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

• Clinical and Endoscopic Evaluation of the Efficacy of Combination Therapy [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  The primary efficacy outcome will be assessed by comparing the change in the modified Baron score from baseline to the final visit between the treatment groups
• Identify covariates [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  To identify covariates (gender, weight, BMI, albumin, TNF, CRP, disease severity, concomitant medications) that might influence the clearance and or disposition of adalimumab
• Relationship between PK and efficacy [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  To evaluate the relationship between PK and efficacy (PD)

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

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

• 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 Name: MTX
• 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 Name: MTX
• Drug: Adalimumab
  Subjects will receive 18 weekly doses of adalimumab
  Other Name: Humira

• 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
  Interventions:

  • Drug: MTX 12.5
  • Drug: Adalimumab
• 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
  Interventions:

  • Drug: MTX 25
  • Drug: Adalimumab
• 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
  Intervention: Drug: Adalimumab

• 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.
• 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. Epub 2012 Feb 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. Epub 2011 Jan 5.
• 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.

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.