| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Psoriasis, a chronic inflammatory skin disorder, estimated to affect up to 2.5% of the world's population. Plaque-type psoriasis is the most common form of this disease. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Moderate to severe plaque psoriasis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037153 |
| E.1.2 | Term | Psoriasis |
| E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders |
|
| 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 |
| To evaluate the clinical efficacy and safety of oral apremilast 30 mg twice a day (BID) compared with placebo, in subjects with moderate to severe plaque psoriasis at Week 16 |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate the clinical efficacy and safety of etanercept 50 mg subcutaneous (SC) once weekly compared with placebo, in subjects with moderate to severe plaque psoriasis at Week 16.
-To evaluate the relative safety of a crossover from etanercept 50 mg subcutaneous (SC) once weekly to apremilast 30 mg BID, as compared with apremilast dosed since Week 0, in subjects with moderate to severe plaque psoriasis after Week 16.
-Explore relative safety/tolerability of subjects starting apremilast therapy without the 7 day dose titration
OTHER OBJECTIVES:
- To evaluate HRQoL and changes in symptom severity of apremilast 30 mg BID compared with placebo, and the HRQoL and changes in symptom severity of etanercept 50 mg SC once weekly compared with placebo, in subjects with moderate to severe plaque psoriasis at Week 16.
-Explore response to apremilast for subjects originally randomized to etanercept.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or females, ≥ 18 years of age at the time of signing the informed consent document.
2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
3. Able to adhere to the study visit schedule and other protocol requirements.
4. Diagnosis of chronic plaque psoriasis for at least 12 months prior to Screening.
5. Have moderate to severe plaque psoriasis at Screening and Baseline as defined by
a. PASI score ≥ 12 and
b. BSA ≥ 10%, and
c. sPGA ≥ 3 (moderate)
6. Must be a candidate for phototherapy and/or systemic (including etanercept) therapy.
7. Must be in good health (except for psoriasis) as judged by the Investigator, based on medical history, physical examination, 12-lead ECG, clinical laboratories, and urinalysis.
8. Had an inadequate response, intolerance, or contraindication to at least 1 conventional systemic agent for the treatment of psoriasis.
9. No prior exposure to biologics for treatment of psoriatic arthritis or psoriasis.
10. Must meet the following TB screening criteria.
a. No history of latent or active TB prior to screening visit.
b. No signs or symptoms suggestive of active TB in medical history or upon physical examination.
c. No recent close contact with anyone having active TB.
d. TB testing should be conducted as per local health authority guidelines. Within 1 month prior to first administration of IP, have negative diagnostic TB test results (either a negative tuberculin skin test or a negative QuantiFERON®-TB Gold test). The QuantiFERON®-TB Gold test should be used in lieu of the TST (PPD) test if possible.
e. Have a chest radiograph with at least PA view (radiograph must be taken within 12 weeks prior to Screening or during the Screening visit) and read by a qualified radiologist, with no evidence of current active TB or old inactive TB. An additional lateral view is strongly recommended but, not required.
11. Must meet the following laboratory criteria:
a. White blood cell count ≥ 3000/mm3 (≥ 3.0 x 109/L) and < 14,000/mm3 (< 14 x 109/L);
b. Platelet count ≥ 100,000/μL (≥100 x 109/L);
c. Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L);
d. AST (SGOT) and ALT (SGPT) ≤ 2 x upper limit of normal (ULN);
e. Total bilirubin ≤ 2 mg/dL (34 μmol/L);
f. Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L);
g. Hemoglobin A1c ≤ 9.0 %.
12. Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on investigational product and for at least 28 days after the last dose of investigational product.
13. Females of childbearing potential (FCBP) must have a negative pregnancy test at Screening and Baseline. All FCBP who engage in activity in which conception* is possible must use one of the approved contraceptive options described below while on investigational product and for at least 28 days after the last dose of investigational product:
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 nonlatex 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.
*The female subject’s chosen form of contraception must be effective by the time the female subject is randomized into the study (for example, hormonal contraception should be initiated at
least 28 days before randomization). |
|
| E.4 | Principal exclusion criteria |
1.Other than psoriasis, history of any clinically significant cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major uncontrolled disease.
2.Any condition, including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if he/she were to participate in the study.
3.Any condition, including other inflammatory diseases or dermatologic conditions, that confound the ability to interpret data from the study.
4.Prior history of suicide attempt at any time in the subject’s life time prior to screening or randomization, or major psychiatric illness requiring hospitalization within the last 3 years.
5.Pregnant or breast feeding.
6.Have failed more than 3 systemic agents for treatment of psoriasis.
7.History of allergy to any component of the IP, including human immunoglobulin proteins or allergy to etanercept.
8.Hepatitis B surface antigen positive at Screening.
9.Anti-hepatitis C antibody positive at Screening.
10.AST (SGOT) and/or ALT (SGPT) > 1.5 x ULN and total bilirubin > ULN and/or albumin < lower limit of normal (LLN).
11.Latent, active TB or inadequately treated TB.
12.Clinically significant abnormality on 12-Lead ECG at Screening.
13.Clinically significant abnormality, based upon chest radiograph with at least PA view, including any abnormality suggestive of malignancy or current active infection, including TB.
14.Had a nontuberculous mycobacterial infection or opportunistic infection (eg, cytomegalovirus, Pneumocystis carinii, aspergillosis, Clostridium difficile).
15.Had a serious infection (including, but not limited to, hepatitis, pneumonia, sepsis, cellulitis, meningitis or pyelonephritis) or have been hospitalized for an infection. Subject must be cured of infection > 4 weeks before Screening.
16.History of, or ongoing, chronic or recurrent infectious disease, including, but not limited to, chronic renal infection, chronic chest infection (eg, bronchiectasis), sinusitis, recurrent urinary tract infection (eg, recurrent pyelonephritis, chronic nonremitting cystitis), an open, draining, or infected skin wound or ulcer.
17.Have received, or are expected to receive, any live virus or bacterial vaccination within 3 months before first administration of IP, or through Week 20 during the study.
18.Had a BCG vaccination within 1 year prior to screening.
19.History of positive human immunodeficiency virus (HIV), or have congenital or acquired immunodeficiency (eg, common variable immunodeficiency disease).
20.History of known demyelinating diseases such as multiple sclerosis or optic neuritis.
21.History of, or concurrent congestive heart failure (CHF), including medically controlled, asymptomatic CHF.
22.History of lymphoproliferative disease, including lymphoma, or signs suggestive of lymphoproliferative disease, such as lymphadenopathy of unusual size or location, or clinically significant splenomegaly.
23.Active substance abuse or a history of substance abuse within 6 months prior to Screening.
24. Bacterial infections requiring treatment with oral or injectable antibiotics, or significant viral or fungal infections, within 4 weeks of Screening. Any treatment and cure for such infections must have been completed at least 4 weeks prior to Screening.
25. Malignancy or history of malignancy (for exceptions please refer to the protocol)
26.Psoriasis flare or rebound within 4 weeks prior to Screening.
27.Topical therapy within 2 weeks of randomization (including, but not limited to, topical corticosteroids, retinoids or vitamin D analog preparations, tacrolimus, pimecrolimus, or anthralin/dithranol). Exceptions: low-potency corticosteroids
(for example, Class 6 or 7; please see Investigator’s Manual) will be allowed as background therapy and restricted to treatment of the face, axillae, and groin in accordance with the manufacturers’ suggested usage during the course of the study (this restricted usage should be documented). Subjects with scalp psoriasis will be permitted to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions. An unmedicated skin moisturizer (eg, Eucerin®) will be also permitted for body lesions only. Subjects should not use these topical treatments within 24 hours prior to the clinic visit.
28.Systemic therapy for psoriasis within 4 weeks prior to randomization (including, but not limited to, cyclosporine, corticosteroids, methotrexate, retinoids, mycophenolate, thioguanine, hydroxyurea, sirolimus, sulfasalazine, azathioprine, and fumaric acid esters).
29.Use of phototherapy within 4 weeks prior to randomization.
30.Use of any investigational drug within 4 weeks prior to randomization, or 5 pharmacokinetic/pharmacodynamic half lives, if known (whichever is longer).
31.Prolonged sun exposure or use of tanning booths or other ultraviolet light sources.
32.Prior treatment with apremilast or etanercept. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with either apremilast 30 mg BID or placebo who achieve at least a 75% reduction in PASI (PASI-75) at Week 16 from baseline |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
-Proportion of subjects treated with either etanercept or placebo who achieve PASI-75 at Week 16
The following endpoints are all for comparison of apremilast 30 BID versus placebo and etanercept 50 mg SC QW versus placebo:
-Proportion of subjects with an sPGA score of clear (0) or almost clear (1) with at least 2 points reduction at Week 16
-Percent change from baseline in the affected body surface area (BSA %) at Week 16
-Proportion of subjects who achieve PASI-50 at Week 16
-Change from baseline in DLQI total score at Week 16
-Change from baseline in Mental Component Summary (MCS) score of SF-36 at Week 16
-Proportion of subjects with an LS-PGA score of clear (0) or almost clear (1) at Week 16
Safety:
-Type, frequency, severity, and relationship of adverse events to IP
-Number of subjects who prematurely discontinue IP due to any adverse event
-Frequency of clinically significant changes in physical examination, vital signs, electrocardiogram, and/or laboratory findings
-Psoriasis flare/rebound
Exploratory: please refer to the study protocol |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: week 16
Safety and exploratory: week 16 + throughout the study |
|
| 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 | 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 19 |
| 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 |
| Australia |
| Canada |
| 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
|
| Please refer to the protocol |
|
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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