Efficacy and Safety of Adalimumab in Pediatric Subjects With Moderate to Severe Crohn's Disease

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

M06-806 (NCT # NCT00409682) was a Phase 3, multi-center, randomized, double-blind (DB), efficacy, safety, and pharmacokinetic (PK) study designed to evaluate the efficacy of 2 dose regimens for the induction and maintenance of clinical remission in pediatric subjects between the ages of 6 and 17 (inclusive) with moderate to severe Crohn's disease (CD) (defined by Pediatric Crohn's Disease Activity Index \[PCDAI \> 30\]). Subjects must have either failed conventional therapy for CD or have previously received infliximab and lost response/had intolerance to infliximab.

Approximately 186 pediatric subjects between the ages of 6 and 17 were planned to be entered into the study at approximately 55 sites in the US, Canada, and Europe. At least 80 subjects were to be ≥ 13 years old at Baseline and one-third to one-half of the study population were to be subjects who had previously lost response or were intolerant to infliximab.

The duration of the study was to be up to 65 weeks, which included a 1- to 3-week Screening period, an Induction period, a Maintenance period, and a 70-day follow-up phone call for all subjects that either terminated early from the study or did not rollover into the extension study (\[NCT # 00686374\], to evaluate the long-term maintenance of clinical response, safety, and tolerability of repeated administration of adalimumab).

All subjects received an induction regimen administered at Baseline (Week 0) and Week 2. The open-label (OL) induction dose was based on the subject's Baseline body weight. Subjects weighing ≥ 40 kg were to receive 160 mg at Week 0 and 80 mg adalimumab at Week 2. Subjects weighing \< 40 kg were to receive 80 mg at Week 0 and 40 mg adalimumab at Week 2.

At Week 4, subjects were to be randomized 1:1 to 1 of 2 DB maintenance treatment groups (Low-Dose or High-Dose), stratified by Week 4 clinical responder status (clinical response was defined as decrease in PCDAI of ≥ 15 points from the Baseline score), body weight at Week 4 and prior exposure to infliximab. Subjects randomized to the High-Dose treatment group were to receive either 40 mg adalimumab subcutaneous (SC) every other week (eow) (if Week 4 body weight ≥ 40 kg) or 20 mg adalimumab SC eow (if Week 4 body weight \< 40 kg). Subjects randomized to the Low-Dose treatment group were to receive either 20 mg adalimumab SC eow (if Week 4 body weight ≥ 40 kg) or 10 mg adalimumab SC eow (if Week 4 body weight \< 40 kg).

Subject's body weight taken at Week 26 was to be used to readjust the maintenance dosing regimen for a subject whose body weight had increased from \< 40 kg to ≥ 40 kg during the study.

Subjects were expected to remain on blinded eow therapy throughout the 48-week study DB Maintenance period. However, starting at the Week 12 study visit, subjects who experienced a disease flare (increase in the PCDAI ≥ 15 points when compared to Week 4 and an absolute PCDAI above 30) or were non-responders (not achieving a decrease in the PCDAI score of at least 15 points when compared to the Baseline score for 2 consecutive visits at least 2 weeks apart) could be switched from blinded eow dosing to blinded every week (ew) dosing, continuing with the same blinded dose. During blinded ew treatment, if a subject continued to experience a flare or met the definition of non-response following an 8 week course of DB ew therapy, they were to be switched to OL ew therapy. The dosage of the OL ew therapy was 20 mg for subjects \< 40 kg and 40 mg for subjects ≥ 40 kg.

This study used the PCDAI to determine efficacy of the study drug. The primary efficacy endpoint is the proportion of subjects who are in clinical remission at Week 26, as measured by the PCDAI in the intent-to-treat population. Clinical remission is defined as a PCDAI score of ≤ 10.

The clinical response indicators include clinical remission as defined by PCDAI score at Week 52 and clinical response as defined by PCDAI score at Week 26 and at Week 52.

The patient reported outcome is the change from Baseline in total IMPACT III scores at Week 26 and Week 52.

The safety parameters (adverse events, laboratory data, and vital signs) were assessed at all visits throughout the study.

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.