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Clinical Trial Results:
A Phase 2, open-label, multicenter study to assess the safety and efficacy of certolizumab pegol in children and adolescents with active Crohn’s disease (NURTURE Study)

Summary
EudraCT number	2014-004381-24
Trial protocol	Outside EU/EEA
Global end of trial date	02 Jul 2012

Results information
Results version number	v1(current)
This version publication date	30 Jun 2016
First version publication date	10 Jul 2015
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

C87035

ISRCTN number

US NCT number

NCT00899678

WHO universal trial number (UTN)

Sponsor organisation name

UCB Celltech

Sponsor organisation address

208 Bath Road, Slough, United Kingdom, SL1 3 WE

Public contact

Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 4815 15, clinicaltrials@ucb.com

Scientific contact

Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.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?

Yes

Analysis stage

Final

Date of interim/final analysis

08 Oct 2012

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Jul 2012

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of this study is to assess the efficacy of certolizumab pegol in children and adolescents with moderately to severely active Crohn’s disease (CD). This study also assesses certolizumab pegol treatment in this population with respect to: - Safety - Tolerability - Efficacy (secondary efficacy variables, including the impact upon growth and development) - Immunogenicity - Pharmacokinetics - Subject-reported outcomes

Protection of trial subjects

Not applicable

Background therapy

Corticosteroids at screening were tapered according to a schedule between Week 2 and Week 8. In the event of a flare in Crohn’s disease, corticosteroids could be reintroduced at the same dose as at Week 0.

Evidence for comparator

Not applicable

Actual start date of recruitment

01 Jun 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

4 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Canada: 23

Country: Number of subjects enrolled

New Zealand: 5

Country: Number of subjects enrolled

United States: 67

Worldwide total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The Participant Flow refers to the Safety Set (SS) population. The Safety Population includes all subjects enrolled who received at least 1 injection of study treatment.

Screening details

During an Induction Period (Weeks 0 to 6), subjects were administered Certolizumab Pegol (CZP) subcutaneously every 2 weeks (Q2W). Subjects who showed a clinical response at Week 6 were randomized in a 1:1 ratio to one of 2 dose groups. Subjects who did not respond at Week 6 were withdrawn from the study.

Period 1 title

Study Overall (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Induction Only

Arm description

Induction Only is the period between the Week 0 dose and prior to first maintenance dose (Week 8). Induction Only includes all subjects who received a dose during the Induction Period but did not receive any treatment during the Maintenance Period. During the Induction Period (Weeks 0 to 6), subjects were administered Certolizumab Pegol (CZP) subcutaneously every 2 weeks (Q2W) (for a total of 3 administrations of drug) at a dose of either: - 400 mg for subjects ≥ 40 kg - 200 mg for subjects 20 to < 40 kg

Arm type

Experimental

Investigational medicinal product name

Certolizumab Pegol

Investigational medicinal product code

Certolizumab Pegol

Other name

Cimzia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Maintenance High-Dose group: 400 mg Certolizumab Pegol for subjects ≥ 40 kg or 200 mg Certolizumab Pegol for subjects 20 to < 40 kg Maintenance Low-Dose Maintenance Low-Dose group: 200 mg Certolizumab Pegol for subjects ≥ 40 kg or 100 mg Certolizumab Pegol for subjects 20 to < 40 kg

Maintenance Low-Dose

Arm description

Maintenance Low-Dose group*: 200 mg Certolizumab Pegol once every 4 weeks for subjects ≥ 40 kg or 100 mg Certolizumab Pegol once every 4 weeks for subjects 20 to < 40 kg *prior to this dosing regimen, subjects underwent an induction of Certolizumab Pegol administered subcutaneously every 2 weeks (total 3 injections) at of either 400 mg for subjects ≥ 40 kg or 200 mg for subjects 20 to < 40 kg

Arm type

Experimental

Investigational medicinal product name

Certolizumab Pegol

Investigational medicinal product code

Certolizumab Pegol

Other name

Cimzia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Maintenance High-Dose

Arm description

Maintenance High-Dose group*: 400 mg Certolizumab Pegol once every 4 weeks for subjects ≥ 40 kg or 200 mg Certolizumab Pegol once every 4 weeks for subjects 20 to < 40 kg *prior to this dosing regimen, subjects underwent an induction of Certolizumab Pegol administered subcutaneously every 2 weeks (total 3 injections) at of either 400 mg for subjects ≥ 40 kg or 200 mg for subjects 20 to < 40 kg

Arm type

Experimental

Investigational medicinal product name

Certolizumab Pegol

Investigational medicinal product code

Certolizumab Pegol

Other name

Cimzia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 1	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Started	27	37	35
Completed	2	12	7
Not completed	25	25	28
Consent withdrawn by subject	-	1	2
Other	1	2	2
AE, non-serious non-fatal	3	4	3
AE, unknown	-	1	-
SAE, non-fatal	3	5	2
Lack of efficacy	17	11	18
Protocol deviation	1	1	1

Baseline characteristics

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Reporting group title

Induction Only

Reporting group description

Reporting group title

Maintenance Low-Dose

Reporting group description

Reporting group title

Maintenance High-Dose

Reporting group description

Reporting group values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose	Total
Number of subjects	27	37	35	99
Age categorical
Units: Subjects
6-11 years	6	9	8	23
12-17 years	21	28	27	76
Age Continuous
Units: years
arithmetic mean (standard deviation)	13.8 ( 2.67 )	13.2 ( 2.41 )	13.4 ( 2.46 )	-
Gender Categorical
Units: Subjects
Female	10	10	21	41
Male	17	27	14	58
Race/Ethnicity, Customized
Units: Subjects
American Indian / Alaskan Native	0	0	0	0
Asian	1	0	0	1
Black	3	3	8	14
Native Hawaiian or other Pacific islander	0	0	0	0
White	22	32	27	81
Other / Mixed	1	2	0	3
Weight
Units: kilogram
arithmetic mean (standard deviation)	46.5 ( 12.565 )	45.67 ( 14.638 )	50.35 ( 18.569 )	-
Height
Units: centimeter
arithmetic mean (standard deviation)	157.46 ( 13.841 )	155.32 ( 13.589 )	157.22 ( 13.32 )	-
Body Mass Index (BMI)
Units: kilogram per square meter
arithmetic mean (standard deviation)	18.39 ( 2.504 )	18.51 ( 3.531 )	19.79 ( 4.897 )	-
Body Surface Area (BSA)
Units: square meter
arithmetic mean (standard deviation)	1.42 ( 0.25 )	1.39 ( 0.272 )	1.47 ( 0.319 )	-

End points

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Reporting group title

Induction Only

Reporting group description

Reporting group title

Maintenance Low-Dose

Reporting group description

Reporting group title

Maintenance High-Dose

Reporting group description

Primary: Percentage of subjects in clinical remission at Week 62

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End point title

Percentage of subjects in clinical remission at Week 62 ^[1]

End point description

Clinical remission is defined as a Pediatric Crohn’s Disease Activity Index (PCDAI) score ≤ 10. The Pediatric Crohn’s Disease Activity Index (PCDAI) consists of 4 domains (laboratory, height/weight, examination, and history) with several assessments that are converted into a PCDAI score which can range from 0 to 100 points, with a higher score indicating more severe disease activity.

End point type

Primary

End point timeframe

Week 62

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[2]	37	35
Units: percentage of participants
number (confidence interval 95%)
number (95 % CI)	( to )	24.3 (10.5 to 38.1)	17.1 (4.7 to 29.6)

Notes
[2] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Secondary: Absolute Pediatric Crohn’s Disease Activity Index (PCDAI) scores at Week 62

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End point title

Absolute Pediatric Crohn’s Disease Activity Index (PCDAI) scores at Week 62

End point description

The Pediatric Crohn’s Disease Activity Index (PCDAI) consists of 4 domains (laboratory, height/weight, examination, and history) with several assessments that are converted into a PCDAI score which can range from 0 to 100 points, with a higher score indicating more severe disease activity.

End point type

Secondary

End point timeframe

Week 62

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[3]	11	7
Units: Score on a scale
arithmetic mean (standard deviation)
mean (standard deviation)	( )	8.18 ( 6.9 )	7.14 ( 7.83 )

Notes
[3] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Secondary: Change in Pediatric Crohn's Disease Activity Index (PCDAI) scores from Week 0 to the end of the study (Week 62)

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End point title

Change in Pediatric Crohn's Disease Activity Index (PCDAI) scores from Week 0 to the end of the study (Week 62)

End point description

The Pediatric Crohn's Disease Activity Index (PCDAI) consists of 4 domains (laboratory, height/weight, examination, and history) with several assessments that are converted into a PCDAI score which can range from 0 to 100 points, with a higher score indicating more severe disease activity. A negative value in change from Baseline indicates an improvement from Baseline to Week 62.

End point type

Secondary

End point timeframe

From Week 0 to Week 62

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[4]	11	7
Units: units on a scale
arithmetic mean (standard deviation)
mean (standard deviation)	( )	-29.77 ( 8.097 )	-27.14 ( 5.669 )

Notes
[4] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Secondary: Percentage of subjects achieving clinical response from Week 0 to the end of the study (Week 62)

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End point title

Percentage of subjects achieving clinical response from Week 0 to the end of the study (Week 62)

End point description

Clinical response is defined as a decrease from Week 0 in Pediatric Crohn’s Disease Activity Index (PCDAI) score of ≥ 15 points and a total PCDAI score ≤ 30 points. The Pediatric Crohn’s Disease Activity Index (PCDAI) consists of 4 domains (laboratory, height/weight, examination, and history) with several assessments that are converted into a PCDAI score which can range from 0 to 100 points, with a higher score indicating more severe disease activity.

End point type

Secondary

End point timeframe

From Week 0 to Week 62

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[5]	37	35
Units: percentage of participants
number (confidence interval 95%)
number (95 % CI)	( to )	29.7 (15 to 44.5)	20 (6.7 to 33.3)

Notes
[5] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Secondary: C-Reactive Protein (CRP) levels at Week 62

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End point title

C-Reactive Protein (CRP) levels at Week 62

End point description

The C-Reactive Protein (CRP) is a considered marker of inflammation in subjects with Crohn’s Disease (CD)

End point type

Secondary

End point timeframe

Week 62

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[6]	11	7
Units: mg/L
geometric mean (confidence interval 95%)
geometric mean (95 % CI)	( to )	7.2 (2.5 to 20.7)	5.8 (2.1 to 15.7)

Notes
[6] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Secondary: Change in C-Reactive Protein (CRP) levels from Week 0 to the end of the study (Week 62)

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End point title

Change in C-Reactive Protein (CRP) levels from Week 0 to the end of the study (Week 62)

End point description

The C-Reactive Protein (CRP) is a considered marker of inflammation in subjects with Crohn’s Disease (CD). Changes from Baseline in CRP levels are expressed as a ratio with the value measured at Baseline as the denominator.

End point type

Secondary

End point timeframe

From Week 0 to Week 62

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[7]	11	7
Units: ratio
geometric mean (confidence interval 95%)
geometric mean (95 % CI)	( to )	0.49 (0.17 to 1.41)	1.84 (0.27 to 12.71)

Notes
[7] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Secondary: Erythrocyte Sedimentation Rate (ESR) at Week 62

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End point title

Erythrocyte Sedimentation Rate (ESR) at Week 62

End point description

The Erythrocyte Sedimentation Rate (ESR) is a considered biomarker of inflammation in subjects with Crohn’s Disease (CD).

End point type

Secondary

End point timeframe

Week 62

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[8]	12	7
Units: mm/h
geometric mean (confidence interval 95%)
geometric mean (95 % CI)	( to )	20.9 (11.8 to 37.2)	25.2 (12.3 to 51.7)

Notes
[8] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Secondary: Change in Erythrocyte Sedimentation Rate (ESR) from Week 0 to the end of the study (Week 62)

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End point title

Change in Erythrocyte Sedimentation Rate (ESR) from Week 0 to the end of the study (Week 62)

End point description

The Erythrocyte Sedimentation Rate (ESR) is a considered biomarker of inflammation in subjects with Crohn’s Disease (CD). Changes from Baseline in CRP levels are expressed as a ratio with the value measured at baseline as the denominator.

End point type

Secondary

End point timeframe

From Week 0 to Week 62

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[9]	12	7
Units: ratio
geometric mean (confidence interval 95%)
geometric mean (95 % CI)	( to )	0.57 (0.31 to 1.04)	1.08 (0.39 to 3.02)

Notes
[9] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Secondary: Change in growth scores (Tanner stage [assessing puberty]) from Week 0 to the end of the study (Week 62)

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End point title

Change in growth scores (Tanner stage [assessing puberty]) from Week 0 to the end of the study (Week 62)

End point description

The Tanner stage is an assessment of developmental stage on external genitalia and pubic hair (boys), and on breast and pubic hair (girls). Values range from 1 to 5 where a higher number indicates more development.

End point type

Secondary

End point timeframe

From Week 0 to Week 62

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[10]	10	7
Units: participants
Increase from Stage I to Stage II		2	0
Increase from Stage I to Stage III		1	1
Increase from Stage II to Stage III		0	1
Increase from Stage III to Stage IV		2	0
Increase from Stage IV to Stage V		0	1
Decrease from Stage IV to Stage III		1	1
Subjects remained in Stage I		0	1
Subjects remained in Stage III		0	2
Subjects remained in Stage IV		1	0
Subjects remained in Stage V		3	0

Notes
[10] - Subjects from "Induction Only" were not included in the Analysis of this End Point.

No statistical analyses for this end point

Secondary: Percentage of subjects who initiated steroid tapering

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End point title

Percentage of subjects who initiated steroid tapering

End point description

Subjects receiving corticosteroids at Screening may start a defined tapering schedule between Weeks 2 and 8. Corticosteroid tapering must start at the latest by Week 8. Corticosteroid doses are tapered at different rates depending on the subject’s dose.

End point type

Secondary

End point timeframe

From Week 2 up to Week 8

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[11]	21	20
Units: percentage of subjects
number (confidence interval 95%)
number (95 % CI)	( to )	71.4 (52.1 to 90.8)	65 (44.1 to 85.9)

Notes
[11] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Secondary: Percentage of subjects in corticosteroid-free remission at the end of the study

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End point title

Percentage of subjects in corticosteroid-free remission at the end of the study

End point description

Corticosteroid use at end of study is defined as 84 days past the last dose of study medication. Remission is assessed at the last visit where Pediatric Crohn’s Disease Activity index (PCDAI) data is available.

End point type

Secondary

End point timeframe

Last/Withdrawal Visit (up to Week 62)

End point values	Induction Only	Maintenance Low-Dose	Maintenance High-Dose
Number of subjects analysed	0 ^[12]	21	20
Units: percentage of paticipants
number (confidence interval 95%)
number (95 % CI)	( to )	23.8 (5.6 to 42)	15 (0 to 30.6)

Notes
[12] - Subjects from "Induction Only" were not included in the analysis of this End Point.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events (AEs) were collected over 68 weeks (from Week -6 to Week 62).

Adverse event reporting additional description

Adverse Events (AEs) refer to the Safety Set (SS) population. All subjects in the Safety Population (n=99) participated in the Induction Period. There were 27 subjects who did not continue into the Maintenance Period.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Induction Period

Reporting group description

Reporting group title

Maintenance Low-Dose

Reporting group description

Reporting group title

Overall Study

Reporting group description

Overall Study comprises Induction Period and Maintenance Period (Week -6 to Week 62).

Reporting group title

Maintenance High-Dose

Reporting group description

Serious adverse events	Induction Period	Maintenance Low-Dose	Overall Study	Maintenance High-Dose
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 99 (6.06%)	4 / 37 (10.81%)	14 / 99 (14.14%)	4 / 35 (11.43%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Investigations
Weight decreased
subjects affected / exposed	0 / 99 (0.00%)	0 / 37 (0.00%)	1 / 99 (1.01%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 99 (1.01%)	0 / 37 (0.00%)	1 / 99 (1.01%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 99 (0.00%)	1 / 37 (2.70%)	1 / 99 (1.01%)	0 / 35 (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
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 99 (0.00%)	0 / 37 (0.00%)	1 / 99 (1.01%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	0 / 99 (0.00%)	1 / 37 (2.70%)	1 / 99 (1.01%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	1 / 99 (1.01%)	0 / 37 (0.00%)	1 / 99 (1.01%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 99 (0.00%)	1 / 37 (2.70%)	1 / 99 (1.01%)	0 / 35 (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
Haematochezia
subjects affected / exposed	1 / 99 (1.01%)	0 / 37 (0.00%)	2 / 99 (2.02%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 99 (1.01%)	0 / 37 (0.00%)	1 / 99 (1.01%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 99 (0.00%)	1 / 37 (2.70%)	1 / 99 (1.01%)	0 / 35 (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
Infections and infestations
Candidiasis
subjects affected / exposed	0 / 99 (0.00%)	1 / 37 (2.70%)	1 / 99 (1.01%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 99 (0.00%)	0 / 37 (0.00%)	1 / 99 (1.01%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	2 / 99 (2.02%)	0 / 37 (0.00%)	2 / 99 (2.02%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	0 / 99 (0.00%)	1 / 37 (2.70%)	1 / 99 (1.01%)	0 / 35 (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
Salmonellosis
subjects affected / exposed	1 / 99 (1.01%)	0 / 37 (0.00%)	1 / 99 (1.01%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 99 (0.00%)	0 / 37 (0.00%)	1 / 99 (1.01%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perineal abscess
subjects affected / exposed	0 / 99 (0.00%)	1 / 37 (2.70%)	1 / 99 (1.01%)	0 / 35 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 99 (1.01%)	0 / 37 (0.00%)	1 / 99 (1.01%)	0 / 35 (0.00%)
occurrences causally related to treatment / all	0 / 1	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	Induction Period	Maintenance Low-Dose	Overall Study	Maintenance High-Dose
Total subjects affected by non serious adverse events
subjects affected / exposed	59 / 99 (59.60%)	28 / 37 (75.68%)	78 / 99 (78.79%)	27 / 35 (77.14%)
Investigations
C-reactive protein increased
subjects affected / exposed	0 / 99 (0.00%)	0 / 37 (0.00%)	2 / 99 (2.02%)	2 / 35 (5.71%)
occurrences all number	0	0	2	2
Weight decreased
subjects affected / exposed	2 / 99 (2.02%)	2 / 37 (5.41%)	4 / 99 (4.04%)	1 / 35 (2.86%)
occurrences all number	2	2	7	3
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 99 (0.00%)	2 / 37 (5.41%)	2 / 99 (2.02%)	0 / 35 (0.00%)
occurrences all number	0	2	2	0
Ligament sprain
subjects affected / exposed	0 / 99 (0.00%)	2 / 37 (5.41%)	2 / 99 (2.02%)	0 / 35 (0.00%)
occurrences all number	0	2	2	0
Nervous system disorders
Headache
subjects affected / exposed	9 / 99 (9.09%)	4 / 37 (10.81%)	12 / 99 (12.12%)	3 / 35 (8.57%)
occurrences all number	12	10	26	4
General disorders and administration site conditions
Fatigue
subjects affected / exposed	3 / 99 (3.03%)	3 / 37 (8.11%)	6 / 99 (6.06%)	0 / 35 (0.00%)
occurrences all number	3	4	7	0
Injection site pain
subjects affected / exposed	22 / 99 (22.22%)	4 / 37 (10.81%)	22 / 99 (22.22%)	6 / 35 (17.14%)
occurrences all number	55	17	108	36
Pyrexia
subjects affected / exposed	9 / 99 (9.09%)	6 / 37 (16.22%)	20 / 99 (20.20%)	9 / 35 (25.71%)
occurrences all number	15	7	31	9
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	4 / 99 (4.04%)	3 / 37 (8.11%)	10 / 99 (10.10%)	4 / 35 (11.43%)
occurrences all number	4	4	12	4
Abdominal pain upper
subjects affected / exposed	4 / 99 (4.04%)	5 / 37 (13.51%)	9 / 99 (9.09%)	2 / 35 (5.71%)
occurrences all number	4	5	12	3
Anal inflammation
subjects affected / exposed	0 / 99 (0.00%)	0 / 37 (0.00%)	2 / 99 (2.02%)	2 / 35 (5.71%)
occurrences all number	0	0	2	2
Constipation
subjects affected / exposed	3 / 99 (3.03%)	3 / 37 (8.11%)	7 / 99 (7.07%)	1 / 35 (2.86%)
occurrences all number	3	3	7	1
Crohn's disease
subjects affected / exposed	0 / 99 (0.00%)	5 / 37 (13.51%)	12 / 99 (12.12%)	7 / 35 (20.00%)
occurrences all number	0	7	15	8
Diarrhoea
subjects affected / exposed	7 / 99 (7.07%)	3 / 37 (8.11%)	12 / 99 (12.12%)	3 / 35 (8.57%)
occurrences all number	7	5	19	7
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 99 (2.02%)	2 / 37 (5.41%)	5 / 99 (5.05%)	2 / 35 (5.71%)
occurrences all number	2	2	6	2
Mouth ulceration
subjects affected / exposed	2 / 99 (2.02%)	3 / 37 (8.11%)	8 / 99 (8.08%)	3 / 35 (8.57%)
occurrences all number	2	3	8	3
Nausea
subjects affected / exposed	6 / 99 (6.06%)	3 / 37 (8.11%)	10 / 99 (10.10%)	2 / 35 (5.71%)
occurrences all number	8	3	13	2
Stomatitis
subjects affected / exposed	2 / 99 (2.02%)	1 / 37 (2.70%)	5 / 99 (5.05%)	2 / 35 (5.71%)
occurrences all number	3	1	6	2
Toothache
subjects affected / exposed	1 / 99 (1.01%)	3 / 37 (8.11%)	3 / 99 (3.03%)	0 / 35 (0.00%)
occurrences all number	1	3	4	0
Vomiting
subjects affected / exposed	6 / 99 (6.06%)	3 / 37 (8.11%)	13 / 99 (13.13%)	6 / 35 (17.14%)
occurrences all number	7	3	20	10
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	5 / 99 (5.05%)	3 / 37 (8.11%)	8 / 99 (8.08%)	2 / 35 (5.71%)
occurrences all number	5	3	13	5
Oropharyngeal pain
subjects affected / exposed	5 / 99 (5.05%)	2 / 37 (5.41%)	8 / 99 (8.08%)	2 / 35 (5.71%)
occurrences all number	5	2	9	2
Rhinorrhoea
subjects affected / exposed	0 / 99 (0.00%)	1 / 37 (2.70%)	3 / 99 (3.03%)	2 / 35 (5.71%)
occurrences all number	0	1	3	2
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	3 / 99 (3.03%)	1 / 37 (2.70%)	5 / 99 (5.05%)	1 / 35 (2.86%)
occurrences all number	3	1	5	1
Rash
subjects affected / exposed	2 / 99 (2.02%)	3 / 37 (8.11%)	5 / 99 (5.05%)	0 / 35 (0.00%)
occurrences all number	2	6	8	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 99 (6.06%)	4 / 37 (10.81%)	12 / 99 (12.12%)	2 / 35 (5.71%)
occurrences all number	7	4	13	2
Myalgia
subjects affected / exposed	0 / 99 (0.00%)	2 / 37 (5.41%)	2 / 99 (2.02%)	0 / 35 (0.00%)
occurrences all number	0	2	2	0
Infections and infestations
Ear infection
subjects affected / exposed	1 / 99 (1.01%)	2 / 37 (5.41%)	4 / 99 (4.04%)	1 / 35 (2.86%)
occurrences all number	1	2	4	1
Influenza
subjects affected / exposed	1 / 99 (1.01%)	3 / 37 (8.11%)	6 / 99 (6.06%)	2 / 35 (5.71%)
occurrences all number	1	3	7	3
Nasopharyngitis
subjects affected / exposed	5 / 99 (5.05%)	1 / 37 (2.70%)	8 / 99 (8.08%)	2 / 35 (5.71%)
occurrences all number	5	1	8	2
Pharyngitis
subjects affected / exposed	1 / 99 (1.01%)	2 / 37 (5.41%)	3 / 99 (3.03%)	0 / 35 (0.00%)
occurrences all number	1	2	3	0
Sinusitis
subjects affected / exposed	2 / 99 (2.02%)	3 / 37 (8.11%)	5 / 99 (5.05%)	1 / 35 (2.86%)
occurrences all number	2	3	6	1
Upper respiratory tract infection
subjects affected / exposed	0 / 99 (0.00%)	8 / 37 (21.62%)	10 / 99 (10.10%)	2 / 35 (5.71%)
occurrences all number	0	9	11	2
Urinary tract infection
subjects affected / exposed	0 / 99 (0.00%)	0 / 37 (0.00%)	2 / 99 (2.02%)	2 / 35 (5.71%)
occurrences all number	0	0	2	2
Viral infection
subjects affected / exposed	2 / 99 (2.02%)	4 / 37 (10.81%)	9 / 99 (9.09%)	3 / 35 (8.57%)
occurrences all number	3	4	12	5
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 99 (4.04%)	3 / 37 (8.11%)	8 / 99 (8.08%)	1 / 35 (2.86%)
occurrences all number	4	3	8	1

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Were there any global substantial amendments to the protocol? Yes

14 Apr 2009

No subjects had been enrolled in the study at the time of this amendment. This amendment: - Identified a new Sponsor Clinical Program Director and Clinical Research Physician - Corrected an inconsistency in definition of positive and negative purified Protein derivative (PPD) tests - Reduced the number of blood draws by consolidating laboratory tests and decreasing the number of PCDAI assessments - Required North American site to use the PPD test; Rest of World sites had the option of using the QuantiFERON®-TB GOLD (QFT-GOLD) if the PPD test was not available. - Generalized location of study sites - Removed C-reactive protein (CRP) from the standard clinical chemistry laboratory battery - Corrected an inconsistency in timing of chest x-ray - Changed the method and timing of the wrist x-ray used to calculate bone age - Removed the “up to the age of 14 years” restriction on the Work Productivity and Activity Impairment Questionnaire for CD (WPAI:CD) - Specified the WPAI:CD assessments obtained during reinduction - Clarified administration of WPAI:CD for children and WPAI:CD for working individuals - Revised the wording of some WPAI:CD questions and made minor format changes - Corrected definition of scores for height velocity on PCDAI - Clarified rationale for calculating the PCDAI - Changed “rescue medication” to “rescue therapy” throughout

20 Oct 2009

At the time of this amendment, 4 subjects had been enrolled in the study. This amendment: - Updated fax number for UCB study physician - Specified the assessments used to determine the effect of treatment on the subject’s CD (exploratory variable) - Added a provision to do the PK assessments on the 10 subjects who completed the Induction Period in 2 stages depending on rate of completion of the Induction Period in each age group - Modified inclusion criteria for duration of CD diagnosis (Inclusion #2), use of parenteral corticosteroids prior to Screening (Inclusion #8 and Exclusion #12), use of antibiotics (Inclusion #8), and exclusion criteria for prior use of anti-TNFα agents (Exclusion #9) to better correspond with clinical practice Clarified Exclusion criteria #1 (regarding draining fistula) and #16 (regarding negative test results for immunoglobulin G (IgG) against Varicella zoster) Clarified hormonal contraceptives, added duration of contraceptive use in after discontinuation of study treatment to reflect updates to company core data sheet, and reconciled an inconsistency in wording between text in the protocol summary section and Section 9.2 (Exclusion #26)

20 Oct 2009

- Added Exclusion criterion #28 dealing with hypersensitivity or intolerance to CZP or polyethylene glycol (PEG) - Added visit windows to accommodate occasional scheduling difficulties with the understanding that study treatment cannot exceed a total of 60 weeks - Deleted the Week 13 visit (PK and immunologic blood sampling) to reduce the number of study visits - Updated number of clinical studies conducted and changed reference to “current” Investigator Brochure rather than specifying the version - Specified the corticosteroid dose that would be considered rescue therapy - Added a wrist x-ray at Week 60 in addition to Week 0 to assess growth over the course of treatment - Incorporated previous administrative amendment regarding timing of vital signs in relationship to dosing - Expanded use of QFT-Gold to North American sites (all sites can use either PPD or QFT-Gold) to facilitate TB testing at the sites - Corrected an error in location of TB questionnaire - Corrected an inconsistency in laboratory values used to calculate the Week 0 PCDAI score - Updated the entire AE section to reflect current standard operating procedures and template language - Added statistical analyses of Tanner stage

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
14 Jun 2011	Enrollment was temporarily suspended on 14-Jun-2011, in agreement with the study’s DSMB recommendation, due to a higher than expected number of premature withdrawals. Enrollment was permanently terminated in Apr2012 following discussion with the Food and Drug Administration (FDA).	-

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, open-label, multicenter study to assess the safety and efficacy of certolizumab pegol in children and adolescents with active Crohn’s disease (NURTURE Study)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects in clinical remission at Week 62

Primary: Percentage of subjects in clinical remission at Week 62

Secondary: Absolute Pediatric Crohn’s Disease Activity Index (PCDAI) scores at Week 62

Secondary: Absolute Pediatric Crohn’s Disease Activity Index (PCDAI) scores at Week 62

Secondary: Change in Pediatric Crohn's Disease Activity Index (PCDAI) scores from Week 0 to the end of the study (Week 62)

Secondary: Change in Pediatric Crohn's Disease Activity Index (PCDAI) scores from Week 0 to the end of the study (Week 62)

Secondary: Percentage of subjects achieving clinical response from Week 0 to the end of the study (Week 62)

Secondary: Percentage of subjects achieving clinical response from Week 0 to the end of the study (Week 62)

Secondary: C-Reactive Protein (CRP) levels at Week 62

Secondary: C-Reactive Protein (CRP) levels at Week 62

Secondary: Change in C-Reactive Protein (CRP) levels from Week 0 to the end of the study (Week 62)

Secondary: Change in C-Reactive Protein (CRP) levels from Week 0 to the end of the study (Week 62)

Secondary: Erythrocyte Sedimentation Rate (ESR) at Week 62

Secondary: Erythrocyte Sedimentation Rate (ESR) at Week 62

Secondary: Change in Erythrocyte Sedimentation Rate (ESR) from Week 0 to the end of the study (Week 62)

Secondary: Change in Erythrocyte Sedimentation Rate (ESR) from Week 0 to the end of the study (Week 62)

Secondary: Change in growth scores (Tanner stage [assessing puberty]) from Week 0 to the end of the study (Week 62)

Secondary: Change in growth scores (Tanner stage [assessing puberty]) from Week 0 to the end of the study (Week 62)

Secondary: Percentage of subjects who initiated steroid tapering

Secondary: Percentage of subjects who initiated steroid tapering

Secondary: Percentage of subjects in corticosteroid-free remission at the end of the study

Secondary: Percentage of subjects in corticosteroid-free remission at the end of the study

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase 2, open-label, multicenter study to assess the safety and efficacy of certolizumab pegol in children and adolescents with active Crohn’s disease (NURTURE Study)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects in clinical remission at Week 62

Primary: Percentage of subjects in clinical remission at Week 62

Secondary: Absolute Pediatric Crohn’s Disease Activity Index (PCDAI) scores at Week 62

Secondary: Absolute Pediatric Crohn’s Disease Activity Index (PCDAI) scores at Week 62

Secondary: Change in Pediatric Crohn's Disease Activity Index (PCDAI) scores from Week 0 to the end of the study (Week 62)

Secondary: Change in Pediatric Crohn's Disease Activity Index (PCDAI) scores from Week 0 to the end of the study (Week 62)

Secondary: Percentage of subjects achieving clinical response from Week 0 to the end of the study (Week 62)

Secondary: Percentage of subjects achieving clinical response from Week 0 to the end of the study (Week 62)

Secondary: C-Reactive Protein (CRP) levels at Week 62

Secondary: C-Reactive Protein (CRP) levels at Week 62

Secondary: Change in C-Reactive Protein (CRP) levels from Week 0 to the end of the study (Week 62)

Secondary: Change in C-Reactive Protein (CRP) levels from Week 0 to the end of the study (Week 62)

Secondary: Erythrocyte Sedimentation Rate (ESR) at Week 62

Secondary: Erythrocyte Sedimentation Rate (ESR) at Week 62

Secondary: Change in Erythrocyte Sedimentation Rate (ESR) from Week 0 to the end of the study (Week 62)

Secondary: Change in Erythrocyte Sedimentation Rate (ESR) from Week 0 to the end of the study (Week 62)

Secondary: Change in growth scores (Tanner stage [assessing puberty]) from Week 0 to the end of the study (Week 62)

Secondary: Change in growth scores (Tanner stage [assessing puberty]) from Week 0 to the end of the study (Week 62)

Secondary: Percentage of subjects who initiated steroid tapering

Secondary: Percentage of subjects who initiated steroid tapering

Secondary: Percentage of subjects in corticosteroid-free remission at the end of the study

Secondary: Percentage of subjects in corticosteroid-free remission at the end of the study

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2, open-label, multicenter study to assess the safety and efficacy of certolizumab pegol in children and adolescents with active Crohn’s disease (NURTURE Study)