| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10004212 |
| E.1.2 | Term | Behcet's disease |
| E.1.2 | System Organ Class | 100000004866 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The aim of this study is to underpin clinically effective prescribing of the biologic drugs infliximab (IFX) and alpha interferon (aIFN) for Behçet’s Disease (BD).
The primary objective of the study is to undertake a randomised controlled trial to compare IFX versus aIFN in patients with BD who are unresponsive to standard oral therapy.
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to; (1) examine whether IFNL3 and IFNL4 SNPs can predict response to aIFN and/or IFX in BD, and (2) examine the potential for urine metabolomics to act as a biomarker for drug response to IFX and/or aIFN in BD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The inclusion criteria are adult individuals who are:
1. Diagnosed to have BD by International Study Group (ISG) criteria or International Criteria for BD (ICBD);
2. Have refractory disease as defined by the UK Centres of Excellence criteria (failure to respond to steroid and/or immunosuppressive therapy with significant or major organ-threatening disease) and therefore qualify for biologic therapy with either IFX or aIFN. A summary drugs pathway is attached as an appendix to the Protocol. Patients will have failed to respond to or have been intolerant of azathioprine at a dose of >2mg/kg (or comparable drug) and/or prednisolone at a dose of >40mg/day typically for more than three months, or with evidence of either organ threatening disease or unacceptable adverse events from immunosuppressive medication;
3. Able to give informed consent;
4. Have not previously received a biologic agent; and
5. Aged over 18 years.
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| E.4 | Principal exclusion criteria |
The principal exclusion criteria are adult individuals who;
1. Have a contraindication to either IFX or aIFN (e.g., active infection, severe liver disease, neutropenia, previous malignancy);
2. Are not likely to comply e.g., cannot attend for assessments because of excessive travel requirements;
3. Express a strong preference for one of the two potential therapies.
4. Have heart disease or severe heart failure.
5. Have been diagnosed with Multiple Sclerosis.
6. Have evidence of infection with HIV.
or
7. . a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the study duration plus 6 months.
b) Women who are pregnant or breastfeeding.
c) Sexually active fertile men not using effective birth control if their partners are WOCBP.
Reproductive Status of Trial Participants
Definition of Women of Child-Bearing Potential (WOCBP)
WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilisation (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal (see definition below).
Post-menopause is defined as:
• Women who have had amenorrhea for 12 consecutive months (without another cause) and who have a documented serum follicle-stimulating hormone (FSH) level > 35 mIU/mL.
• Women who have irregular menstrual periods and a documented serum FSH level > 35 mIU/mL.
• Women who are taking hormone replacement therapy (HRT).
The following women are WOCBP:
• Women using the following methods to prevent pregnancy: Oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as intrauterine devices or barrier methods (diaphragm, condoms, spermicides).
• Women who are practicing abstinence.
• Women who have a partner who is sterile (e.g. due to vasectomy).
WOCBP entering the trial must:
• Be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 6 months after the last dose of study drug in such a manner that the risk of pregnancy is minimised. The decision about the appropriate methods to be used to prevent pregnancy should be determined by discussions with the study subject.
• Have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 0 to 72 hours before the first dose of study drug.
• Must not be breast-feeding.
Sexually active fertile men entering the trial must:
• Use effective birth control if their partners are WOCBP for the duration of the trial plus 6 months.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome will be a modified version of the Behçet’s Disease Activity Index (BDAI) after three months of therapy, which will range from 0 to 30 for a patient. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After three months of treatment. |
|
| E.5.2 | Secondary end point(s) |
• Modified BDAI after six months of treatment
• Significant improvement in organ involvement within (a) the primary organ system that resulted in the decision to start a biologic agent and (b) other organ systems assessed by: (I)Ocular: reduction in vitreous haze using the SUN consensus group grading scale and visual acuity change from baseline. A reduction of 2 or more is considered to be clinically significant. (II) Oral ulcer activity: change in ulcer severity score (USS). An improvement of 20% is considered to be clinically meaningful. (III) Change in number of genital ulcers: a reduction of 50% is considered to be clinical significant.
(IV) Musculoskeletal: Likert pain score (an improvement of 20% is considered to be clinically meaningful)
• Adverse events in each group
• Reduction in dose of prednisolone (or equivalent glucocorticoid) at three months: a
clinically meaningful reduction is considered to be 50% of baseline or dose of
<15mg/day prednisolone
• Reduction in dose of prednisolone (or equivalent glucocorticoid) at six months: a
clinically meaningful reduction is considered to be 50% of baseline or dose of
<7.5mg/day prednisolone.
• Quality of life scores at three months and six months compared to baseline. The QoL instruments used will be EQ-5D and BD-QoL: a reduction of 20% would be of clinical importance
• Physician’s Global Assessment of disease activity (a 7 point Likert Scale completed
as part of (but assessed independently of) the BDAI) i) at 3 months and ii) at 6
months.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After three and six months of treatment. |
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| 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 | No |
| 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 | No |
| E.6.13 | Others | No |
| 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 | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| The end of the trial is defined as the point at which "the last patient has completed their final study assessment". |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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