Study of Adalimumab Treatment for Induction and Maintenance of Clinical Remission in Subjects With Crohn's Disease

A Multi-Center, Open-Label Study of the Fully Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction and Maintenance of Clinical Remission in Subjects With Moderate to Severe Crohn's Disease

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00409617

Enrollment

945

Registered

2006-12-11

Start date

2006-12-31

Completion date

2008-07-31

Last updated

2011-10-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Crohn's Disease

Brief summary

The purpose of this study is to evaluate the safety of adalimumab for treatment of patients with moderate to severe Crohn's Disease (CD) and to measure the effects of treatment on patient general well-being, health-related quality of life (QoL), fistula healing, CD-related extra-intestinal manifestations, work performance, and overall activity.

Detailed description

This is an open-label, multi-center, study designed to evaluate the safety and efficacy of adalimumab on inducing and maintaining clinical remission in subjects with moderate to severe Crohn's Disease. Approximately 1000 subjects with a diagnosis of moderate to severe Crohn's Disease (Harvey Bradshaw Index score \>= 7) will be enrolled at approximately 200 sites within Europe. Enrollment will be dependent on meeting all screening criteria. Study medication will be administered by subcutaneous injection. At Baseline (Week 0), all subjects will receive a dose of 160 mg adalimumab. At Week 2, all subjects will receive a dose of 80 mg adalimumab. Starting at Week 4, all subjects will begin receiving injections of adalimumab 40 mg every other week and will continue every other week dosing through Week 20 except in the case of disease flare or non-response. Starting at Week 12, subjects who experience a disease flare (flare is defined by an increase in the Harvey Bradshaw Index \>=3 and a total Index score of \>=7 when compared to Week 4) or are not responding to adalimumab treatment (non-response is defined as a decrease in the Harvey Bradshaw Index by fewer than 3 points compared to Baseline) will be permitted to increase study therapy to adalimumab 40 mg every week. If the subject continues to demonstrate a lack of improvement on every week adalimumab therapy, they may be withdrawn from the study. Prior to Week 8 subjects will not be allowed to increase or decrease Crohn's specific concomitant medications except in the event of concomitant Crohn's treatment-related toxicities assessed as moderate to severe. Changes in concomitant medications at/after Week 8 will be at the Investigator's discretion. Subjects will be evaluated for safety and efficacy at Baseline (Week 0), Weeks 2, 4, 8, 12, and 20, and at unscheduled visits. Efficacy evaluations include HBI, Short Inflammatory Bowel Disease Questionnaire (SIBDQ), Work Productivity Activity Index (WPAI) questionnaire, fistula counts, health care resource utilization (HCRU), and evaluation of CD-related extra-intestinal manifestations (EIMs). Safety assessments include vital signs, physical examination, general laboratory analyses, urinalysis, and monitoring of adverse events (AEs).

Interventions

BIOLOGICALadalimumab

Adalimumab 40 mg Every Other Week dosing

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Diagnosis of moderate to severe Crohn's Disease confirmed by endoscopy or radiologic evaluation for greater than 4 months (16 weeks) * Inadequate response to conventional therapy for Crohn's Disease * Subjects \>=18 and \<=75 years of age and in good health (Investigator discretion) with a recent stable medical history * Harvey Bradshaw Index score of 7 or higher

Exclusion criteria

* Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study * Subject who has had surgical bowel resections within the past 6 months or is planning any resection at any time point while enrolled in the study * Female subject who is pregnant or breast-feeding or considering becoming pregnant * Previous treatment with adalimumab or previous participation in an adalimumab clinical study * Subject considered by the investigator, for any reason, to be an unsuitable candidate for the study * Subjects with any prior exposure to Tysabri® (natalizumab) * Subjects on prednisone \>40 mg/day (or equivalent), subjects on budesonide \>9 mg/day, or subjects who are taking prednisone and budesonide concurrently at Baseline

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants in Clinical Remission at Treatment Week 20. Clinical Remission Defined as Harvey Bradshaw Index (HBI) Score Less Than 5.	Week 20 of treatment	5-items that assess general well-being, abdominal pain, diarrhea, abdominal mass, and complications. Score is total of 1) subject well-being (0=very well; 4=terrible); 2) abdominal pain (0=none; 3=severe); 3) diarrhea (number of time per day); 4) abdominal mass (0=none; 3=definite and tender); 5) complications (number). Maximum total score for HBI is not specified, is dependent on number of diarrhea times each day and number of complications. Clinical remission = HBI less than 5. Highest total score at Baseline was 47. Missing data were imputed using non-responder imputation (NRI).

Secondary

Measure	Time frame	Description
Number of Participants Who Had a Reduction in Number of Draining Fistulas of at Least 50% From Baseline to Week 20	Week 20 of treatment	A count of the number of cutaneous fistulas draining was performed during each physical examination. Among participants who had draining fistulas at Baseline, the number of participants who had a reduction in the number of draining fistulas of at least 50% from Baseline to Week 20 of treatment was determined. Fistulas were classified as abdominal or perianal.
Number of Participants Who Had Extra-intestinal Manifestations (EIM) at Baseline and Resolution by Week 20.	Week 20 of treatment	Number of participants who had EIM at baseline and had resolution of those manifestations at Week 20. EIM were skin lesions, eye lesions, joint complaints, CD-related hepatic disease, thrombosis, and nephrolithiasis. EIMs were determined by physical examination.
Mean Change in Total Score of Short Inflammatory Bowel Disease Questionnaire (SIBDQ) From Baseline to Week 20	Week 20 of treatment	10-item assessment of health-related quality of life (QoL) in patients with inflammatory bowel disease. Participant marks an option from 1 to 7 for each item. For some items, 1=None of the time; for other items, 1=All of the time. Value for all items are summed. Total score=10 to 70; a high score=good quality of life (QoL). An increase in score indicates improvement. An absolute change in the SIBDQ score of 9 is considered a minimum clinically important difference (MCID) for a patient.
Number of Participants Who Were Responders at Week 20 of Treatment. A Responder Was Defined as a Participant Who Had a Decrease of 3 or More on the HBI.	Week 20 of treatment	5-items that assess general well-being, abdominal pain, diarrhea, abdominal mass, and complications. Score is total of 1) subject well-being (0=very well; 4=terrible); 2) abdominal pain (0=none; 3=severe); 3) diarrhea (number of time per day); 4) abdominal mass (0=none; 3=definite and tender); 5) complications (number). Participants who had a decrease from Baseline of at least 3 points in HBI total score were considered responders. Missing data were imputed using non-responder imputation (NRI).
Mean Change in Percent Impairment While Working From Baseline to Week 20 of Treatment	Week 20 of treatment	Percent impairment while working is a component of the Work Productivity and Activity Impairment measure. A score of 0% = no impairment. A decrease in mean score indicates lessening of impairment.
Mean Change in Overall Work Productivity and Activity Impairment Score From Baseline to Week 20	Week 20 of treatment	6-items that assess impairment in work productivity and daily activity during the 7 days before the assessment. It measures the percentage of overall impairment in work productivity and daily activity due to CD. A WPAI score of 0% = no impairment and a score of 100% = total loss of work productivity or activity. An absolute change in WPAI score of 7% is considered the minimum clinically important difference (MCID).
Mean Change in Activity Impairment Score From Baseline to Week 20	Week 20 of treatment	Daily activity is one component of the Work Productivity and Activity Impairment Questionnaire. 0% = no impairment. A decrease in the mean indicates improvement.
Mean Change in Percent Work Time Missed Due to Crohn's Disease From Baseline to Week 20 of Treatment	Week 20 of treatment	Percent Work Time Missed (Absenteeism) due to CD is one component of the Work Productivity and Activity Impairment (WPAI) Questionnaire. Score of 0% = no impairment. A decrease in the mean indicates improvement.

Countries

Austria, Belgium, Czechia, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Norway, Portugal, Slovakia, Spain, Sweden, Switzerland, United Kingdom

Participant flow

Participants by arm

Arm	Count
Open Label Adalimumab 40 mg Every Other Week or Every Week Participants received adalimumab 160 mg by subcutaneous injection at Week 0 and adalimumab 80 mg by subcutaneous injection at Week 2. Beginning at Week 4 of the study, participants received adalimumab 40 mg every other week. Beginning at Week 12, participants who experienced a disease flare (increase in Harvey Bradshaw Index of 3 or more compared to Week 4 and a total Index score of 7 or higher) and participants who did not respond to every other week treatment (non-response defined as a decrease in HBI by fewer than 3 points compared to Baseline) could switch to adalimumab 40 mg every week.	945
Total	945

Arm

Count

Open Label Adalimumab 40 mg Every Other Week or Every Week

Participants received adalimumab 160 mg by subcutaneous injection at Week 0 and adalimumab 80 mg by subcutaneous injection at Week 2. Beginning at Week 4 of the study, participants received adalimumab 40 mg every other week. Beginning at Week 12, participants who experienced a disease flare (increase in Harvey Bradshaw Index of 3 or more compared to Week 4 and a total Index score of 7 or higher) and participants who did not respond to every other week treatment (non-response defined as a decrease in HBI by fewer than 3 points compared to Baseline) could switch to adalimumab 40 mg every week.

945

Total

945

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Administrative reasons	1
Overall Study	Adverse Event	57
Overall Study	Lack of Efficacy	54
Overall Study	Lost to Follow-up	2
Overall Study	Not described	14
Overall Study	Protocol Violation	24
Overall Study	Withdrawal by Subject	8

Baseline characteristics

Characteristic	Open Label Adalimumab 40 mg Every Other Week or Every Week
Age, Categorical <=18 years	12 Participants
Age, Categorical >=65 years	14 Participants
Age, Categorical Between 18 and 65 years	919 Participants
Age Continuous	35.3 years STANDARD_DEVIATION 11.29
Region of Enrollment Austria	47 participants
Region of Enrollment Belgium	72 participants
Region of Enrollment Czech Republic	37 participants
Region of Enrollment Denmark	43 participants
Region of Enrollment Finland	5 participants
Region of Enrollment France	141 participants
Region of Enrollment Germany	266 participants
Region of Enrollment Greece	25 participants
Region of Enrollment Ireland	11 participants
Region of Enrollment Italy	64 participants
Region of Enrollment Norway	27 participants
Region of Enrollment Portugal	19 participants
Region of Enrollment Slovakia (Slovak Republic)	18 participants
Region of Enrollment Spain	47 participants
Region of Enrollment Sweden	35 participants
Region of Enrollment Switzerland	15 participants
Region of Enrollment United Kingdom	73 participants
Sex: Female, Male Female	568 Participants
Sex: Female, Male Male	377 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	395 / —
serious Total, serious adverse events	181 / —

Outcome results

Primary

Number of Participants in Clinical Remission at Treatment Week 20. Clinical Remission Defined as Harvey Bradshaw Index (HBI) Score Less Than 5.

5-items that assess general well-being, abdominal pain, diarrhea, abdominal mass, and complications. Score is total of 1) subject well-being (0=very well; 4=terrible); 2) abdominal pain (0=none; 3=severe); 3) diarrhea (number of time per day); 4) abdominal mass (0=none; 3=definite and tender); 5) complications (number). Maximum total score for HBI is not specified, is dependent on number of diarrhea times each day and number of complications. Clinical remission = HBI less than 5. Highest total score at Baseline was 47. Missing data were imputed using non-responder imputation (NRI).