Efficacy and Safety of Adalimumab in Pediatric Subjects With Moderate to Severe Crohn's Disease
Condition: Crohn's Disease
MeSH terms: Crohn Disease
Intervention: Adalimumab; Adalimumab; Adalimumab
Intervention description: All subjects received an open-label adalimumab induction regimen. Subjects weighing greater than or equal to 40 kg at Baseline received 160 mg at Week 0 and 80 mg at Week 2. Subjects weighing less than 40 kg at Baseline received 80 mg at Week 0 and 40mg at Week 2.; Subjects randomized to the Low-Dose treatment group received either 20 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 10 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blind (DB) ew therapy they could be switched to open-label ew therapy.; Subjects randomized to the High-Dose treatment group received either 40 mg adalimumab every other week (eow) (if Week 4 body weight [BW] was greater than or equal to 40 kg) or 20 mg adalimumab eow (if Week 4 BW less than 40 kg). Starting at the Week 12 study visit, subjects who experienced a disease flare or were non-responders could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. If a subject continued to experience a flare or met the definition of non-response following an 8-week course of double-blinded (DB) ew therapy they could be switched to open-label ew therapy.
Intervention MeSH terms: Adalimumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 192.0
Sex: All
Minimum age: 6 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Crohn's Disease

Summary:

      The purpose of this study is to determine Efficacy, Pharmacokinetics, and Safety of
      Adalimumab in Pediatric Subjects With Moderate to Severe Crohn's Disease
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subjects between the ages of 6 and 17, inclusive, prior to baseline dosing.

          2. Subjects with a diagnosis of Crohn's disease for greater than 12 weeks prior to
             screening, confirmed by endoscopy or radiologic evaluation.

          3. PCDAI > 30 despite concurrent treatment with an oral corticosteroid, and/or
             azathioprine (AZA) or 6-mercaptopurine (6-MP) or methotrexate (MTX) as defined below:

               -  Oral corticosteroid - Prednisone of ≥ 10 mg/day or equivalent, but not exceeding
                  40 mg, with a stable dose for at least two weeks prior to Baseline.

               -  Azathioprine or 6-MP - AZA dose of ≥ 1.5 mg/kg/day or 6-MP dose of ≥ 1 mg/kg/day
                  rounded to the nearest available tablet formulation, or a dose that is the
                  highest tolerated for the subject, in the opinion of the investigator (for
                  example due to leukopenia, elevated liver enzymes, nausea, etc.) for at least 8
                  weeks prior to Baseline with a stable dose for at least 4 weeks prior to
                  Baseline.

               -  MTX dose of ≥ 5 mg once weekly, either subcutaneously (SC), intramuscularly (IM),
                  or orally for subjects whose body weight is ≥ 20 kg, or a dose that is the
                  highest tolerated for the subject, in the opinion of the investigator (for
                  example due to leukopenia, elevated liver enzymes, nausea, etc.) for at least 8
                  weeks prior to Baseline with a stable dose for at least 4 weeks prior to
                  Baseline.

               -  MTX dose of 0.2 mg/kg, up to 5 mg, once weekly, either SC, IM, or orally for
                  subjects whose body weight is < 20 kg, or a dose that is the highest tolerated
                  for the subject, in the opinion of the investigator (for example due to
                  leukopenia, elevated liver enzymes, nausea, etc.) for at least 8 weeks prior to
                  Baseline with a stable dose for at least 4 weeks prior to Baseline.

               -  Concurrent therapy will not be required for subjects who within the past 2 years
                  in the opinion of the Investigator have not responded to or could not tolerate
                  systemic corticosteroids, AZA, 6-MP, or MTX as defined below:

                    -  Corticosteroids:

                         -  Failed to successfully respond to corticosteroids, or

                         -  Medical complications and/or adverse events (AEs) from corticosteroids
                            that in the judgment of their physician, precludes their use (e.g.
                            psychosis, uncontrolled diabetes, osteoporosis, or osteonecrosis).

                    -  Azathioprine, 6-MP or MTX: -

                         -  Failed to successfully respond to these drugs or

                         -  Medical complications and/or AEs that in the judgment of their
                            physician, precludes their use (e.g. allergic reaction, pancreatitis,
                            elevated liver enzymes, hepatitis or leukopenia).

          4. If female, subjects who were sexually active and were of child-bearing potential
             practicing an approved method of birth control throughout the study and for 150 days
             after study completion. Examples of approved methods of birth control included the
             following:

               -  Condoms, sponge,foam,jellies,diaphragm, or intrauterine device (IUD)

               -  Oral,parenteral, or intravaginal contraceptives for 12 weeks prior to adalimumab
                  administration

               -  A vasectomized partner.

          5. Parent or legal guardian,as required,had voluntarily signed and dated an informed
             consent form (IFC), approved by an Institutional Review Board (IRB)/ Independent
             Ethics Committee (IEC).

          6. Adequate cardiac, renal and hepatic function as determined by principal investigator
             and demonstrated by Screening laboratory evaluations, questionnaires, and physical
             examination results that are within normal limits.

          7. Parent or legal guardian was willing to actively supervise storage and administration
             of study drug and to ensure that the time of each dose was accurately recorded in the
             subject's diary.

          8. Subjects who had previously received infliximab, providing the subject had an initial
             response and then discontinued use due to a loss of response, or discontinued use due
             to intolerance.

        Exclusion Criteria:

          1. History of cancer or lymphoproliferative disease other than a successfully and
             completely treated cutaneous squamous cell or basal cell carcinoma or
             carcinoma-in-situ of the cervix.

          2. History of listeria, histoplasmosis, chronic or active hepatitis B infection, human
             immunodeficiency virus (HIV), an immunodeficiency syndrome, central nervous system
             (CNS) demyelinating disease, or active tuberculosis (TB) (receiving treatment or not
             receiving treatment), severe infections such as sepsis and opportunistic infections.

          3. Subject with infectious colitis, ulcerative colitis or indeterminate colitis as
             determined by the investigator and Abbott Medical Monitor.

          4. Subject with symptomatic known obstructive strictures.

          5. Subject who had surgical bowel resections within the past 24 weeks of the Baseline
             visit or planned any resection at any time point while enrolled in the study.

          6. Subject with an ostomy or ileo-anal pouch. (Subjects with a previous ileo-rectal
             anastomosis were not excluded).

          7. Subject who had short bowel syndrome as determined by the investigator.

          8. Subject who was currently receiving total parenteral nutrition (TPN).

          9. Females who were pregnant or were currently breast-feeding.

         10. Subject who had received any investigational chemical agent in the past 30 days or 5
             half-lives prior to Baseline (whichever was longer).

         11. Subject who had received any investigational biological agent in the past 16 weeks or
             5 half-lives prior to Baseline (whichever was longer).

         12. Subject who has had systemic antibiotic, antiviral or antifungal treatment(s) within 3
             weeks prior to Baseline for any non-Crohn's related infections.

         13. Subject with a history of clinically significant drug or alcohol abuse in the last
             year.

         14. Subjects with a poorly controlled medical condition such as: uncontrolled diabetes,
             recurrent infections, unstable ischemic heart disease, moderate to severe heart
             failure, recent cerebrovascular accidents and any other condition which, in the
             opinion of the investigator or the Sponsor, would put the subject at risk by
             participation in the protocol.

         15. Subjects with positive C. difficile stool assay.

         16. Subject who previously used infliximab within eight weeks of Baseline.

         17. Subject who previously used infliximab and had not clinically responded at any time
             ("primary non-responder") unless subject experienced a treatment limiting reaction to
             infliximab.

         18. Previous treatment with any other anti-TNF agent except infliximab.

         19. Received previous treatment with adalimumab or previous participation in an adalimumab
             clinical study.

         20. Screening laboratory and other analyses showing any of the following abnormal results:

               -  Electrocardiogram (ECG) - with clinically significant abnormalities;

               -  Aspartate transaminase (AST) or alanine transaminase (ALT) >1.75 x the upper
                  limit of the reference range;

               -  Total bilirubin ≥ 3 mg/dL;

               -  Serum creatinine > 1.6 mg/dL;

         21. Subjects on AZA, 6-MP, or MTX who had not been on these medications for at least 8
             weeks prior to Baseline and on stable doses of these medications for at least 4 weeks
             prior to Baseline. Subjects who had been on AZA, 6-MP, or MTX who had discontinued
             these medications within 8 weeks of Baseline.

         22. Subjects on aminosalicylates, or Crohn's-related antibiotics (fluoroquinolones such as
             ciprofloxacin or nitroimidazole derivatives such as metronidazole) that had not been
             on stable doses of these medications for at least 4 weeks prior to Baseline. In
             addition, subjects on aminosalicylates or Crohn's-related antibiotic treatments who
             had discontinued these medications within four weeks of Baseline.

         23. Subjects on prednisone > 40 mg/day (or equivalent) or subjects on < 10 mg/day
             prednisone and subjects who were not on a stable dose for at least 2 weeks prior to
             Baseline. In addition, subjects who discontinued prednisone (or equivalent) within 2
             weeks of Baseline.

         24. Subjects on growth hormone that had not been on a stable dose for at least 12 weeks
             prior to Baseline. Subjects had to consent to remain on a stable dose through the
             duration of the study.

         25. Subjects on budesonide > 9 mg/day and subjects who were not on stable doses for at
             least 2 weeks prior to Baseline. In addition, subjects who discontinued budesonide
             within 2 weeks of Baseline.

         26. Subjects who were currently taking both budesonide and prednisone (or equivalent).

         27. Subjects who had undergone therapeutic enemas within two weeks prior to Baseline.

         28. Subjects who had been on cyclosporine (intravenous [IV], oral), tacrolimus (any form),
             or mycophenolate mofetil within 28 days of Baseline.

         29. Subjects who had been on Kineret® (anakinra) must discontinue use 2 days prior to
             Baseline.

         30. Subjects with any prior exposure to Tysabri (natalizumab).

         31. Subjects with known hypersensitivity to the excipients of adalimumab as stated in the
             label.

         32. Subjects with a previous history of dysplasia of the gastrointestinal tract.

         33. Subjects who weighed < 17 kg at Screening.

         34. Subject not in compliance with prior and concomitant medications.