Pharmacokinetics of Adalimumab With Methotrexate for Treatment of Patients With Ulcerative Colitis (UC)

• Sponsor: Alimentiv Inc. (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01716039
• Collaborator: Abbott (Industry)
• Enrollment: 22
• Arms: 3
• Duration (Months): 37.6

Study Details

Study Description

Brief Summary

Assess the body's reaction to dose-response relationship for the adalimumab/Methotrexate interaction in subjects with moderately to severely active ulcerative colitis.

Condition or Disease	Intervention/Treatment	Phase
Ulcerative Colitis	Drug: MTX 12.5; Drug: MTX 25; Drug: Adalimumab	Phase 2

Detailed Description

Assess the Pharmacokinetic dose-response relationship for the adalimumab/Methotrexate interaction in subjects with moderately to severely active UC.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Study to Evaluate the Pharmacokinetics of Adalimumab in Combination With Methotrexate for the Treatment of Patients With Ulcerative Colitis
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Jul 18, 2016
• Actual Study Completion Date: Jul 18, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: MTX 12.5 Receive once weekly oral dosing with MTX 12.5 mg (n=40) two weeks prior to the initiation of adalimumab 18 weekly doses of MTX and/or placebo in addition to doses of adalimumab	Drug: MTX 12.5; once weekly oral dosing with MTX 12.5 mg (n=40) two weeks prior to the initiation of adalimumab. Randomization will be stratified by disease activity (modified Mayo Score ≤9 or >9). Subjects will receive 18 weekly doses of MTX in addition to doses of adalimumab; Other Names: MTX ; Drug: Adalimumab; Subjects will receive 18 weekly doses of adalimumab; Other Names: Humira
Active Comparator: MTX 25 mg Once weekly oral dosing with MTX 25 mg (n=40) two weeks prior to the initiation of adalimumab 18 weekly doses of MTX in addition to doses of adalimumab	Drug: MTX 25; once weekly oral dosing with MTX 25 mg (n=40) two weeks prior to the initiation of adalimumab. Randomization will be stratified by disease activity (modified Mayo Score ≤9 or >9). Subjects will receive 18 weekly doses of MTX in addition to doses of adalimumab; Other Names: MTX ; Drug: Adalimumab; Subjects will receive 18 weekly doses of adalimumab; Other Names: Humira
Placebo Comparator: Placebo Once weekly oral dosing with placebo (n=20) two weeks prior to the initiation of adalimumab. Subjects will receive 18 weekly doses of placebo in addition to doses of adalimumab	Drug: Adalimumab; Subjects will receive 18 weekly doses of adalimumab; Other Names: Humira

Outcome Measures

Primary Outcome Measures

1. Change in the Modified Baron Score From Baseline to the Final Visit (Week 18) Between the Treatment Groups [Baseline up to Week 18]

   The modified Baron score is scored on a 0-4 scale that evaluates friability, vascular pattern, bleeding and ulceration on a 5-point grading scale with a higher score indicating more severe disease activity. The mean change and 95% CI are based on least square means from the analysis of covariance

Secondary Outcome Measures

1. Change in the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Score From Baseline to the Final Visit (Week 18) Between the Treatment Groups. [Baseline up to Week 18]

   UCEIS is a simple scoring tool that contains3 items (vascular pattern, bleeding, and ulceration). The UCEIS scores 3 endoscopic items: vascular pattern (ranges 0-2 points), bleeding (ranges 0-3 points), and the presence of ulcers and erosions (ranges 0-3 points).The total UCEIS is calculated by adding up the 3 item scores(range,0-8points), with higher scores representing more severe disease activity. The mean change and 95% CI are based on least square means from the analysis of covariance

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or non-pregnant, non-lactating females. Females of child bearing potential must have a negative serum pregnancy test prior to randomization, and must use a hormonal (oral, implantable or injectable) or barrier method of birth control throughout the study. Females unable to bear children must have documentation of such in the source records (i.e., tubal ligation, hysterectomy, or post-menopausal [defined as a minimum of one year since the last menstrual period]).

• Diagnosis of UC confirmed by established criteria, regardless of disease duration.

• Moderate to severely active UC, defined by a modified Mayo Score ≥6, with confirmed endoscopic activity by central reader (Mayo endoscopic subscore ≥2).

• Require initiation with adalimumab for induction of remission.

• Ability of subject to swallow study drug capsules.

• Ability of subject to participate fully in all aspects of this clinical trial.

• Written informed consent must be obtained and documented.

Exclusion Criteria:

• Prior treatment with a TNF antagonist or biological therapy.

• Prior treatment with MTX.

• Disease limited to the rectum (proctitis).

• Documented presence of antibodies against adalimumab.

• Contraindication for anti-TNF or MTX therapy.

• Contraindication for endoscopy.

• Ostomy.

• Planned surgery.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Alimentiv Inc.
• Abbott

Investigators

• Principal Investigator: Brian Feagan, MD, Robarts Research Institute - Western University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Baert F, Noman M, Vermeire S, Van Assche G, D' Haens G, Carbonez A, Rutgeerts P. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med. 2003 Feb 13;348(7):601-8.
• Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, Panaccione R, Fedorak RN, Tighe MB, Huang B, Kampman W, Lazar A, Thakkar R. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011 Jun;60(6):780-7. doi: 10.1136/gut.2010.221127. Epub 2011 Jan 5.
• Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005 Dec 8;353(23):2462-76. Erratum in: N Engl J Med. 2006 May 18;354(20):2200.
• Rutgeerts P, Van Assche G, Sandborn WJ, Wolf DC, Geboes K, Colombel JF, Reinisch W; EXTEND Investigators, Kumar A, Lazar A, Camez A, Lomax KG, Pollack PF, D'Haens G. Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial. Gastroenterology. 2012 May;142(5):1102-1111.e2. doi: 10.1053/j.gastro.2012.01.035. Epub 2012 Feb 8.

• Responsible Party: Alimentiv Inc.
• ClinicalTrials.gov Identifier: NCT01716039
• Other Study ID Numbers: RP1204
• First Posted: Oct 29, 2012
• Last Update Posted: Jun 23, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by Alimentiv Inc.: Moderately to severely active Ulcerative Colitis
• Additional relevant MeSH terms: Colitis; Colitis, Ulcerative; Ulcer; Adalimumab

Study Results

Participant Flow

Arm/Group Title	Placebo	MTX 12.5 mg	MTX 25 mg
Arm/Group Description	Participants randomized to receive placebo at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab	Participants randomized to receive Methotrexate 12.5 mg at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab	Participants randomized to receive Methotrexate 25.0 mg at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab
Period Title: Overall Study
STARTED	4	8	10
COMPLETED	3	6	8
NOT COMPLETED	1	2	2

Baseline Characteristics

Arm/Group Title	Placebo	MTX 12.5 mg	MTX 25 mg	Total
Arm/Group Description	Participants randomized to receive placebo at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab	Participants randomized to receive Methotrexate 12.5 mg at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab:18 weekly doses of adalimumab	Participants randomized to receive Methotrexate 25.0 mg at Week 00 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab	Total of all reporting groups
Overall Participants	4	8	10	22
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.9 (14.6)	46.2 (13.7)	48.5 (13.5)	46.5 (13.3)
Sex/Gender, Customized (Count of Participants)
Male	4 100%	3 37.5%	7 70%	14 63.6%
Female	0 0%	5 62.5%	3 30%	8 36.4%
Disease Duration (Years) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.8 (8.0)	5.1 (3.7)	7.0 (9.3)	7.0 (7.4)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	75.0 (15.3)	75.5 (15.2)	89.6 (20.5)	81.8 (18.5)
C-Reactive protein (CRP) (mg/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/L]	6.6 (3.9)	5.2 (2.7)	15.1 (16.1)	9.9 (11.8)
Fecal Calprotectin (ug/g) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ug/g]	606.7 (566.6)	675.8 (431.6)	545.2 (362.0)	603.7 (400.1)
Mayo Clinic Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	9.0 (1.2)	8.6 (2.1)	8.7 (2.1)	8.7 (1.9)

Outcome Measures

1. Primary Outcome

Title	Change in the Modified Baron Score From Baseline to the Final Visit (Week 18) Between the Treatment Groups
Description	The modified Baron score is scored on a 0-4 scale that evaluates friability, vascular pattern, bleeding and ulceration on a 5-point grading scale with a higher score indicating more severe disease activity. The mean change and 95% CI are based on least square means from the analysis of covariance
Time Frame	Baseline up to Week 18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	MTX 12.5mg	MTX 25 mg
Arm/Group Description	Participants randomized to receive placebo at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks. Adalimumab: 18 weekly doses of adalimumab	Participants randomized to receive Methotrexate 12.5 mg at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks. Adalimumab: 18 weekly doses of adalimumab	Participants randomized to receive Methotrexate 25.0 mg at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab
Measure Participants	4	8	10
Mean (Standard Deviation) [score on a scale]	0.7 (1.2)	1.1 (1.6)	0.9 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, MTX 12.5mg
	Comments
	Type of Statistical Test	Other
	Comments	Comparing the change in the modified Baron score from baseline to week 18 between the treatment groups
Statistical Test of Hypothesis	p-Value	0.758
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, MTX 25 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Change in the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Score From Baseline to the Final Visit (Week 18) Between the Treatment Groups.
Description	UCEIS is a simple scoring tool that contains3 items (vascular pattern, bleeding, and ulceration). The UCEIS scores 3 endoscopic items: vascular pattern (ranges 0-2 points), bleeding (ranges 0-3 points), and the presence of ulcers and erosions (ranges 0-3 points).The total UCEIS is calculated by adding up the 3 item scores(range,0-8points), with higher scores representing more severe disease activity. The mean change and 95% CI are based on least square means from the analysis of covariance
Time Frame	Baseline up to Week 18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	MTX 12.5 mg	MTX 25 mg
Arm/Group Description	Participants randomized to receive placebo at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks. Adalimumab: 18 weekly doses of adalimumab	Participants randomized to receive Methotrexate 12.5 mg at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab	Participants randomized to receive Methotrexate 25.0 mg at Week 0(two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab
Measure Participants	4	8	10
Mean (95% Confidence Interval) [score on a scale]	0.5	0.7	1.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, MTX 12.5mg, MTX 25 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.908
	Comments	p-value for the overall treatment difference is based on an analysis of covariance adjusting for baseline UCEIS
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	Through study completion, an average of 18 weeks
Arm/Group Title	Placebo		MTX 12.5 mg		MTX 25 mg
Arm/Group Description	Participants randomized to receive placebo at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab		Participants randomized to receive Methotrexate 12.5 mg at Week 0 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab: 18 weekly doses of adalimumab		Participants randomized to receive Methotrexate 25.0 mg at Week 00 (two weeks prior to the initiation of adalimumab induction therapy) and then every week for 18 weeks Adalimumab:18 weekly doses of adalimumab
All Cause Mortality
	Placebo		MTX 12.5 mg		MTX 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		MTX 12.5 mg		MTX 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		2/8 (25%)		1/10 (10%)
Gastrointestinal disorders
Colitis ulcerative	0/4 (0%)		1/8 (12.5%)		1/10 (10%)
Infections and infestations
Urosepsis	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		MTX 12.5 mg		MTX 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/4 (75%)		8/8 (100%)		5/10 (50%)
Eye disorders
Eye pain	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Ocular hyperaemia	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Gastrointestinal disorders
Abdominal pain	0/4 (0%)		1/8 (12.5%)		1/10 (10%)
Colitis ulcerative	1/4 (25%)		1/8 (12.5%)		0/10 (0%)
Dysgeusia	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Nausea	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Diarrhoea	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Epigastric discomfort	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Haematochezia	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Constipation	0/4 (0%)		0/8 (0%)		1/10 (10%)
Vomiting	0/4 (0%)		0/8 (0%)		1/10 (10%)
Throat irritation	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
General disorders
Asthenia	0/4 (0%)		0/8 (0%)		1/10 (10%)
Injection site erythema	0/4 (0%)		0/8 (0%)		1/10 (10%)
Infections and infestations
Viral upper respiratory tract infection	0/4 (0%)		1/8 (12.5%)		1/10 (10%)
Urinary tract infection	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Metabolism and nutrition disorders
Dehydration	0/4 (0%)		0/8 (0%)		1/10 (10%)
Musculoskeletal and connective tissue disorders
Neck pain	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Nervous system disorders
Headache	1/4 (25%)		0/8 (0%)		1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	0/4 (0%)		0/8 (0%)		1/10 (10%)
Cough	0/4 (0%)		0/8 (0%)		1/10 (10%)
Skin and subcutaneous tissue disorders
Contusion	1/4 (25%)		0/8 (0%)		0/10 (0%)
Rash	1/4 (25%)		0/8 (0%)		1/10 (10%)
Alopecia	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Erythema nodosum	0/4 (0%)		1/8 (12.5%)		0/10 (0%)
Vascular disorders
Pallor	0/4 (0%)		0/8 (0%)		1/10 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI of this Investigator-Initiated study had right to prior publication. If PI did not commence publication within 12months after the close of trial at all sites or after PI's manuscript was accepted for publication, whichever occurs first, the Sub-I and Sub-Institution were free to publish or present, provided that the Sub-I provided to the PI any doc. to be submitted for publication at least 30days prior to the planned date of submission for publication to permit a review of the Manuscript.