| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate to severe Crohn’s Disease |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.1 |
| E.1.2 | Classification code | 10011401 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the Main Study will be to compare the efficacy of infliximab + placebo capsules and infliximab combined with azathioprine (AZA) to azathioprine + placebo infusions in the treatment of patients with moderate-to-severe Crohn’s disease.
The primary objective of the Study Extension will be to evaluate the long-term efficacy and safety of infliximab and/or AZA through week 54. |
|
| E.2.2 | Secondary objectives of the trial |
1) To assess the effect of infliximab and/or AZA on complete mucosal healing in patients with Crohn’s disease.
2) To assess the corticosteroid-sparing abilities of therapy with infliximab and/or AZA in patients with moderate-to-severe Crohn’s disease. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
To be eligible for the trial, patients must meet all of the following criteria:
1) Are considered eligible according to the following tuberculosis (TB) screening criteria:
a. Have no history of latent or active TB prior to screening.
b. Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c. Have had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB prior to or simultaneously with the first administration of study agent.
d. Within 1 month prior to the first administration of study agent, either have a negative tuberculin skin test or have a newly identified positive tuberculin skin test during screening in which active TB has been ruled out and for which appropriate treatment for latent TB has been initiated either prior to or simultaneously with the first administration of study agent.
e. Have a chest radiograph (both posterior-anterior and lateral views), taken within 3 months prior to the first administration of study agent and read by a qualified radiologist, with no evidence of current active TB or old inactive TB.
2) Are 18 years of age or older at the time of informed consent; may be male or female.
3) Have a CDAI score of ≥ 220 and ≤ 400.
4) Have Crohn’s disease of at least 6 weeks duration, with colitis, ileitis, or ileocolitis, confirmed by radiography or endoscopy.
5) Are EITHER:
a. Corticosteroid-dependent (ie, patients who become symptomatic after a decrease in corticosteroid dose such that they have a CDAI ≥ 220 [budesonide alone does not qualify as a corticosteroid for the purpose of this criterion]), OR
b. Are being considered for their second (or greater) course of oral systemic corticosteroids (prednisone or equivalent), (budesonide alone does not qualify as a corticosteroid for the purpose of this criterion) for active Crohn’s disease within the past 12 months, OR
c. Are 5-ASA failures (i.e., patients who have not had an adequate response to a course of 5-ASA [sulfasalazine] 3 g/day for at least 4 weeks, or mesalamine 2.4 g/day or equivalent for at least 4 weeks). OR
d. Are budesonide failures (i.e., patients who have not had an adequate response to a course of budesonide 6 mg/day for at least 4 weeks). Budesonide failures who are 5-ASA-naive are eligible for this study.
6) Are able to adhere to the concomitant medication requirements as described in the protocol, section 4.1: Inclusion Criteria (under bullet six).
7) Are able to adhere to the study visit schedule and other protocol requirements.
8) Are capable of providing written informed consent. Written informed consent must be obtained prior to performing any study-related procedures.
9) Women of childbearing potential and all men must be using adequate birth control measures (eg, abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) throughout the study and must continue such precautions for 6 months after receiving the last study agent infusion.
10) The screening laboratory tests must meet the following criteria:
a. Hemoglobin > 8.5 g/dL
b. White blood cell (WBC) count > 3.5 billion cells/L
c. Neutrophils > 1.5 billion cells/L
d. Platelets >100 billion cells/L
e. Aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) levels must be within 2 times the upper limit of normal (ULN) for the laboratory conducting the test. Alkaline phosphatase levels must be within 3 times ULN for the laboratory conducting the test. |
|
| E.4 | Principal exclusion criteria |
Patients who:
1) Have local manifestations of Crohn’s disease such as strictures, abscesses, or other disease complications for which surgery might be indicated (conditions possibly confounding the evaluation of benefit from study treatment) or which might preclude utilization of CDAI to assess response to therapy If an abscess has been present previously, at least 6 weeks must have elapsed between drainage of the abscess and screening. 2) Have had intra-abdominal surgery within 3 months prior to screening. 3) Have received treatment with pure parenteral nutrition (TPN) within 6 weeks of screening. Enteral nutrition therapy is permitted. 4) Have an ostomy or stoma. 5) Have known severe fixed symptomatic stenosis of the large or small intestine. 6) Are pregnant, nursing, or planning pregnancy (both men and women) during the trial or within the 6-month period thereafter. 7) Have shown a previous immediate hypersensitivity response, including anaphylaxis, to an immunoglobulin product (plasma-derived or recombinant, eg, monoclonal antibody). 8) Have a known allergy to murine proteins or other chimeric proteins. 9) Have received within 3 months prior to screening or are expected to receive any live virus (eg, small pox) or live bacterial vaccinations during the trial or up to 3 months after the last administration of study agent. 10) Have had a serious infection (eg, hepatitis, pneumonia, or pyelonephritis), or have been hospitalized for an infection, or have been treated with intravenous antibiotics for an infection within 2 months prior to screening. 11) Have a history of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, prior to screening. 12) Have had a Bacille Calmette-Guerin (BCG) vaccination within 12 months of screening. 13) Have had a nontuberculous mycobacterial infection or opportunistic infection (eg, cytomegalovirus, Pneumocystis carinii, aspergillosis) within 6 months prior to screening. 14) Have a chest radiograph within 3 months prior to randomization that shows an abnormality suggestive of a malignancy or current active infection, including TB. 15) Are considered ineligible according to the TB eligibility assessment, screening and early detection of reactivation rules defined in the protocol. 16) Have documented current active hepatitis B (surface antigen positive) or a history of documented hepatitis C infection. 17) Have documented human immunodeficiency virus (HIV) infection. 18) Have current signs or symptoms of or a history of systemic lupus erythematosus; severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic, or cerebral diseases.
19) Have a transplanted organ (with the exception of a corneal transplant performed > 3 months prior to screening). 20) Have a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location or splenomegaly. 21) Have any known malignancy or history of malignancy within the 5-year period prior to screening (except for squamous or basal cell carcinoma of the skin that has been completely excised without evidence of recurrence). 22) Have multiple sclerosis or other central demyelinating disorder. 23) Have had a chronic or recurrent infectious disease including but not limited to chronic renal infection; chronic chest infection (eg, bronchiectasis); sinusitis; recurrent urinary tract infection (recurrent pyelonephritis or chronic nonremitting cystitis); open, draining, or infected skin wound or ulcer. 24) Have a serious concomitant illness that could interfere with the patient’s participation in the trial. 25) Have used any investigational drug within 30 days prior to screening, or within 5 half-lives of the investigational agent, whichever is longer. 26) Are currently participating in another investigative trial using an investigational agent, procedure, or medical device during participation in this trial. 27) Have previously participated in 3 or more investigative trials in Crohn’s disease within 5 years prior to screening. Participation in registry studies (eg, TREAT) does not constitute an Exclusion criterion. Patients participating in the TREAT registry must discontinue from the registry before enrolling in SONIC. 28) Have a history of substance abuse (drug or alcohol) within the previous 3 years, history of noncompliance to medical regimens, or other condition/circumstance that could interfere with the patient’s adherence to protocol requirements (eg, psychiatric disease, lack of motivation, travel, etc). 29) Have a concomitant diagnosis or any history of congestive heart failure (CHF). 30) Are unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access. 31) Are known to have a homozygous mutant or heterozygous thiopurine methyltransferase (TPMT) phenotype. 32) Weigh more than 140 kg (310 lbs). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the proportion of patients in corticosteroid-free clinical remission, ie, patients with a CDAI of less than 150 who have not been taking oral systemic corticosteroids (prednisone or equivalent) for at least 3 weeks and have not been taking budesonide at a dose greater than 6 mg/day for at least 3 weeks at week 26. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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