| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| SUBJECTS WITH ACTIVE BEHÇET’S DISEASE |
|
| E.1.1.1 | Medical condition in easily understood language |
| Behcet's disease causes inflammation in blood vessels throughout the body and manifests mainly as mouth or genital ulcers with eye and skin lesions. The exact cause is unknown. |
|
| 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 | 19.0 |
| 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 |
|
| 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 |
| To evaluate the efficacy of apremilast in the treatment of oral ulcers in active Behçet’s disease |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of apremilast in subjects with Behçet’s disease
- To evaluate the effect of apremilast on Patient Reported Outcomes (PROs) in subjects with Behçet’s disease
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
2. Male and female subjects ≥18 years of age at the time of signing the informed consent document.
3. Able to adhere to the study visit schedule and other protocol requirements.
4. Diagnosed with Behçet’s disease meeting the International Study Group (ISG) criteria.
5. Oral ulcers that occurred at least 3 times in the previous 12-month period, including oral ulcers at the Screening Visit.
6. Subjects must have at least 2 oral ulcers at Visit 1 (Screening Visit), and:
a) at least 2 oral ulcers at Visit 2 (day of randomization), when Visit 2 occurs at least 14 days after Visit 1,
OR
b) at least 3 oral ulcers at Visit 2 (day of randomization), when Visit 2 occurs at any time between 1 day and 42 days after Visit 1.
7. Have prior treatment with at least 1 non-biologic BD therapy, such as, but not limited to, topical corticosteroids, or systemic treatment.
8. Candidate for systemic therapy, for the treatment of oral ulcers.
a. A candidate for systemic therapy is a subject, judged by the study Investigator, as someone whose mucocutaneous ulcers are considered inappropriate for topical therapy based on the severity of disease and extent of the affected area, or whose oral ulcers cannot be adequately controlled by topical therapy.
9. Laboratory Measures: Must meet the following laboratory measures:
• Hemoglobin > 9 g/dL
• White blood cell (WBC) count ≥ 3000 /microL (≥ 3.0 X 109/L) and ≤14,000/microL (≤14 X 109/L)
• Platelet count ≥ 100,000 /microL (≥ 100 X 109/L)
• Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L)
• Total bilirubin ≤ 2.0 mg/dL
• Aspartate transaminase (AST [serum glutamic oxaloacetic transaminase, SGOT]) and alanine transaminase (ALT [serum glutamate pyruvic transaminase, SGPT]) <1.5 X ULN. Subjects who fail screening due to ≥ 1.5 X ULN AST/SGOT and/or ALT/SGPT will be allowed to repeat AST/SGOT and/or ALT/SGPT tests within the screening period. Repeat test results should be ≤ ULN (within reference range) to be eligible.
Laboratory tests will be allowed to be repeated 1 time, if in the Investigator’s clinical judgment, there is a reasonable possibility of the repeat tests not meeting the exclusion values, and with concurrence from the Medical Monitor.
10. Contraception Requirements:
All FCBP must use one of the approved contraceptive options as described below while taking apremilast and for at least 28 days after administration of the last dose of the apremilast.
At the time of study entry, and at any time during the study when a FCBP’s contraceptive measures or ability to become pregnant changes, the Investigator will educate the subject regarding contraception options and the correct and consistent use of effective contraceptive methods in order to successfully prevent pregnancy.
All FCBP must have a negative pregnancy test at Visits 1 and 2. All FCBP subjects who engage in activity in which conception is possible must use one of the approved contraceptive options described below:
Option 1: Any one of the following highly effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner’s vasectomy;
OR
Option 2: Male or female condom (latex condom or non latex condom NOT made out of natural [animal] membrane [for example, polyurethane]); PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide.
Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (latex or non-latex condoms NOT made out of natural [animal] membrane [for example, polyurethane]) while on IP and for at least 28 days after the last dose of IP.
|
|
| E.4 | Principal exclusion criteria |
1. Behçet’s disease-related active major organ involvement – pulmonary (eg, pulmonary artery aneurysm), vascular (eg, thrombophlebitis), gastrointestinal (eg, ulcers along the gastrointestinal tract), and central nervous systems (eg, meningoencephalitis) manifestations, and ocular lesions (eg, uveitis) requiring immunosuppressive therapy; however:
• Previous major organ involvement is allowed if it occurred at least 1 year prior to screening and is not active at time of enrollment.
• Subjects with mild BD-related ocular lesions not requiring systemic immunosuppressive therapy are allowed.
• Subjects with BD-related arthritis and BD-skin manifestations are also allowed.
Previous and Current Medications:
2. Previous exposure to biologic therapies for the treatment of BD oral ulcers
* Previous biologic therapy exposure is allowed for other indications, including other manifestations of BD
3. Prior use of apremilast.
4. Use of any investigational medication within 4 weeks prior to Visit 2 or
5 pharmacokinetic/pharmacodynamic half-lives (whichever is longer).
5. Current use of strong cytochrome P450 enzyme inducers (eg, rifampin, phenobarbital,
carbamazepine, phenytoin)
6. Having received concomitant immune modulating therapy (except oral or topical corticosteroids) within:
- Seven days prior to Visit 2 (Baseline Visit; day of randomization) for colchicine
- Ten days prior to Visit 2 (Baseline Visit; day of randomization) for azathioprine and mycophenolate mofetil
- Four weeks (28 days) prior to Visit 2 (Baseline Visit; day of randomization) for cyclosporine, methotrexate, cyclophosphamide, thalidomide, and dapsone
Note: Oral and topical corticosteroids must have been tapered as appropriate and discontinued prior to the day of Visit 2 (day of randomization).
- At least 5 terminal half-lives for all biologics, including, but not limited to, those listed below; within:
- Four weeks prior to Visit 2 (Baseline Visit; day of randomization) for etanercept
- Eight weeks prior to Visit 2 (Baseline Visit; day of randomization) for infliximab
- Ten weeks prior to Visit 2 (Baseline Visit; day of randomization) for adalimumab, golimumab, certolizumab, abatacept, and tocilizumab
- Six months prior to Visit 2 (Baseline Visit; day of randomization) for secukinumab
7. Having received intra-articular or parenteral corticosteroids within 6 weeks (42 days)
prior to Visit 2 (Baseline Visit; day of randomization).
General Health:
8. Any significant medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from participating in the study.
9. Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study.
10. Inability to provide voluntary consent.
11. Pregnant women or breast feeding mothers.
12. Systemic or opportunistic fungal infection.
13. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or
other infections (including but not limited to tuberculosis and atypical mycobacterial
disease, hepatitis B and C and herpes zoster, histoplasmosis, coccidiomycosis, but
excluding onychomycosis) or any major episode of infection requiring hospitalization or
treatment with IV or oral antibiotics within 4 weeks of the Screening Phase.
14. Clinically significant abnormality on chest radiograph.
15. Clinically significant abnormality on 12-lead ECG.
16. History of positive test for, or any clinical suspicion of, human immunodeficiency virus
(HIV), or congenital or acquired immunodeficiency (eg, common variable
immunodeficiency disease).
17. Malignancy or history of malignancy, except for:
- treated (ie, cured) basal cell or squamous cell in situ skin carcinomas;
- treated (ie, cured) cervical intraepithelial neoplasia (CIN) or carcinoma in situ of the cervix with no evidence of recurrence within the previous 5 years of Visit 1.
18. Any condition that confounds the ability to interpret data from the study.
19. Scheduled surgery or other interventions that would interrupt the subject’s participation
in the study.
20. Prior history of suicide attempt at any time in the subject’s lifetime prior to Visit 2
(Baseline Visit; day of randomization) or major psychiatric illness requiring
hospitalization within 3 years prior to Visit 2 (Baseline Visit; day of randomization). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Area under the curve (AUC) for the number of oral ulcers from baseline through Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after the start of the double-blind, placebo-controlled phase |
|
| E.5.2 | Secondary end point(s) |
• Complete response rate for oral ulcers at Week 12
- A complete response is defined as the proportion of subjects who are oral ulcer free.
• Change from baseline in the pain of oral ulcers as measured by VAS at Week 12
• Complete response rate for genital ulcers at Week 12 for subjects who had genital ulcers at Baseline
- A complete response is defined as the proportion of subjects who are genital ulcer free.
• Change from Baseline in the pain of genital ulcers, as measured by VAS at Week 12 in subjects who had genital ulcers at baseline
• Change from baseline in disease activity as measured by Behçet’s Disease Current Activity scores (BD Current Activity Form) at Week 12
• Change from baseline in the BD QoL score at Week 12
• Change from Baseline in Behçet’s Syndrome Activity Score (BSAS) at Week 12
• Time to oral ulcer resolution (complete response), ie, the first instance when a subject has a complete response, during the Placebo-controlled Phase
• Proportion of subjects with no oral ulcers following complete response, ie, the first time when a subject has a complete response, during the Placebo-controlled Phase
• Number of oral ulcers following loss of complete response, ie, the first instance when a subject has a reappearance of oral ulcers following a complete response, during the Placebo-controlled Phase
• Time to recurrence of oral ulcers following loss of complete response, ie, the first instance when a subject has a reappearance of oral ulcers following a complete response, during the Placebo-controlled Phase
• Change from baseline in the total score of the Static Physician’s Global Assessment (PGA) of skin lesions (acne-like lesions, folliculitis and erythema nodosum) of BD at Week 12 in subjects who had BD skin lesions at baseline
• Proportion of subjects achieving an oral ulcer complete response (oral ulcer free) by week 6, after start of dosing, and who remain oral ulcer free for at least 6 additional weeks during the 12 week Placebo-controlled Phase
Safety Endpoints
Safety and tolerability as defined by the following:
• Type, frequency, severity, and relationship of the AEs to apremilast
• Number of subjects who prematurely discontinue IP due to any AE
• Frequency of clinically significant changes in physical examination, vital signs, and/or laboratory findings
• Absolute weight and the percentage of weight change at each visit (as indicated in Section 5) compared to baseline
Exploratory Pharmacokinetic / Pharmacodynamic Endpoints
• PK parameters from non-compartmental analysis including, but not limited to, maximum observed plasma concentration (Cmax), time to Cmax (tmax), and area under the plasma concentration-time curve from time zero to 12 hours post-dose and/or from time zero to the last quantifiable concentration (AUC0-12 and/or (AUC0-t)
• Change from baseline in the plasma concentration of inflammatory biomarkers and leukocyte subsets
Exploratory Pharmacogenetic Endpoint
• Assessment of genetic markers for BD or pharmacodynamic response to apremilast, including but not limited to, HLA-B51, IL-10, IL-23R and IL-12RB2 SNPs at baseline (See Section 6.7.13 for additional markers)
Exploratory Endpoint(s)
• The AUC for the combined number of oral and genital ulcers from baseline through Week 12
• Proportion of subjects with new (ie, in subjects with no history of) or worsening (ie, in subjects with history of) uveitis, arthritis, skin lesions; vascular, gastrointestinal and central nervous system BD manifestations by visit
• Change from baseline in number of tender and/or swollen joints associated with BD at Week 12 in subjects who had BD-related tender and/or swollen joints at baseline
• Time to genital ulcer complete response, ie, the first instance when a subject has a complete response, during the Placebo-controlled Phase
• Proportion of subjects with no genital ulcers following complete response, ie, the first time when a subject has a complete response, during the Placebo-controlled Phase
• Number of genital ulcers following loss of complete response, ie, the first instance when a subject has a reappearance of genital ulcers following a complete response, during the Placebo-controlled Phase
• Time to recurrence of genital ulcers following loss of complete response, ie, the first instance when a subject has a reappearance of genital ulcers following a complete response, during the Placebo-controlled Phase
• Cumulative number of oral ulcers per patient for the entire placebo-controlled period
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks after the start of the double-blind, placebo-controlled phase followed by 52 weeks after the active treatment phase |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 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.8.2.4 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | No |
| 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 |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Turkey |
| United States |
|
| 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 Trial is defined as either the date of the last visit of the last subject to complete the study, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical Analysis Plan, whichever is the later date. |
|
| 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 |
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