| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe plaque psoriasis |
|
| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071117 |
| E.1.2 | Term | Plaque psoriasis |
| E.1.2 | System Organ Class | 100000004858 |
|
| 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 show non-inferiority of FP187 to Fumaderm® after 20 weeks of treatment with a 500 mg daily dose of FP187 (250 mg BID) against a 720 mg daily dose of Fumaderm® (240 mg TID) on two co-primary endpoints:
- The proportion of patients achieving PASI75 with the predefined non-inferiority margin of 15 per cent points difference in PASI75.
- The proportion of patients achieving a “clear” or “almost clear” score, or a 2 point improvement from baseline on sPGA.
Both endpoints will be assessed after 20 weeks of treatment, and the non-inferiority margin for the proportions of patients achieving each endpoint will be 15 percentage points. |
|
| E.2.2 | Secondary objectives of the trial |
• Compare the efficacy of 500mg FP187 (250mg BID) to 720mg Fumaderm (240mg TID) & placebo at weeks 4, 8, 12, 16 & 20 on:
- proportion of patients achieving sPGA of ‘clear’ or ‘almost clear’, or at least a 2 point improvement from baseline
-proportion of patients achieving PASI75
-proportion of patients achieving PASI50 & PASI90
-the absolute & relative change in PASI and in BSA
-proportion of responders on the combined PASI50 & Dermatology Life Quality Index (DLQI)≤5
-the patient achieving DLQI ≤5
-the patient rated DLQI
-pruritus measured on a VAS scale
-at weeks 12 & 20 on Patient Benefit Index
-at week 20 on improvement on nail disease using the NAPSI score
•Assess pain relief in patients with psoriasis arthritis
•Investigate lab safety on haematology and renal function, liver enzymes & standard biochemistry in the 3 treatment arms
•Assess safety & tolerability of FP187 during the full duration of the trial based on AE and SAE reporting and supportive questionnaires |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients of either sex at least 18 years of age
Patients with a clinical diagnosis of stable moderate to severe plaque psoriasis (PASI value above 10) for at least 6 months prior to trial start will be eligible for randomization for the trial.
Patients with a clinical diagnosis of plaque psoriasis defined as skin areas with erythema, induration and scaling, with an affected body surface area (BSA)>10% and in total to be scoring > 10 on the PASI scale and on the sPGA score at least as moderate (≥3 at the 6-point scale), defined as:
-Systemic treatment naive patients who cannot be controlled in their disease symptoms with a topical treatment and are candidates for systemic treatment; or
- Patients who have failed under treatment with other first or second line systemic treatments.
Signed and dated informed consent,
Females of childbearing potential must be either surgically sterile (hysterectomy or tubal ligation) or use a highly effective (failure rate <1%) medically accepted contraceptive method during the trial as well as one month after trial is finished such as:
– Systemic contraceptive (oral, implant, injection),
– Intrauterine device (IUD) inserted for at least one month prior to trial entrance
Willingness and ability to comply with the trial procedures.
Besides psoriasis, patient is in good general health in the opinion of the Investigator, as determined by medical history, physical examination, vital signs (systolic and diastolic blood pressure [upper limit 160/95] pulse rate [between 50 and 100]), electrocardiogram (ECG), and clinical laboratory parameters (haematology, biochemistry and urinalysis)). Minor deviations of laboratory values from the normal range may be accepted, if judged by the Investigator to have no clinical relevance.
Patients have to have a DLQI>10 |
|
| E.4 | Principal exclusion criteria |
Female patients who are pregnant or breast-feeding or planning to become pregnant during the entire trial period as well as male patients planning pregnancy with their partner during the entire trial period or practice unprotected sexual relationship during the entire trial period.
Male patients planning pregnancy with their partner during the entire trial period, or practicing unprotected sexual relationship during the entire trial period.
Known allergy to any of the constituents of the products being tested,
Pustular forms of psoriasis, erythrodermic or guttate psoriasis,
Known immunosuppressive diseases (e.g., AIDS/HIV),
Presence of another serious or progressive disease including skin malignancies, which, according to the Investigator may interfere with treatment outcome,
Active skin disease such as atopic dermatitis, rosacea, lupus erythematous, or other inflammatory or infectious skin disease which, according to the Investigator may interfere with treatment outcome,
Use of topical medical treatment or UVB treatment during the 2 weeks preceding Visit 3
Use of systemic anti-psoriatic treatment preceding Visit 3:
– Methotrexate, cyclosporine, steroids or PUVA treatment within 4 weeks,
– Biological treatment (efalizumab, adalimumab, infliximab, etanercept) within 12 weeks, or Stelara within 20 weeks
– Acitretin within 6 months,
-– Not named drugs should have a wash-out of 5 times their half-life
Treatment with Fumaderm® or other DMF containing products during the past 12 weeks prior to Visit 3,
Has within the past 4 weeks prior to Visit 3 been treated with drugs influencing the course of the psoriasis such as antimalarial drugs, or lithium,
Treatment with retinoids, other immunosuppressive treatment, cytostatics or drugs with known harmful effects on the kidneys within the last 3 month, also if currently kidney functions are normal.
Has on-going stomach or intestinal problems (e.g. gastritis or peptic ulcer),
Has liver enzyme results (AST, ALT,) > 2 x upper normal limit (ULN) or gamma-GT results > 2.5 x ULN
Has an estimated Creatinine Clearance (Cockcroft-Gault): < 60 ml/min,
Has leucopenia (leukocyte count < 3.5x109/l) or eosinophilia (count > 750/μl) or lymphocytopenia (count < 1.02 x109/l),
Has protein in the urine stick test at Visit 1 and at Visit 2, and confirmed in a subsequent complete urine analysis
Participation in another clinical trial during the last two months preceding Visit 3 or participation in a trial with treatment with biologicals within 6 months prior to Visit 3,
Patients who are involved in the organisation of the clinical investigation or are in any way dependent on the Investigator or sponsor
Patients in whom Fumaderm® is contraindicated. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of patients achieving PASI75 (from baseline) and the responder rate of sPGA as co-primary endpoint (achieving a score of “clear” or “almost clear”, or a 2 point improvement on a 6-point scale) both measured after 20 weeks of treatment for Placebo, FP187 and Fumaderm® patients. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary endpoint measured after 20 weeks of treatment for Placebo, FP187 and Fumaderm® patients. |
|
| E.5.2 | Secondary end point(s) |
-Proportion of patients with “clear” or “almost clear”, or a 2 point improvement on the 6-point sPGA scale at weeks 4, 8, 12, 16 and 20;
-The proportion of patients achieving PASI75 at weeks 4, 8, 12, 16 and 20;
-The proportion of patients achieving PASI50 and PASI90 at weeks 4, 8, 12, 16 and 20;
-The absolute and relative reduction in PASI at weeks 4, 8, 12, 16 and 20;
-The absolute and relative reduction in BSA at weeks 4, 8, 12, 16 and 20
-The proportion of responders on the combined PASI50 AND DLQI≤5 at weeks 4, 8, 12, 16 and 20;
-The proportion of patients achieving DLQI≤5 at weeks 4, 8, 12, 16 and 20 on the patient rated DLQI;
-The absolute and relative change from baseline on DLQI at weeks 4, 8, 12, 16 and 20
-The change from baseline to weeks 12 and 20 in PBI;
-The change from baseline to weeks 4, 8, 12, 16 and 20 on pruritus measured on a VAS scale;
-The change from baseline of pain reported in patients with psoriasis arthritis measured on a VAS scale
-The change from baseline to week 20 in nail disease using the NAPSI score.
Safety endpoints:
-The incidence of change in laboratory data, in particular haematology (WBC, eosinophils, lymphocytes), biochemistry (liver enzymes, renal parameters including creatinine, calculated creatinine clearance and proteinuria);
-The incidence and severity of flushing reported
-The incidence and severity of diarrhea, abdominal pain, nausea and vomiting reported
-The drop-out rate due to drug related AE’s
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints measured at various timepoints throughout the duration of the trial, see E.5.2. above. |
|
| 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 | 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 |
| Adaptive group sequential design with one interim analysis after 40% sample have >12 weeks treatment |
|
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Canada |
| France |
| Germany |
| Russian Federation |
| Ukraine |
|
| 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
|
|
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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