified adding subjects with total colectomy with ileorectal anastomosis, multiple small bowel re-section resulting in malabsorption or the need for total parenteral nutrition. Exclusion Criterion 17 was modified to allow oral ibuprofen use to less than or equal to 800 mg/day as needed. Exclusion Criterion 21 was updated to include “experimental biologics”, that had or had not been indicated for Crohn’s disease (eg, vedolizumab, abatacept, etc), or received marketing approval during this study, unless the subject’s last dose was greater than or equal to 12 months at screening. Exclusion Criterion 22, modified to indicate that the prohibition of use of bismuth subsalicylate products was after signing the informed consent. In Section 9.4, language was added to allow for an early pharmacokinetics (PK) readout after 24 to 32 subjects (6 to 8 per treatment) had their Week 4 PK sample analyzed.

02 Feb 2012

Amendment 2 occurred on 02 February 2012. The duration of the study enrollment was changed from 12 to 21 months, the number of sites increased from 100 to approximately 160 and completion time for the study was changed to approximately 32 months versus 24 months. Inclusion Criterion 5 was revised requiring a 2-week stable dose prior to randomization for subjects on mesalamine, oral steroids and/or immunosuppressants. Exclusion Criterion 14, Clostridium difficile testing was updated to ensure sensitivity testing is completed per recent practice guidelines. Exclusion Criterion 21, added information that biologics do not include anti-tumor necrosis factors (anti-TNFs). The washout period for anti-TNFs was changed to 6 weeks from 30 days/5 half-lives (whichever was longer).

20 Sep 2012

Amendment 3 occurred on 20 September 2012, and incorporated the removal of the Prometheus inflammatory bowel disease (IBD) biomarker as an exploratory endpoint. Sample size determination was revised to accommodate the interim futility analysis. Clarification was provided on missing data imputation, and the description of the interim analysis plan was added as well as noting the external Data Monitoring Committee would review the results of the analysis. For the secondary pharmacodynamic (PD) objective, removed “mean” from change of baseline for PD markers to allow for flexibility (ie, median or mean percentage change). Added “genotype” to specify the type of thiopurine S-methyltransferase (TPMT) test. For approximate duration of study, enrollment was changed from 21 months to 30 months; and study completion was changed from approximately 32 months to 41 months due to enrollment extension. For Inclusion Criterion 7, added historical colonoscopy within 8 weeks prior to screening documenting ulceration and retrospectively completing the Simple Endoscopic Score for Crohn’s Disease (SES-CD) as acceptable. For Exclusion Criterion 2, clarified requirement for computed tomography (CT) or magnetic resonance (MR) enterography and added definition of active fistulae. Exclusion Criterion 27, newly added that “Subjects with known allergy or hypersensitivity to the investigational product or its components” were to be excluded.

27 Feb 2013

Amendment 4 occurred on 27 February 2013 to address the changes in tuberculosis (TB) testing as a result of a special safety concern that occurred in the B0151006 study investigating PF-04236921 for the indication of systemic lupus erythematosus (SLE). TB testing was also recommended for subjects undergoing certain steroid regimens. Baseline window was extended from 7 days to 10 days.

22 Aug 2013

Amendment 5 occurred on 22 August 2013 to stop further enrollment in the 200 mg dosing arm, as well as any further dosing in the 200 mg arm. The External Data Monitoring Committee (E-DMC) recommended that the 200 mg dose be halted in the B0151003 study as a precaution since there were safety concerns in the Lupus population utilizing the same compound at 200 mg. Statistical sections modified to reflect change in study design. Language was added throughout the protocol along with recommendations and instructions for how these subjects would be followed.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Enrollment into the 200 mg arm was halted on 14 August 2013 before reaching the planned sample size due to safety findings in NCT01405196. Hence the 200 mg vs placebo comparisons were excluded from the primary analyses and reported separately.

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Clinical trials

Clinical Trial Results: A Double-Blind, Randomized, Placebo-Controlled, Dose Ranging Study to Evaluate the Efficacy and Safety of PF-04236921 in Subjects With Crohn’s Disease Who are Anti-TNF Inadequate Responders (ANDANTE)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The CDAI-70 response rate at Week 8 in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Primary: The CDAI-70 response rate at Week 8 in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Primary: The CDAI-70 response rate at Week 8 in subjects who received placebo and PF-04236921 200 mg

Primary: The CDAI-70 response rate at Week 8 in subjects who received placebo and PF-04236921 200 mg

Primary: The CDAI-70 response rate at Week 12 in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Primary: The CDAI-70 response rate at Week 12 in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Primary: The CDAI-70 response rate at Week 12 in subjects who received placebo and PF-04236921 200 mg

Primary: The CDAI-70 response rate at Week 12 in subjects who received placebo and PF-04236921 200 mg

Secondary: The CDAI-70 response rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Secondary: The CDAI-70 response rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Secondary: The CDAI-70 response rate over time in subjects who received placebo and PF-04236921 200 mg

Secondary: The CDAI-70 response rate over time in subjects who received placebo and PF-04236921 200 mg

Secondary: The CDAI remission rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Secondary: The CDAI remission rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Secondary: The CDAI remission rate over time in subjects who received placebo and PF-04236921 200 mg

Secondary: The CDAI remission rate over time in subjects who received placebo and PF-04236921 200 mg

Secondary: The CDAI-100 response rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Secondary: The CDAI-100 response rate over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Secondary: The CDAI-100 response rate over time in subjects who received placebo and PF-04236921 200 mg

Secondary: The CDAI-100 response rate over time in subjects who received placebo and PF-04236921 200 mg

Secondary: Change from baseline in CDAI score over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Secondary: Change from baseline in CDAI score over time in subjects who received placebo, PF-04236921 10 mg and PF-04236921 50 mg

Secondary: Change from baseline in CDAI score over time in subjects who received placebo and PF-04236921 200 mg

Secondary: Change from baseline in CDAI score over time in subjects who received placebo and PF-04236921 200 mg

Secondary: Percentages of subjects with confirmed positive anti-drug antibodies (ADAs)

Secondary: Percentages of subjects with confirmed positive anti-drug antibodies (ADAs)

Secondary: Percentages of subjects with confirmed positive neutralizing antibodies (NAbs)

Secondary: Percentages of subjects with confirmed positive neutralizing antibodies (NAbs)

Secondary: Serum PF-04236921 concentration over time

Secondary: Serum PF-04236921 concentration over time

Secondary: Number of subjects who withdrew from the study due to treatment-emergent adverse events (AEs)

Secondary: Number of subjects who withdrew from the study due to treatment-emergent adverse events (AEs)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Double-Blind, Randomized, Placebo-Controlled, Dose Ranging Study to Evaluate the Efficacy and Safety of PF-04236921 in Subjects With Crohn’s Disease Who are Anti-TNF Inadequate Responders (ANDANTE)