| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe Crohn's disease (CDAI = 220 and =450) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| 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 |
| Efficacy of AIN457 at 6 weeks on mean CDAI |
|
| E.2.2 | Secondary objectives of the trial |
- % of subjects achieving remission and/or response, as defined by CDAI <150 or a decrease of at least 70 points from baseline
- Effect of AIN457 on mean CDAI at 2 and 4 weeks
- Area under CDAI score curve from week 4 to week 10
- Maintenance of remission and/or response during f/u period and at the end of study
- PK of AIN457
- Safety and tolerability of AIN457
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female; 18-75 years old
2. Females must have negative pregnancy test results at screening and baseline. WoCBP must be using simultaneously double-barrier or two acceptable methods of contraception from the time of screening and for the duration of the study, through study completion and for 4 months following study completion. Periodic abstinence and withdrawal are not acceptable methods of contraception. Postmenopausal females must have had no regular menstrual bleeding for at least 2 years prior to initial dosing. If menopause is confirmed by serum FSH level of >40 IU/L at screening, pregnancy test will be required only at screening. Female subjects who report surgical sterilization must have had the procedure at least 6 months prior to initial dosing. Surgical sterilization procedures should be supported with clinical documentation made available to the sponsor and/or PI and noted in the Relevant Medical History / Current Medical Conditions section of the CRF. If female subjects have male partners who have undergone vasectomy, the vasectomy must have occurred more than 6 months prior to first dosing.
3. Male subjects willing to use simultaneously two acceptable methods of contraception (e.g. spermicidal gel plus condom) for entire duration of the study, up to the study completion visit and at least for 6 months following the completion of the study. Periodic abstinence and withdrawal are not acceptable methods of contraception.
4. Diagnosis of CD for at least 3 months prior to screening.
5. Confirmation of CD by endoscopic or imaging examination.
6. Moderate to severe active CD at baseline, defined as: CDAI =220 and =450 Note: Baseline CRP values may be either within normal limits or elevated. However, not more than 50% of all patients included in the trial should belong to the subgroup of patients with normal CRP values. The upper limit of normal (ULN) for serum CRP is defined as =10mg/L (=1mg/dl)
7. Patients with active disease despite prior treatment with corticosteroids for at least 2 weeks, or immunosuppressants for at least 3 months. Patients who are being treated with azathioprine, 6-MP or MTX are eligible but must have been on a stable dose for at least 10 weeks prior to baseline. Patients treated with corticosteroids are eligible but must have been on a stable dose of prednisolone not exceeding 40 mg for two weeks prior to baseline.
Patients who are being treated with immunosuppressants other than those listed above, such as cyclosporine, tacrolimus and mycophenolate, are not eligible. These subjects will be required to stop immunosuppressants prior to baseline. These patients are eligible after observing a wash out period as specified in Exclusion criterion #7.
8. Absence of clinically relevant abnormalities for screening laboratory test results.
9. Able to communicate well with the investigator, and to understand and comply with the requirements of the study.
10. Understand and sign the written informed consent.
|
|
| E.4 | Principal exclusion criteria |
1 BMI > 34
2 +ve PPD tuberculin skin test (= 5 mm) at or 6 mo prior screening (MMWR 2000). PPD test not to be done in subjects who had a TB vaccination.These subjects will be eligible to participate if – according to local guidelines – latent tuberculosis can be excluded. For sites using QuantiFeron test, a +ve test at screening will exclude subject. If the result for either PPD or QuantiFeron test is indeterminate, subject will be excluded
3 Active bowel structuring disease and pre-stenotic dilation on radiography
4 Fistulizing disease complicated by sepsis and/or untreated abscess
5 Multiple bowel surgeries/clinically important short bowel syndrome
6a Concomitant treatment w anti-TNF-a therapy (or other biological therapy), and systemic immunosuppressive agents, e.g. cyclosporine, mycophenolate, pimecrolimus, or tacrolimus, except azathioprine, its metabolite 6-MP and MTX. The following washout period will be required for such subjects to be eligible to participate in the trial.
- 3 mo washout prior to baseline (WPB) for certolizumab
- 2 mo WPB for adalimumab, etanercept and infliximab
- 1 mo WPB for cyclosporine, mycophenolate, pimecrolimus, tacrolimus, and any other systemic immunosuppressants not listed under exclusion criterion #7b
b. Patients who are being treated with azathioprine, 6-MP and MTX are eligible but must have been on a stable dose for at least 10 weeks prior to baseline and throughout the whole study period.
7 Prior therapy w rituximab
8 Corticosteroids dose equivalent to >40mg dose of prednisone/day
9 Subjects demonstrating clinical improvement due to other CD therapy
10 Symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, GI, endocrine, pulmonary, cardiac, neurologic, cerebral, psychiatric, or other disease
11 Active or history of clinically significant cardiac abnormalities, e.g. • Requiring QT-prolonging drugs
• QTc >450msec, long QT-syndrome (own/ family history) or w family history of sudden unexplained death
• LBBB or subjects who have been hospitalized for heart failure of cardiac etiology in previous 6 mo, and subjects w significant and persistent LVEV dysfunction (< 40%) • History (3 mo) of significant, persistent arrhythmias e.g. ventricular fibrillation, tachycardia, atrial fibrillation, flutter
• Symptomatic coronary artery disease • Presence of severe cardiac disease (NYHA Class = III) and/or abnormal ECG - considered by the investigator unsafe for the study
12 Liver disease/injury indicated by SGOT (AST), SGPT (ALT), ?-GGT, alkaline phosphatase, or serum bilirubin, guided by following criteria
• Any single parameter may not exceed 2xULN. A single parameter elevated up to and including 2xULN to be re-checked once more asap, and at least prior to enrollment / randomization, to rule out lab error
• If total bilirubin conc. increased > 2xULN, total bilirubin to be differentiated into direct and indirect reacting bilirubin. Serum bilirubin should not exceed value of 1.6 mg/dL (27 µmol/L). Recheck results must be within normal limits
13 Total WBC count outside range of 4500–13,000/µl, or platelets <100,000/µl at screening
14 History of severe hypersensitivity to any biological, including serious allergic reaction, lupus-like syndrome, demyelinating disease
15 Donation/loss of = 400 mL blood within 8 wks prior to dosing or longer if required by local regulation
16Administration of live vaccines within 6 mo prior to dosing
17 History of immunodeficiency diseases, incl. +ive HIV (ELISA and Western blot) test result
18 +ve Hep B surface antigen (HBsAg) or Hep C test result
19 Significant illness within 2 wks prior to dosing or any active systemic infection or medical condition that may require treatment or therapeutic intervention during the study.
20 History or presence of impaired renal function as indicated by clinically significantly abnormal
creatinine >1.3 mg/dL, blood urea nitrogen (BUN) >30 mg/dL, or > +1 albumin on the urinary dipstick
• Proteinuria, active sediments, casts, WBCs in urine • Urinary obstruction or difficulty in voiding at screening
• History of renal trauma, glomerulonephritis, or subject with one kidney
21 History of malignancy (other than basal cell carcinoma or adequately treated carcinoma-in-situ of the cervix)
22 Unable or unwilling to undergo multiple venipunctures (poor tolerability or lack of easy access to veins)
23 Immune-compromised conditions such as recent surgical procedure; history of drug/alcohol abuse within 12 mo prior dosing. Subjects, who are unable to discontinue analgesic medications containing opiates/opioids, cannabinoids for medical use
24 Participation in any CT within 4 wks prior initial dosing or five half-lives of the IMP, whichever is longer, and for any other limitation of participation (local regulations)
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| A Bayesian approach will be adopted to assess the efficacy as measured by the change from baseline in the CDAI 6 weeks after infusion 1, that is, at visit 8 (primary endpoint and analysis). |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Proteomics, soluble markers |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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