| 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 | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011401 |
| E.1.2 | Term | Crohn's disease |
|
| 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 | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Full title: SONIC Open-Label Extension Study
Date: 12 March 2008, 7th amendment of original SONIC protocol
The primary objective is to assess the long-term efficacy of infliximab maintenance therapy in achieving and/or maintaining remission at week 52(approximately 1 year) after enrollment in SONIC OLE in patients with Crohn’s disease. Patients in clinical remission will be defined as those with a CDAI < 150.
The secondary objectives are:
1. To evaluate the benefits of long-term maintenance treatment with infliximab.
2. To assess the rate of discontinuation from long-term maintenance treatment with
infliximab.
3. To evaluate health-related quality of life and pharmacoeconomic benefits of long-term maintenance treatment with infliximab. Safety will be assessed by analysis of adverse events and serious adverse events throughout the study. |
|
| E.3 | Principal inclusion 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.
d. Within 1 month prior to the first administration of study agent have a negative tuberculin skin test.
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. For European Countries Only: If according to country-specific guidelines lateral views are not done, having only the posterior-anterior view is acceptable.
2) Are 21 years of age or older at the time of the first study infusion (Week 0); may be male or female.
3) Have a CDAI score of ≥ 220 and ≤ 450.
4) Have Crohn’s disease of at least 6 weeks duration, with colitis, ileitis, or ileocolitis, confirmed by radiography or endoscopy. Single or multiple draining fistulas may be present provided there is no evidence of active fistula-related abscess.
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 (ie, patients who have not had an adequate response to at least a 4-week course of 5-ASA or sulfasalazine (ie, 2.4 g/day 5-ASA or equivalent in sulfasalazine [Germany only: 3 to 4 g/day 5-ASA or equivalent in sulfasalazine] 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 [Germany only: ≥9 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 who are (or become) sexually active must use adequate birth control measures (eg, 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. WBC count > 3.5 billion cells/L
c. Neutrophils > 1.5 billion cells/L
d. Platelets >100 billion cells/L
e. AST and ALT levels must be within 2 times the ULN for the laboratory conducting the test. Alkaline phosphatase levels must be within 3 times ULN for the laboratory conducting the test.
For the OLE extension the following criteria are applicable:
1. Must have completed the week 50 visit in the Main study.
2. Have a CDAI score of ≤450 at the time of the first infusion.
3. Are able to adhere to the concomitant medication requirements as detailed in
Section 7 of this Appendix.
4. Are able to adhere to the SONIC OLE visit schedule (see Section 6 of this
Appendix).
5. Are capable of providing written informed consent. Written informed consent
must be obtained prior to performing any procedures in SONIC OLE.
6. Women of childbearing potential and all men who are (or become) sexually
active must use adequate birth control measures (eg, 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 infliximab infusion.
7. The screening laboratory tests must meet the following criteria:
a. Hemoglobin > 8.5 g/dL (5.3 mmol/L)
b. White blood cell (WBC) count > 3.5 x 109 cells/L
c. Neutrophils > 1.5 x 109 cells/L
d. Platelets >100 x 109 cells/L
e. ALT levels must be within 5 times the ULN for the laboratory
conducting the test. |
|
| E.4 | Principal exclusion criteria |
1)Have local manifestations of CD like strictures, active fistula-related abscesses, or other complications for which surgery might be indicated or 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 6 months prior to screening.
3)Have received treatment with parenteral nutrition within 6 weeks of screening.
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 during the trial or within 6-month period thereafter.
7)Have shown an hypersensitivity response, including anaphylaxis, to an immunoglobulin product.
8)Have an 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 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, or been hospitalized for an infection, or treated with intravenous antibiotics for an infection within 2 months prior to screening.
11)Have a history of latent or active granulomatous infection.
12)Have had a BCG vaccination within 12 months of screening.
13)Have had a nontuberculous mycobacterial infection or opportunistic infection 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 current active hepatitis B or a history of hepatitis C infection.
17)Have HIV infection.
18)Have signs, symptoms of or a history of SLE; severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic, or cerebral diseases.
19)Have a transplanted organ.
20)Have a history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, like lymphadenopathy of unusual size or location or splenomegaly.
21)Have any known malignancy or history of malignancy within the 5-year prior to screening.
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; sinusitis; recurrent urinary tract infection; open, draining, or infected skin wound or ulcer.
24)Have a 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 participating in another trial using an investigational agent, procedure, or device during participation in this trial.
27)Have previously participated in 3 or more investigative trials in CD within 5 years prior to screening. Patients participating in the TREAT registry must discontinue from the registry before enrolling in SONIC.
28)Have a history of substance abuse 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.
29)Have a concomitant diagnosis or any history of 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.TPMT phenotype should not be assayed in patients within 90 days of receipt of a red blood cell transfusion.
32)Weigh more than 140 kg.
33)Have previously received natalizumab.
34)Have recently close contact with a person with active TB.
35)Positive stool culture for enteric pathogens, pathogenic ova, or parasites, or Clostridium difficile toxin.
For the SONIC OLE extension:
1.Are deemed ineligible according to the TB screening criteria defined in the protocol.
2.Have experienced an adverse event during or within 1 hour following the study agent infusion in the SONIC Main study, resulting in bronchospasm with wheezing, dyspnea requiring ventilatory support, or hypotension with a >40 mm Hg decrease in systolic blood pressure that is associated with symptoms.
3.Have had a delayed hypersensitivity reaction.
4.Are pregnant, nursing, or planning pregnancy during the OLE or within the 6-month period thereafter.
5.Have been unblinded to study treatment in the SONIC Main study.
6.Have been diagnosed with a malignancy.
7.Have previously received any other TNF-a blocking agent or any other biological drug.
8.Have required or requires a Crohn’s disease-related surgery.
|
|
| 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.
The primary end point of the SONIC OLE extension wil be the proportion of patients in clinical remission, ie, patients with a CDAI of less than 150, at the week 52 visit of the SONIC OLE. |
|
| 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 | No |
| 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.8.1.7.1 | Other trial design description |
| The OLE extension will be an open label trial |
|
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 | No |
| 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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