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Clinical Trial Results:
A Phase 2, randomized, placebo-controlled, multicenter study to investigate the efficacy and safety of apremilast (CC-10004) for treatment of subjects with active ulcerative colitis.

Summary
EudraCT number	2014-002981-64
Trial protocol	CZ BG IT
Global end of trial date	03 Jun 2019

Results information
Results version number	v1(current)
This version publication date	13 Mar 2020
First version publication date	13 Mar 2020
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

CC-10004-UC-001

ISRCTN number

US NCT number

NCT02289417

WHO universal trial number (UTN)

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, United States, 07901

Public contact

Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@celgene.com

Scientific contact

Denesh Chitkara, Celgene Corporation, 01 908-897-5751, dchitkara@celgene.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

03 Jun 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Jun 2019

Was the trial ended prematurely?

Main objective of the trial

To evaluate the clinical efficacy of apremilast (30 mg twice daily [BID] and 40 mg BID), compared with placebo, in subjects with active ulcerative colitis (UC).

Protection of trial subjects

Patient Confidentiality, Informed Consent, Archiving of Essential Documents

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Jan 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

1 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 9

Country: Number of subjects enrolled

Bulgaria: 10

Country: Number of subjects enrolled

Canada: 3

Country: Number of subjects enrolled

Czech Republic: 6

Country: Number of subjects enrolled

France: 18

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Hungary: 3

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

Poland: 36

Country: Number of subjects enrolled

Russian Federation: 2

Country: Number of subjects enrolled

Ukraine: 13

Country: Number of subjects enrolled

United States: 41

Country: Number of subjects enrolled

New Zealand: 3

Worldwide total number of subjects

170

EEA total number of subjects

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)

158

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 61 sites in Australia (3 sites) and New Zealand (1 site); Bulgaria (6 sites), Czech Republic (2 sites), Hungary (3 sites), Poland (9 sites), Russia (1 site), and Ukraine (10 sites); Canada (2 sites) and United States (13 sites); and France (4 sites), Germany (1 site), Italy (4 sites), and the Netherlands (2 sites).

Screening details

A total of 170 participants were randomized in a 1:1:1 ratio and received apremilast (30 mg BID or 40 mg BID), or identically appearing placebo and stratified based on concomitant use of oral corticosteroids and previous exposure to immunosuppressants.

Period 1 title

Placebo-Controlled Phase Weeks 0-12

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Blinding implementation details

The blind was not to be broken during the study unless, in the opinion of the investigator, it was necessary to safely treat the subject. The decision to break the blind in emergency situations was the responsibility of the treating physician, which was not be delayed or refused by the sponsor. However, the investigator could contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the interest of the subject.

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants were randomized to identically matching placebo capsules and received placebo capsules by mouth (PO) twice a day (BID) for 12 weeks during the double-blind placebo-controlled phase.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Placebo capsules (identical in appearance to apremilast) BID.

Apremilast 30 mg

Arm description

Participants were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

Arm type

Experimental

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg capsules BID

Apremilast 40 mg

Arm description

Participants were randomized to 40 mg apremilast capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

Arm type

Experimental

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 40 mg capsules BID

Number of subjects in period 1	Placebo	Apremilast 30 mg	Apremilast 40 mg
Started	58	57	55
Completed	51	53	52
Not completed	7	4	3
Consent withdrawn by subject	1	3	2
Adverse event, non-fatal	3	-	1
Lost to follow-up	-	1	-
Lack of efficacy	3	-	-

Period 2 title

Active Treatment Phase Weeks 12-52

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

Are arms mutually exclusive

Yes

Placebo/Apremilast 30 mg

Arm description

Participants initially randomized to placebo capsules in the placebo-controlled period were re-randomized at week 12 to receive 30 mg apremilast capsules BID for 40 weeks during the active treatment phase.

Arm type

Experimental

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg capsules BID.

Placebo/Apremilast 40 mg

Arm description

Participants initially randomized to placebo in the placebo-controlled period were re-randomized at week 12 to receive 40 mg apremilast capsules BID for 40 weeks during the active treatment phase.

Arm type

Experimental

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 40 mg capsules BID.

Apremilast 30 mg/Apremilast 30 mg

Arm description

Participants were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase. At week 12, participants who achieved at least a 20% decrease from baseline in the total Mayo score (TMS) continued to receive 30 mg apremilast capsules BID for an additional 40 weeks during the active treatment phase.

Arm type

Experimental

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg capsules BID.

Apremilast 30 mg/ Apremilast 40 mg

Arm description

Participants initially randomized to 30 mg apremilast capsules BID in the placebo-controlled phase who did not achieve at least 20% decrease in the TMS were re-assigned to 40 mg apremilast capsules BID for 40 weeks during the active treatment phase.

Arm type

Experimental

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 40 mg capsules BID.

Apremilast 40 mg/Apremilast 40 mg

Arm description

Participants initially randomized to 40 mg apremilast capsules BID in the placebo-controlled phase continued to receive 40 mg apremilast capsules BID for an additional 40 weeks during the active treatment phase, regardless of achieving a 20% decrease in TMS or not.

Arm type

Experimental

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 40 mg capsules BID.

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 40 mg capsules BID.

Number of subjects in period 2	Placebo/Apremilast 30 mg	Placebo/Apremilast 40 mg	Apremilast 30 mg/Apremilast 30 mg	Apremilast 30 mg/ Apremilast 40 mg	Apremilast 40 mg/Apremilast 40 mg
Started	26	25	41	12	52
Completed	17	20	39	7	39
Not completed	9	5	2	5	13
Consent withdrawn by subject	-	1	-	1	1
Adverse event, non-fatal	2	2	1	1	4
Miscellaneous	1	-	-	-	1
Pregnancy	-	-	-	-	1
Lost to follow-up	-	-	-	-	1
Lack of efficacy	6	2	1	3	5

Period 3 title

Extension Phase Weeks 52-104

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Extension Phase: Apremilast 30 mg

Arm description

Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and receive 30 mg apremilast BID for an additional 52 weeks. This includes participants assigned to 30 mg apremilast BID at week 12, and participants who entered the extension phase after implementation of Protocol Amendment 4.

Arm type

Experimental

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg capsules BID

Extension Phase Apremilast 40 mg

Arm description

Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and receive 40 mg apremilast BID for an additional 52 weeks. This includes participants assigned to 30 mg apremilast BID at week 12. After implementation of Protocol Amendment 4 participants were switched to 30 mg apremilast BID for the remainder of the extension phase.

Arm type

Experimental

Investigational medicinal product name

Apremilast

Investigational medicinal product code

Other name

Otezla; CC-10004

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Apremilast 40 mg capsules BID

Number of subjects in period 3 ^[1]	Extension Phase: Apremilast 30 mg	Extension Phase Apremilast 40 mg
Started	45	54
Completed	38	48
Not completed	7	6
Consent withdrawn by subject	2	1
Adverse event, non-fatal	2	3
Miscellaneous	1	-
Lack of efficacy	2	2

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all subjects advanced to the next phase either by choice or due to disease.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Participants were randomized to identically matching placebo capsules and received placebo capsules by mouth (PO) twice a day (BID) for 12 weeks during the double-blind placebo-controlled phase.

Reporting group title

Apremilast 30 mg

Reporting group description

Participants were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

Reporting group title

Apremilast 40 mg

Reporting group description

Participants were randomized to 40 mg apremilast capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

Reporting group values	Placebo	Apremilast 30 mg	Apremilast 40 mg	Total
Number of subjects	58	57	55	170
Age categorical
Units: Subjects
Adults (18-64 years)	54	54	50	158
From 65-84 years	4	3	5	12
85 years and over	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	42.9 ( 14.04 )	40.1 ( 13.50 )	43.4 ( 14.92 )	-
Sex: Female, Male
Units: Participants
Female	25	18	21	64
Male	33	39	34	106
Race
Units: Subjects
Asian	0	0	1	1
White	54	52	45	151
Other	1	1	1	3
Not Reported or Collected	3	4	8	15
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	2	1	5	8
Not Hispanic or Latino	55	54	46	155
Unknown or Not Reported	1	2	4	7
Baseline Use of Oral Corticosteroids
Units: Subjects
Use of Baseline Corticosteroids	17	14	12	43
Non-Use of Corticosteroids	41	43	43	127
Previous Exposure to Immunosuppressants
Units: Subjects
Previous Exposure to Immunosuppressants	17	18	16	51
No Previous Exposure to Immunosuppressants	41	39	39	119
Duration of Ulcerative Colitis
Units: Years
arithmetic mean (standard deviation)	6.85 ( 7.043 )	6.15 ( 5.432 )	8.63 ( 10.278 )	-
Baseline Total Mayo Score (TMS)
The TMS is an instrument designed to measure disease activity of Ulcerative Colitis (UC). The Mayo score ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease: • Stool Frequency Subscore (SFS) • Rectal Bleeding Subscore (RBS) • Endoscopy Subscore • Physician’s Global Assessment (PGA)
Units: units on a scale
arithmetic mean (standard deviation)	8.2 ( 1.68 )	8.5 ( 1.62 )	8.1 ( 1.67 )	-
Modified Mayo Score (MMS)
The MMS was based on the stool frequency, rectal bleeding and endoscopy subscores of the total Mayo score, and excluded the Physician's Global subscore, since this was a global measure that is subjective in nature. The MMS range from 0 to 9 points with zero indicating no symptoms of active ulcerative colitis and 9 indicating the most severe symptoms.
Units: units on a scale
arithmetic mean (standard deviation)	6.1 ( 1.51 )	6.4 ( 1.48 )	6.0 ( 1.47 )	-
Partial Mayo Score (PMS)
The partial Mayo score is the sum of the rectal bleeding score, the stool frequency score and the physician's global assessment. The partial Mayo score range is from 0 to 9 points with zero indicating no symptoms of active ulcerative colitis and 9 indicating the most severe symptoms and assessment.
Units: units on a scale
arithmetic mean (standard deviation)	5.6 ( 1.46 )	5.8 ( 1.44 )	5.5 ( 1.57 )	-
Mayo Endoscopic Subscore (MES)
The Mayo endoscopy subscore findings are defined as: 0 = Normal or inactive disease 1 = Mild Disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions) 3 = Severe Disease (spontaneous bleeding, ulceration).
Units: units on a scale
arithmetic mean (standard deviation)	2.6 ( 0.49 )	2.7 ( 0.45 )	2.6 ( 0.49 )	-

End points

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Reporting group title

Placebo

Reporting group description

Participants were randomized to identically matching placebo capsules and received placebo capsules by mouth (PO) twice a day (BID) for 12 weeks during the double-blind placebo-controlled phase.

Reporting group title

Apremilast 30 mg

Reporting group description

Participants were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

Reporting group title

Apremilast 40 mg

Reporting group description

Participants were randomized to 40 mg apremilast capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

Reporting group title

Placebo/Apremilast 30 mg

Reporting group description

Reporting group title

Placebo/Apremilast 40 mg

Reporting group description

Participants initially randomized to placebo in the placebo-controlled period were re-randomized at week 12 to receive 40 mg apremilast capsules BID for 40 weeks during the active treatment phase.

Reporting group title

Apremilast 30 mg/Apremilast 30 mg

Reporting group description

Reporting group title

Apremilast 30 mg/ Apremilast 40 mg

Reporting group description

Reporting group title

Apremilast 40 mg/Apremilast 40 mg

Reporting group description

Reporting group title

Extension Phase: Apremilast 30 mg

Reporting group description

Reporting group title

Extension Phase Apremilast 40 mg

Reporting group description

Subject analysis set title

Apremilast 30 mg

Subject analysis set type

Safety analysis

Subject analysis set description

TEAEs during the apremilast 30 mg BID treatment for participants who received 30 mg apremilast capsules BID only and participants who initially received 30 mg apremilast capsules BID and switched to 40 mg apremilast capsules BID at Week 12, and participants who initially received placebo capsules BID and switched to 30 mg apremilast capsules BID at Week 12.

Subject analysis set title

Apremilast 40 mg

Subject analysis set type

Safety analysis

Subject analysis set description

TEAEs during the apremilast 40 mg BID treatment for participants who received 40 mg apremilast capsules BID only, and participants who initially received placebo BID and switched to 40 mg apremilast capsules BID at Week 12.

Subject analysis set title

Apremilast 30 mg/Apremilast 40 mg

Subject analysis set type

Safety analysis

Subject analysis set description

TEAEs during the apremilast 40 mg BID treatment for participants who initially received 30 mg apremilast BID and switched to 40 mg apremilast BID at Week 12.

Subject analysis set title

Extension Phase: Apremilast 30 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and received 30 mg apremilast BID for an additional 52 weeks. Includes participants assigned to 30 mg apremilast BID at week 12, and participants who entered the extension phase after implementation of Protocol Amendment 4.

Subject analysis set title

Extension Phase Apremilast 40 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who completed 52 weeks of treatment and had a Mayo endoscopy score ≤ 1 at week 52 were eligible to participate in the 52-week extension phase and received 40 mg apremilast BID for an additional 52 weeks. After implementation of Protocol Amendment 4 participants were switched to 30 mg apremilast BID for the remainder of the extension phase

Primary: Percentage of Participants who Achieved a Clinical Remission by Total Mayo Score (TMS) at Week 12

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End point title

Percentage of Participants who Achieved a Clinical Remission by Total Mayo Score (TMS) at Week 12

End point description

Clinical remission was defined as a total Mayo score ≤ 2 points, with no individual subscore exceeding 1 point. The TMS is an instrument designed to measure disease activity of UC. The Mayo score ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease. • Stool Frequency Subscore (SFS) • Rectal Bleeding Subscore (RBS) • Endoscopy Subscore • Physician’s Global Assessment (PGA). Two-sided 95% confidence intervals (CI) for the within-group proportions are based on the Wilson score method. The intent to treat (ITT) population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.

End point type

Primary

End point timeframe

Week 12

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: Percentage of Participants
number (confidence interval 95%)	12.1 (6.0 to 22.9)	31.6 (21.0 to 44.5)	21.8 (12.9 to 34.4)

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0142 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Differences in Percentages

Point estimate

19.2

Confidence interval

level

95%

sides

2-sided

lower limit

3.4

upper limit

33.6

Notes
[1] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[2] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 40 mg

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.2689 ^[4]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified

Point estimate

7.7

Confidence interval

level

95%

sides

2-sided

lower limit

-6.9

upper limit

22.9

Notes
[3] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method
[4] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Secondary: Percentage of Participants who Achieved a Clinical Response by Total Mayo Score and the Reduction in the Rectal Bleeding Subscore at Week 12

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End point title

Percentage of Participants who Achieved a Clinical Response by Total Mayo Score and the Reduction in the Rectal Bleeding Subscore at Week 12

End point description

Clinical response was defined as a decrease from baseline in the TMS of at least 3 points and at least 30%, along with a reduction in the rectal bleeding subscore (RBS) of at least 1 point or an absolute RBS of ≤ 1. The TMS is an instrument designed to measure disease activity of UC. The Mayo score ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higher scores indicating more severe disease. • Stool Frequency Subscore (SFS) • Rectal Bleeding Subscore • Endoscopy Subscore • Physician’s Global Assessment (PGA) Rectal bleeding (subscore 0-3) was defined as: 0 = No blood seen 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool 3 = Blood alone passes Two-sided 95% CI for the within-group proportions are based on the Wilson score method. The ITT population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.

End point type

Secondary

End point timeframe

Baseline to Week 12

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: Percentage of Participants
number (confidence interval 95%)	46.6 (34.3 to 59.2)	61.4 (48.4 to 72.9)	67.3 (54.1 to 78.2)

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

equivalence ^[5]

P-value

= 0.1224 ^[6]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

14.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.6

upper limit

31.5

Notes
[5] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[6] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 40 mg

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.0401 ^[8]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

19.4

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

Notes
[7] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[8] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Secondary: Percentage of Participants who Achieved an Endoscopic Remission at Week 12

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End point title

Percentage of Participants who Achieved an Endoscopic Remission at Week 12

End point description

An endoscopic remission was defined as a Mayo endoscopic subscore (MES) of 0 at Week 12. The MES subscore findings were defined as: 0 = Normal or inactive disease 1 = Mild Disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions) 3 = Severe Disease (spontaneous bleeding, ulceration) The endoscopy subscores consisted of findings that were centrally read through proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease. Two-sided 95% CIs for the within-group percentage were based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: Percentage of Participants
number (confidence interval 95%)	3.4 (1.0 to 11.7)	8.8 (3.8 to 18.9)	7.3 (2.9 to 17.3)

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.2472 ^[10]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

5.2

Confidence interval

level

95%

sides

2-sided

lower limit

-5.7

upper limit

16.7

Notes
[9] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[10] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 40 mg

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.4628 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.5

upper limit

14.6

Notes
[11] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[12] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Secondary: Percentage of Participants who Achieved an Endoscopic Response at Week 12

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End point title

Percentage of Participants who Achieved an Endoscopic Response at Week 12

End point description

An endoscopic response is defined as a decrease from baseline of at least 1 point in the MES at Week 12. The Mayo endoscopy subscore findings were defined as: 0 = Normal or inactive disease 1 = Mild Disease (erythema, decreased vascular pattern, mild friability) 2 = Moderate Disease (marked erythema, lack of vascular pattern, friability erosions) 3 = Severe Disease (spontaneous bleeding, ulceration). The endoscopy subscores consisted of findings that were centrally read through proctosigmoidoscopy, graded from 0 to 3 with higher scores indicating more severe disease. Two-sided 95% CIs for the within-group percentage were based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: Percentage of Participants
number (confidence interval 95%)	41.4 (29.6 to 54.2)	73.7 (61.0 to 83.4)	47.3 (34.7 to 60.2)

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.0005 ^[14]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

13.8

upper limit

47.4

Notes
[13] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[14] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 40 mg

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.6878 ^[16]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-14.4

upper limit

21.5

Notes
[15] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[16] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Secondary: Percentage of Participants Who Achieved a Rectal Bleeding Subscore (RBS) of ≤ 1 at Week 12

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End point title

Percentage of Participants Who Achieved a Rectal Bleeding Subscore (RBS) of ≤ 1 at Week 12

End point description

The RBS was measured as: 0 = No blood seen 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool most of the time 3 = Blood alone passes The daily bleeding score represents the most severe bleeding of the day. Two-sided 95% CI for the within-group proportions are based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: Percentage of Participants
number (confidence interval 95%)	72.4 (59.8 to 82.2)	84.2 (72.6 to 91.5)	87.3 (76.0 to 93.7)

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.1388 ^[18]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

11.5

Confidence interval

level

95%

sides

2-sided

lower limit

-4.1

upper limit

26.1

Notes
[17] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[18] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 40 mg

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.0788 ^[20]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

13.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

27.7

Notes
[19] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[20] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Secondary: Percentage of Participants Who Achieved Clinical Remission in the Modified Mayo Subscore (MMS) at Week 12

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End point title

Percentage of Participants Who Achieved Clinical Remission in the Modified Mayo Subscore (MMS) at Week 12

End point description

Clinical remission was defined as a modified Mayo score of ≤ 2, with no individual subscore > 1, at Week 12. The MMS was based on a modification of the total Mayo score (TMS) which included the stool frequency, rectal bleeding, and endoscopic subscores of the TMS and excluded the Physician's Global Assessment (PGA) subscore, since this was a global measure that is subjective in nature. The MMS ranges from 0 to 9 points with higher scores indicating greater disease severity. The endoscopy subscores was centrally reviewed. Two-sided confidence intervals for the within-group percentage were based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: Percentage of Participants
number (confidence interval 95%)	19.0 (10.9 to 30.9)	43.9 (31.8 to 56.7)	27.3 (17.3 to 40.2)

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.0046 ^[22]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

24.8

Confidence interval

level

95%

sides

2-sided

lower limit

7.5

upper limit

40.1

Notes
[21] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[22] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 40 mg

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.4476 ^[24]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-9.8

upper limit

21.6

Notes
[23] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[24] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Secondary: Percentage of Participants Who Achieved Clinical Response in the Modified Mayo Subscore (MMS) at Week 12

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End point title

Percentage of Participants Who Achieved Clinical Response in the Modified Mayo Subscore (MMS) at Week 12

End point description

Clinical response in the MMS was defined as a decrease from baseline in the MMS of at least 2 points and at least 25%, along with a reduction in the RBS of at least 1 point or an absolute RBS ≤ 1. The MMS was based on the stool frequency, rectal bleeding, and endoscopic subscores of the TMS and excluded the PGA subscore. The MMS ranges from 0 to 9 points with higher scores indicating greater disease severity. The RBS was measured as: 0 = No blood seen 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool most of the time 3 = Blood alone passes. The daily bleeding score represents the most severe bleeding of the day. The endoscopy subscores was centrally reviewed. Two-sided confidence intervals for the within-group percentage were based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: Percentage of Participants
number (confidence interval 95%)	46.6 (34.3 to 59.2)	63.2 (50.2 to 74.5)	67.3 (54.1 to 78.2)

Statistical Analysis 1

Statistical analysis description

Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0755 ^[25]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified difference in proportions

Point estimate

16.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

33.5

Notes
[25] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 40 mg

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.037 ^[27]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified difference in proportions

Point estimate

19.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.5

upper limit

36.4

Notes
[26] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[27] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Secondary: Percentage of Participants Who Achieved Clinical Remission in the Partial Mayo Subscore (PMS) With no Individual Subscore >1 at Week 8

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End point title

Percentage of Participants Who Achieved Clinical Remission in the Partial Mayo Subscore (PMS) With no Individual Subscore >1 at Week 8

End point description

Clinical remission in the partial Mayo subscore was defined as a PMS of 2 points or lower, with no individual subscore >1. The PMS is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 9 (severe disease) and is a composite of 3 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease). Two-sided 95% CI for the within-group proportions are based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.

End point type

Secondary

End point timeframe

Week 8

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: Percentage of Participants
number (confidence interval 95%)	32.8 (22.1 to 45.6)	47.4 (35.0 to 60.1)	52.7 (39.8 to 65.3)

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

P-value

= 0.1167 ^[29]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

14.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.3

upper limit

31.4

Notes
[28] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[29] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 40 mg

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

P-value

= 0.0534 ^[31]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

18.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

34.9

Notes
[30] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[31] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Secondary: Percentage of Participants Who Achieved Clinical Response in the Partial Mayo Subscore at Week 8

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End point title

Percentage of Participants Who Achieved Clinical Response in the Partial Mayo Subscore at Week 8

End point description

Clinical response in the PMS was defined as a decrease from baseline in PMS of at least 2 points and at least 25%, with an accompanying decrease in the RBS of at least 1 point or an absolute RBS of 0 or 1. The PMS score is a discrete ordinal scale ranging from 0 (normal or inactive disease) to 9 (severe disease) and is a composite of 3 subscores: Stool Frequency Subscore, Rectal Bleeding Subscore, and Physician's Global Assessment Subscore, each of which ranges from 0 (normal) to 3 (severe disease). Two-sided 95% CI for the within-group proportions are based on the Wilson score method. The intent to treat population included all participants who received at least one dose of IP. Participants with insufficient data for response determination were considered non-responders.

End point type

Secondary

End point timeframe

Week 8

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: Percentage of Participants
number (confidence interval 95%)	48.3 (35.9 to 60.8)	64.9 (51.9 to 76.0)	81.8 (69.7 to 89.8)

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

115

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

= 0.0758 ^[33]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

16.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

33.3

Notes
[32] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[33] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 40 mg

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

P-value

= 0.0004 ^[35]

Method

Cochran-Mantel-Haenszel

Parameter type

Stratified Difference

Point estimate

32.5

Confidence interval

level

95%

sides

2-sided

lower limit

14.9

upper limit

47.5

Notes
[34] - Stratified difference in percentages is the weighted average of the treatment differences across the strata with the CMH weights, with 2-sided 95% CI based on the stratified Newcombe method.
[35] - Stratification was based on baseline use of PO corticosteroids and previously used immunosuppressants (yes/no).

Secondary: The Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) During the Placebo-Controlled Phase

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End point title

The Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) During the Placebo-Controlled Phase

End point description

A TEAE was defined as any adverse event (AE) occurring or worsening on or after the first treatment of apremilast and up to 28 days after the last apremilast dose or the last follow-up date, whichever occurred earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = asymptomatic or mild symptoms; clinical or diagnostic observations only; Moderate = Symptoms cause moderate discomfort; Severe (could be non-serious or serious) = symptoms causing severe discomfort/pain. Safety population included all participants who were enrolled and received at least 1 dose of IP.

End point type

Secondary

End point timeframe

From the first dose of investigational product (IP) and no later than 28 days after the last dose of IP for those who had completed the study or discontinued (D/C) early; maximum duration of exposure to treatment was 12.00 weeks

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: participants
Any TEAE	31	28	36
Any IP-related TEAE	12	13	20
Any Severe TEAE	4	0	1
Any Serious TEAE	2	0	1
Any Serious IP-related TEAE	0	0	0
Any TEAE Leading to IP Withdrawal	5	0	1
Any TEAE Leading to IP Interruption	1	0	0
Any TEAE Leading to Death	0	0	0

No statistical analyses for this end point

Secondary: The Number of Participants Who Discontinued Apremilast due to Treatment Emergent Adverse Events During the Placebo-Controlled Period

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End point title

The Number of Participants Who Discontinued Apremilast due to Treatment Emergent Adverse Events During the Placebo-Controlled Period

End point description

A TEAE was defined as any AE occurring or worsening on or after the first treatment of apremilast and up to 28 days after the last apremilast dose or the last follow-up date, whichever occurred earlier. A serious AE = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs was assessed by the investigator and based on the following scale: Mild = asymptomatic or mild symptoms; clinical or diagnostic observations only; Moderate = Symptoms cause moderate discomfort; Severe (could be non-serious or serious) = symptoms causing severe discomfort/pain. Safety population included all participants who were enrolled and received at least 1 dose of IP.

End point type

Secondary

End point timeframe

From the first dose of IP and no later than 28 days after the last dose of IP for those who had completed the study or discontinued early; median duration of exposure to treatment was 12.00 weeks

End point values	Placebo	Apremilast 30 mg	Apremilast 40 mg
Number of subjects analysed	58	57	55
Units: participants	5	0	2

No statistical analyses for this end point

Secondary: The Number of Participants Who Experienced TEAEs During the Apremilast (APR) Exposure Period (Active Treatment Phase) Through Week 52

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End point title

The Number of Participants Who Experienced TEAEs During the Apremilast (APR) Exposure Period (Active Treatment Phase) Through Week 52

End point description

End point type

Secondary

End point timeframe

From first dose of IP and no later than 28 days after last dose of IP for those who completed the active treatment phase or D/C early; median duration of exposure = 41.00, 44.15 and 40.00 weeks respectively for 30 mg, 40 mg and 30 mg/40 mg APR arms

End point values	Apremilast 30 mg	Apremilast 40 mg	Apremilast 30 mg/Apremilast 40 mg
Number of subjects analysed	83	80	11
Units: participants
Any TEAE	60	67	8
Any Severe TEAE	5	6	0
Any Serious TEAE	6	8	1
Any TEAE Leading to Drug Withdrawal	3	9	1
Any TEAE Leading to Drug Interruption	1	4	0
Any TEAE Leading to Death	0	0	0

No statistical analyses for this end point

Secondary: The Number of Participants Who Experienced TEAEs During Week 52 to Week 104 (Extension Phase)

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End point title

The Number of Participants Who Experienced TEAEs During Week 52 to Week 104 (Extension Phase)

End point description

End point type

Secondary

End point timeframe

From the first dose of IP at Week 52 and no later than 28 days after the last dose of IP for those who completed the study or had discontinued early; median exposure of apremilast for the total apremilast group was 52 weeks.

End point values	Extension Phase: Apremilast 30 mg	Extension Phase Apremilast 40 mg
Number of subjects analysed	45	54
Units: participants
Any TEAE	16	27
Any Severe TEAE	1	0
Any Serious TEAE	4	3
Any Serious IP-related TEAE	0	1
Any TEAE Leading to IP Withdrawal	2	1
Any TEAE Leading to IP Interruption	1	0
Any TEAE Leading to Death	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of IP and no later than 28 days after the last dose of IP for those who had completed the study D/C early. AEs are reported for the placebo-controlled phase from Week 0 to Week 12 and for the APR exposure period from Week 0 to Week 104.

Adverse event reporting additional description

Median duration of study drug was 12 weeks in the placebo controlled phase, 41.00, 44.15 and 40.00 weeks respectively for 30 mg, 40 mg and 30 mg/40 mg APR arms in the active treatment phase and 52 weeks in the extension phase; MedDRA Version 20.1 was used in the placebo controlled phase and Version 22 in the active treatment and extension phase.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Placebo (Placebo Controlled Period)

Reporting group description

TEAEs for participants who were randomized to identically matching placebo capsules twice a day (BID) for 12 weeks during the double-blind placebo-controlled phase.

Reporting group title

Apremilast 30 mg BID (Placebo Controlled Period)

Reporting group description

TEAEs for participants who were randomized to apremilast 30 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

Reporting group title

Apremilast 40 mg BID (Placebo Controlled Period)

Reporting group description

TEAEs for participants who were randomized to apremilast 40 mg capsules PO BID for 12 weeks during the double-blind placebo-controlled phase.

Reporting group title

Apremilast 30 mg BID (Apremilast Exposure Period)

Reporting group description

Reporting group title

Apremilast 40 mg BID (Apremilast Exposure Period)

Reporting group description

Reporting group title

Apremilast 30/40 mg BID (Apremilast Exposure Period)

Reporting group description

TEAEs during the apremilast 40 mg BID treatment for participants who initially received 30 mg apremilast BID and switched to apremilast 40 mg BID at Week 12

Serious adverse events	Placebo (Placebo Controlled Period)	Apremilast 30 mg BID (Placebo Controlled Period)	Apremilast 40 mg BID (Placebo Controlled Period)	Apremilast 30 mg BID (Apremilast Exposure Period)	Apremilast 40 mg BID (Apremilast Exposure Period)	Apremilast 30/40 mg BID (Apremilast Exposure Period)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 58 (3.45%)	0 / 57 (0.00%)	1 / 55 (1.82%)	9 / 83 (10.84%)	11 / 80 (13.75%)	1 / 11 (9.09%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Epididymal neoplasm
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	1 / 80 (1.25%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congestive cardiomyopathy
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis ulcerative
subjects affected / exposed	2 / 58 (3.45%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	3 / 80 (3.75%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 83 (0.00%)	1 / 80 (1.25%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	1 / 80 (1.25%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	1 / 80 (1.25%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	1 / 80 (1.25%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Menorrhagia
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	1 / 80 (1.25%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	2 / 80 (2.50%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Clostridium difficile infection
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epididymitis tuberculous
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	1 / 80 (1.25%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pilonidal cyst
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal abscess
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	1 / 80 (1.25%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	0 / 11 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo (Placebo Controlled Period)	Apremilast 30 mg BID (Placebo Controlled Period)	Apremilast 40 mg BID (Placebo Controlled Period)	Apremilast 30 mg BID (Apremilast Exposure Period)	Apremilast 40 mg BID (Apremilast Exposure Period)	Apremilast 30/40 mg BID (Apremilast Exposure Period)
Total subjects affected by non serious adverse events
subjects affected / exposed	20 / 58 (34.48%)	26 / 57 (45.61%)	25 / 55 (45.45%)	49 / 83 (59.04%)	53 / 80 (66.25%)	11 / 11 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Angiomyolipoma
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	1
Vascular disorders
Angiopathy
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 58 (3.45%)	3 / 57 (5.26%)	1 / 55 (1.82%)	5 / 83 (6.02%)	3 / 80 (3.75%)	2 / 11 (18.18%)
occurrences all number	2	3	1	5	5	2
Influenza like illness
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	1 / 55 (1.82%)	2 / 83 (2.41%)	2 / 80 (2.50%)	1 / 11 (9.09%)
occurrences all number	0	1	1	2	2	1
Pyrexia
subjects affected / exposed	2 / 58 (3.45%)	1 / 57 (1.75%)	1 / 55 (1.82%)	1 / 83 (1.20%)	2 / 80 (2.50%)	2 / 11 (18.18%)
occurrences all number	2	1	1	1	3	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 83 (0.00%)	5 / 80 (6.25%)	0 / 11 (0.00%)
occurrences all number	1	0	1	0	6	0
Dysphonia
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	1
Respiratory tract congestion
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	1
Rhinitis allergic
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
Rhinorrhoea
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	1
Psychiatric disorders
Depressed mood
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	2 / 83 (2.41%)	4 / 80 (5.00%)	0 / 11 (0.00%)
occurrences all number	0	0	1	2	4	0
Depression
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 55 (1.82%)	0 / 83 (0.00%)	1 / 80 (1.25%)	1 / 11 (9.09%)
occurrences all number	1	0	1	0	1	1
Insomnia
subjects affected / exposed	0 / 58 (0.00%)	2 / 57 (3.51%)	1 / 55 (1.82%)	3 / 83 (3.61%)	2 / 80 (2.50%)	1 / 11 (9.09%)
occurrences all number	0	2	1	3	2	1
Investigations
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
Faecal calprotectin increased
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	1 / 55 (1.82%)	1 / 83 (1.20%)	1 / 80 (1.25%)	1 / 11 (9.09%)
occurrences all number	0	1	1	1	1	1
Nervous system disorders
Headache
subjects affected / exposed	4 / 58 (6.90%)	12 / 57 (21.05%)	14 / 55 (25.45%)	17 / 83 (20.48%)	25 / 80 (31.25%)	2 / 11 (18.18%)
occurrences all number	10	17	20	25	35	2
Migraine
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	1 / 55 (1.82%)	2 / 83 (2.41%)	3 / 80 (3.75%)	1 / 11 (9.09%)
occurrences all number	0	1	2	2	7	1
Sciatica
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	1 / 80 (1.25%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	1	1
Sinus headache
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 58 (1.72%)	1 / 57 (1.75%)	0 / 55 (0.00%)	4 / 83 (4.82%)	4 / 80 (5.00%)	0 / 11 (0.00%)
occurrences all number	1	1	0	4	5	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 58 (1.72%)	3 / 57 (5.26%)	0 / 55 (0.00%)	4 / 83 (4.82%)	3 / 80 (3.75%)	1 / 11 (9.09%)
occurrences all number	1	3	0	4	3	1
Nausea
subjects affected / exposed	5 / 58 (8.62%)	3 / 57 (5.26%)	6 / 55 (10.91%)	8 / 83 (9.64%)	9 / 80 (11.25%)	3 / 11 (27.27%)
occurrences all number	6	3	7	8	10	4
Dyspepsia
subjects affected / exposed	1 / 58 (1.72%)	1 / 57 (1.75%)	0 / 55 (0.00%)	2 / 83 (2.41%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	1	1	0	2	0	2
Anorectal discomfort
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
Colitis ulcerative
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	2 / 83 (2.41%)	6 / 80 (7.50%)	0 / 11 (0.00%)
occurrences all number	1	0	0	2	7	0
Diarrhoea
subjects affected / exposed	2 / 58 (3.45%)	1 / 57 (1.75%)	0 / 55 (0.00%)	5 / 83 (6.02%)	6 / 80 (7.50%)	2 / 11 (18.18%)
occurrences all number	2	1	0	5	6	2
Gastritis
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	1 / 83 (1.20%)	4 / 80 (5.00%)	0 / 11 (0.00%)
occurrences all number	0	0	0	1	4	0
Inguinal hernia
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
Swollen tongue
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
Vomiting
subjects affected / exposed	1 / 58 (1.72%)	2 / 57 (3.51%)	2 / 55 (3.64%)	3 / 83 (3.61%)	3 / 80 (3.75%)	3 / 11 (27.27%)
occurrences all number	1	2	2	3	4	3
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	1 / 83 (1.20%)	2 / 80 (2.50%)	1 / 11 (9.09%)
occurrences all number	0	0	1	1	2	1
Pruritus
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	2 / 80 (2.50%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	2	1
Rash
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	1 / 80 (1.25%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	1	1
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	3 / 55 (5.45%)	0 / 83 (0.00%)	3 / 80 (3.75%)	0 / 11 (0.00%)
occurrences all number	1	0	3	0	5	0
Arthralgia
subjects affected / exposed	2 / 58 (3.45%)	0 / 57 (0.00%)	1 / 55 (1.82%)	5 / 83 (6.02%)	6 / 80 (7.50%)	1 / 11 (9.09%)
occurrences all number	2	0	1	6	7	1
Osteochondrosis
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	1 / 58 (1.72%)	4 / 57 (7.02%)	2 / 55 (3.64%)	7 / 83 (8.43%)	8 / 80 (10.00%)	2 / 11 (18.18%)
occurrences all number	2	4	2	8	11	2
Upper respiratory tract infection
subjects affected / exposed	2 / 58 (3.45%)	1 / 57 (1.75%)	0 / 55 (0.00%)	4 / 83 (4.82%)	4 / 80 (5.00%)	0 / 11 (0.00%)
occurrences all number	2	1	0	4	5	0
Gastroenteritis
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	0 / 55 (0.00%)	3 / 83 (3.61%)	3 / 80 (3.75%)	1 / 11 (9.09%)
occurrences all number	1	0	0	3	3	1
Influenza
subjects affected / exposed	1 / 58 (1.72%)	0 / 57 (0.00%)	1 / 55 (1.82%)	2 / 83 (2.41%)	3 / 80 (3.75%)	1 / 11 (9.09%)
occurrences all number	1	0	1	2	4	1
Periodontitis
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	1 / 83 (1.20%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	1	0	1
Pneumonia
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	1 / 55 (1.82%)	1 / 83 (1.20%)	1 / 80 (1.25%)	1 / 11 (9.09%)
occurrences all number	0	0	1	1	1	1
Sinusitis
subjects affected / exposed	0 / 58 (0.00%)	1 / 57 (1.75%)	0 / 55 (0.00%)	4 / 83 (4.82%)	0 / 80 (0.00%)	1 / 11 (9.09%)
occurrences all number	0	1	0	4	0	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 58 (1.72%)	2 / 57 (3.51%)	1 / 55 (1.82%)	2 / 83 (2.41%)	3 / 80 (3.75%)	1 / 11 (9.09%)
occurrences all number	1	2	1	2	3	1
Iron deficiency
subjects affected / exposed	0 / 58 (0.00%)	0 / 57 (0.00%)	0 / 55 (0.00%)	0 / 83 (0.00%)	2 / 80 (2.50%)	1 / 11 (9.09%)
occurrences all number	0	0	0	0	2	1

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Were there any global substantial amendments to the protocol? Yes

13 Aug 2014

• The planned sample size was reduced from 249 to 165 after an internal decision to keep the Study CC-10004-UC-001 design in line with standard proof-of-concept Phase 2 trials. • The assessment of the primary endpoint was changed from Week 8 to Week 12 because cumulative clinical experience in other indications suggests that apremilast may take a longer time to induce a clinical response than initially anticipated in the approved protocol. Clinical remission at Week 8 was planned to be evaluated as one of the key secondary endpoints. • Secondary endpoints based on a modified Mayo score (without inclusion of PGA) were added based on a recommendation by the Food and Drug Administration during review of the original Investigational New Drug application. • Nonresponder criteria were revised to allow patients with an incomplete response (partial responders) at Week 12 to continue blinded treatment, to assess the potential late response of apremilast in this population. • Exclusion criterion 15 was added to clarify the psychiatric conditions that were exclusionary.

13 Apr 2015

• A treatment extension phase was added to provide all subjects the opportunity to receive active apremilast during the 40-week Blinded Active-treatment Phase. • Concomitant medication restrictions were changed from a prohibition of background oral corticosteroid treatment to instead allow subjects to receive stable doses of prednisone ≤ 20 mg/day or equivalent or budesonide ≤ 9 mg/day. • Stratification was added based on use of oral corticosteroids. Stratification based on use of aminosalicylates was deleted. • The requirement for chest radiograph was removed. • The psychiatric evaluation was updated based on feedback from the Health Authorities. • Several efficacy-related exploratory endpoints were deleted and time points in the secondary and exploratory endpoints were modified due to the change in study duration. • The definition of clinical remission based on the PMS was changed: “The proportion of subjects achieving clinical remission at Week 12, defined as a PMS of ≤ 2, with no individual subscore ≥ 1”. Changed to > 1. • The description in the sparse PK section was updated for clarity.

20 Jul 2016

• An Extension Phase was added for subjects who met the criteria for endoscopic response at Week 52 to allow these subjects to receive blinded, active treatment (apremilast) for an additional 52 weeks (Weeks 52 to 104). • Safety information was updated to reflect the most recent version of the Investigator’s Brochure. • The following exploratory endpoints were added: - The proportion of subjects with endoscopic remission, defined as a Mayo endoscopic subscore ≤ 1, and histological remission at Week 12 - The proportion of subjects achieving a clinical remission in the TMS at Week 12, defined as a TMS ≤ 2 with no individual subscore > 1 and no evidence of friability on the Mayo endoscopic subscore - The exposure-adjusted incidence of UC-related health outcomes (eg, UC-related hospitalizations, emergency room visits, and surgeries)

08 Aug 2018

• The apremilast dose in the Extension Phase was adjusted so that all subjects participating in that phase of the study would receive apremilast 30 mg BID (rather than either apremilast 30 mg BID or 40 mg BID). • Overdose for subjects receiving open-label 30 mg BID in the Extension Phase was defined as 4 or more 30-mg tablets in any 24-hour period (on a per-dose basis) or dosing more than 4 times in 24 hours (on a schedule or frequency basis). • The DMC was decommissioned. After a meeting with the external DMC on 27 Oct 2017, Celgene determined that the DMC was no longer needed to support CC-10004-UC-001, as described in Section 6. • Safety information was updated to reflect the most current information in the Investigator’s Brochure. • Clarification was added that subjects who experienced UC-related symptoms after corticosteroid tapering were permitted to receive the same treatment taken prior to tapering, provided that the dose was the same.

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.

None reported

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Clinical trials

Clinical Trial Results: A Phase 2, randomized, placebo-controlled, multicenter study to investigate the efficacy and safety of apremilast (CC-10004) for treatment of subjects with active ulcerative colitis.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants who Achieved a Clinical Remission by Total Mayo Score (TMS) at Week 12

Primary: Percentage of Participants who Achieved a Clinical Remission by Total Mayo Score (TMS) at Week 12

Secondary: Percentage of Participants who Achieved a Clinical Response by Total Mayo Score and the Reduction in the Rectal Bleeding Subscore at Week 12

Secondary: Percentage of Participants who Achieved a Clinical Response by Total Mayo Score and the Reduction in the Rectal Bleeding Subscore at Week 12

Secondary: Percentage of Participants who Achieved an Endoscopic Remission at Week 12

Secondary: Percentage of Participants who Achieved an Endoscopic Remission at Week 12

Secondary: Percentage of Participants who Achieved an Endoscopic Response at Week 12

Secondary: Percentage of Participants who Achieved an Endoscopic Response at Week 12

Secondary: Percentage of Participants Who Achieved a Rectal Bleeding Subscore (RBS) of ≤ 1 at Week 12

Secondary: Percentage of Participants Who Achieved a Rectal Bleeding Subscore (RBS) of ≤ 1 at Week 12

Secondary: Percentage of Participants Who Achieved Clinical Remission in the Modified Mayo Subscore (MMS) at Week 12

Secondary: Percentage of Participants Who Achieved Clinical Remission in the Modified Mayo Subscore (MMS) at Week 12

Secondary: Percentage of Participants Who Achieved Clinical Response in the Modified Mayo Subscore (MMS) at Week 12

Secondary: Percentage of Participants Who Achieved Clinical Response in the Modified Mayo Subscore (MMS) at Week 12

Secondary: Percentage of Participants Who Achieved Clinical Remission in the Partial Mayo Subscore (PMS) With no Individual Subscore >1 at Week 8

Secondary: Percentage of Participants Who Achieved Clinical Remission in the Partial Mayo Subscore (PMS) With no Individual Subscore >1 at Week 8

Secondary: Percentage of Participants Who Achieved Clinical Response in the Partial Mayo Subscore at Week 8

Secondary: Percentage of Participants Who Achieved Clinical Response in the Partial Mayo Subscore at Week 8

Secondary: The Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) During the Placebo-Controlled Phase

Secondary: The Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) During the Placebo-Controlled Phase

Secondary: The Number of Participants Who Discontinued Apremilast due to Treatment Emergent Adverse Events During the Placebo-Controlled Period

Secondary: The Number of Participants Who Discontinued Apremilast due to Treatment Emergent Adverse Events During the Placebo-Controlled Period

Secondary: The Number of Participants Who Experienced TEAEs During the Apremilast (APR) Exposure Period (Active Treatment Phase) Through Week 52

Secondary: The Number of Participants Who Experienced TEAEs During the Apremilast (APR) Exposure Period (Active Treatment Phase) Through Week 52

Secondary: The Number of Participants Who Experienced TEAEs During Week 52 to Week 104 (Extension Phase)

Secondary: The Number of Participants Who Experienced TEAEs During Week 52 to Week 104 (Extension Phase)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 2, randomized, placebo-controlled, multicenter study to investigate the efficacy and safety of apremilast (CC-10004) for treatment of subjects with active ulcerative colitis.