E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Steroid-refractory ulcerative colitis |
|
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 | 10009900 |
E.1.2 | Term | Colitis ulcerative |
|
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: Assess the efficacy, relative to placebo, of 40 mg basiliximab given intravenously, at 2 week intervals for a total of 3 doses, with concomitant oral corticosteroids, in subjects with steroid-refractory, moderate to severe Ulcerative Colitis. A total of 3 doses will be administered during the 8 week duration of the trial.
Safety: Evaluate the overall safety of this multiple-dose regimen in this patient population.
|
|
E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess: • Efficacy, relative to placebo, of basiliximab 20 mg, given with concomitant oral corticosteroids, according to the same schedule • Safety of basiliximab 20 mg multiple-dose regimen • Pharmacokinetics of both basiliximab regimens in this population • Immunogenicity of multiple doses of basiliximab through measurement of formation of antibodies to basiliximab, and monitoring for hypersensitivity reactions
|
|
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 |
The complete description of these studies is included within the protocol BSX-001, Amendment 4, dated 28th January 2008
Pharmacodynamics
An optional substudy will be conducted in approximately 100 subjects at selected sites. This substudy will assess basiliximab pharmacodynamics through the following analyses: • Saturation and/or depletion of circulating CD25 receptors will be assessed via a Fluorescence Activated Cell Sorting (FACS) lymphocyte subset analysis of whole blood collected from consenting subjects at the Day 1, Week 4, and Week 8 study visits. A total CD3 count will also be determined. • In the same subjects, saturation and/or depletion of tissue CD25 receptors will be assessed via immunohistochemical analysis of rectal biopsy tissue obtained during the Screening, Week 4, and the Week 8 endoscopic procedure. The results of these analyses will also be correlated with serum basiliximab trough levels in the subjects from the active treatment groups.
Steroid Resistance Biomarker Evaluation
An optional substudy will be conducted in approximately 30 adult subjects at selected sites in the U.K. The following evaluations will be performed at the Biomarker Substudy Laboratory (University of Bristol, UK): • Dexamethasone inhibition of lymphocyte proliferation, with and without autologous serum (Creed, 2003) • Assessment of CD25+ cell subsets • Assessment of DNA polymorphisms linked to steroid sensitivity. Stored DNA (from white cells) will not be used for any other purpose. Any cells not used in the above assays may be stored for additional related cell signaling studies.
|
|
E.3 | Principal inclusion criteria |
Subjects must satisfy all of the following inclusion criteria to be eligible for the study: 1. Male or female subjects, age ≥18 years and ≤75 years 2. Weight of 40 kg or greater 3. Signed a current IRB/IEC-approved informed consent form 4. Diagnosis of ulcerative colitis confirmed through screening endoscopy performed no more than 3 days prior to day of randomization (Day -2 to Day 0, with randomization on Day 1). At the time of endoscopy, a rectal biopsy will be obtained and reviewed by a local pathologist to confirm histopathology compatible with the diagnosis of ulcerative colitis. Randomization can proceed without the screening biopsy result if a previous biopsy result compatible with ulcerative colitis is documented and available in the subject’s medical record. 5. Extent of disease must involve at least the left colon (i.e., greater than 15 cm beyond the anal verge as the endoscope is withdrawn) 6. Moderate to severe disease, defined as a total Mayo score of 6 points or greater, including an endoscopic subscore of 2 points or greater. Systemic features of tachycardia, fever, and/or significant anemia should not be present 7. Steroid-refractory disease, defined as moderate to severe disease, without systemic features , despite treatment with prednisone 40 – 50 mg/day (or other oral steroid at equivalent dose) orally for a minimum of 14 days immediately preceding study entry 8. Concomitant azathioprine or 6-mercaptopurine treatment is permitted during the study if initiated at least 12 weeks before study entry, and if the dose has not been changed or stopped for at least 8 weeks before study entry. 9. Concomitant oral aminosalicylate treatment is permitted during the study if initiated at least 4 weeks before study entry, and if the dose has not been changed or stopped during this time. 10. Females of childbearing potential must use an effective birth control method, and be willing to continue birth control during the study, and for 4 months after the last dose of study drug. 11. Females of non-childbearing potential should be surgically sterile (bilateral tubal ligation with surgery at least 6 months before study entry, hysterectomy, or bilateral oophorectomy at least 2 months before study entry) or post-menopausal for at least 2 years.
|
|
E.4 | Principal exclusion criteria |
Presence of any of the following conditions will exclude the subject from eligibility for the study: 1. Prior treatment with basiliximab or daclizumab at any time 2. Prior treatment with cyclosporine, tacrolimus, methotrexate, or any anti- TNF agent within 3 months before study entry 3. Prior treatment with parenteral corticosteroids within 14 days before study entry 4. History of partial colectomy or total proctocolectomy 5. Initiation of azathioprine or 6-mercaptopurine treatment less than 12 weeks before study entry, or discontinuation or change of dose less than 8 weeks before study entry 6. Initiation of oral aminosalicylate treatment , or change of dose, or discontinuation less than 4 weeks before study entry 7. Rectally administered medications containing corticosteroids or aminosalicylates within 2 weeks before screening endoscopy 8. If currently taking a nonsteroidal anti-inflammatory agent (NSAID), the inability to discontinue NSAID use during study participation 9. Intolerance or inability to continue oral corticosteroids during the trial 10. Stool studies that show presence of ova and parasites, significant bacterial pathogens, or C. difficile toxin 11. Baseline endoscopic finding of disease isolated to the rectum (proctitis), fistulas, strictures, skip areas, or small bowel inflammation not consistent with backwash ileitis, or findings of multiple epithelial granulomas on biopsy 12. Presence of toxic megacolon 13. Severely ill patients as evidenced by greater than 6 episodes of loose stools, all of them bloody, during a 24-hour period within the screening window, concurrent with any of the following systemic features: -Heart rate >90 beats/min at rest -Temperature >37.8 degrees C -Hemoglobin <10.5 g/dL 14. Laboratory values as follows: -Hemoglobin <8.5 g/dL -WBC <3.0 x 10E9/L -Neutrophils <1.5 x 10E9 /L -Lymphocytes <0.5 x 10E9 /L -Platelets <100 x 10E9 /L -AST (SGOT) >3 times upper limit of normal -ALT (SGPT) >3 times upper limit of normal 15. Pregnant or breast-feeding female patients 16. Chest radiograph abnormalities consistent with an infectious process 17. HIV infection 18 Known viral Hepatitis B or C infection 19. History of or exposure to tuberculosis within 6 months before study entry 20. History of central nervous system demyelinating disorder 21. History of colonic dysplasia 22. History of malignancy during the previous 5 years or current malignancy, with exception of adequately treated non-melanoma skin cancer or in situ carcinoma of the cervix 23. History of varicella, herpes zoster, or severe viral infection within 6 weeks before study entry, exposure to varicella within 21 days before study entry, or vaccination with live virus within 4 weeks before study entry 24. Any ECG abnormalities unless approved by the Medical Monitor 25. Treatment with an investigational drug or device within 30 days before study entry 26. Treatment with an investigational biologic within 6 months before study entry
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be clinical remission at week 8.
Secondary efficacy endpoints will include:
• Clinical remission at week 4 • Clinical response at weeks 4 and 8 • Mucosal healing at weeks 4 and 8 • Use of rescue medication • Hospitalization or colectomy • Concomitant steroid use (median dose over time and cumulative dose) |
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
1)Immunogenicity and 2)Steroid Resistance Biomarker Evaluation |
|
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
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 | Yes |
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
|
End of trial is defined as last visit by the last subject |
|
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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |