Nail Psoriasis Blinded STUDY SYNOPSIS

Transcription

1 Nail Psoriasis Blinded STUDY SYNOPSIS Study Title Development Phase Phase 3 Study Medication Primary Objective Secondary Objectives A randomized, double-blind, vehicle-controlled, parallel-group trial to assess the efficacy, safety and tolerability of [STUDY DRUG] for topical treatment of nail psoriasis. Group A: [STUDY DRUG] once a day Group B: Vehicle once a day To assess the efficacy of topical [STUDY DRUG] in the treatment of mild to moderate psoriatic fingernail/s (defined as fingernail/s with matrix psoriasis NAPSI score and/or bed psoriasis NAPSI score 1 and 3 at baseline). To assess if the topical treatment with [STUDY DRUG] is able to improve the quality of life and discomfort in patients with psoriatic fingernail. To assess the safety and tolerability of topical [STUDY DRUG] in the treatment of psoriatic fingernail. Primary Endpoint Proportion of patients with clear target nail (NAPSI=0) at Week 24 Secondary Endpoints Exploratory Endpoints Other Endpoints Proportion of affected nails at baseline with NAPSI = 0 at Week 24 Proportion of patients with clear target nail bed (bed NAPSI = 0) at Week 24 Proportion of patients with clear target nail matrix (matrix NAPSI = 0) at Week 24 Proportion of patients with target nail reaching NAPSI-75% at Week 24 Proportion of affected nails at baseline reaching NAPSI-75% at Week 24 Change from baseline in Total NAPSI at Week 24 Time to reach NAPSI = 0 in the target nail Nail PGA response rates Change from baseline in in nail psoriasis VAS discomfort at Week 24 Patient acceptance of study therapy at Week 24 Health Outcome Assessments: EQ-5D, DLQI, SF36 and NPQ10 Safety and tolerability outcomes: Adverse events, skin irritation severity score; laboratory tests and vital signs. Others: Exposure to study medication, treatment compliance, prior medication and concomitant medication, quality of life and reasons for withdrawal.

2 Study Design Study Population and Procedures This is a multicenter, randomized, double-blind, vehiclecontrolled, parallel- group, phase 3, pivotal study. Patients with mild to moderate psoriatic fingernail/s, defined as fingernail/s with matrix psoriasis NAPSI score and/or bed psoriasis NAPSI score 1 and 3 at baseline, will be recruited. The sum of the scores for each nail should range between 1 and 6. The study consists of two arms comparing [STUDY DRUG] and vehicle. Patients meeting the main inclusion criteria will enter the study and will be randomly allocated to one of the two treatment groups: Group A: [STUDY DRUG] Group B: vehicle. Patients will apply the assigned treatment to the affected psoriatic fingernails once daily for 24 weeks. The nails will not be washed for at least six hours after application; therefore, it will be recommended to preferably apply the product before bedtime. Patients should avoid face contact. To remove the product, it is sufficient to wash the nails. No solvent is needed. At the Screening Visit (V0), at visits V2, V3, V4, V5, at the end of treatment period V6 and at the follow-up visit (V7): The Investigator will assess the severity of the pathology and record NAPSI and Nail PGA scores for all affected fingernails. The patient will assess their discomfort on a VAS. The patient will fill-in the quality of life questionnaire. The Investigator will take 4 digital photos under standardized conditions: one photo of the left hand thumb, left hand four fingers, right hand thumb, and the right hand four fingers. At the Screening Visit, the photos will be taken before scraping for KOH direct examination. At the end of the treatment (V6 or early discontinuation), patients will evaluate the acceptability of the study therapy. Safety and tolerability will be monitored throughout the study: safety laboratory investigations (including calcium levels inplasma and urine) will be evaluated at the Screening Visit, at Week 16 and at the End of Treatment or, if applicable, at the early discontinuation visit. Vital signs will be reported at the Screening Visit and at the End of Treatment (V6) or, if applicable, at an early discontinuation visit. The safety analysis will be performed by the central Lab.Adverse Events will be reported at each study visit including any possible

3 Criteria for evaluation skin irritation. Safety Measurements Adverse Events All adverse events (AEs) experienced by a patient during the entire study period must be recorded in the patient s Case Report Form. An AE is any untoward occurrence for a patient or subject undergoing a clinical investigation while receiving a medicinal product, irrespective of whether or not the untoward occurrence is considered related to the product. All markedly abnormal laboratory test results must always be reported as AEs. Any clinically significant changes in vital signs should also be recorded as an AE. Safety Laboratory Test Safety laboratory tests will be performed at the screening, at week 16 and at the end of the treatment period (Week 24) or at the discontinuation visit. These tests will include: haematology, clinical chemistry and urinalysis. The following variables will be measured: Haematology: haemoglobin concentration, haematocrit, red blood cell count and white blood cell count with differential and platelet count. Clinical Chemistry: transaminases (AST, ALT), total serum bilirubin (direct and indirect), γgt, alkaline phosphatase, serum creatinine, blood urea nitrogen, uric acid, glucose, cholesterol, triglycerides, potassium, magnesium, calcium, phosphorus, chloride, protein and albumin. Urinalysis: protein content, glucose content, haemoglobin content, WBC content in sediment, RBC content in sediment, crystals content in sediment, casts content in sediment, calciuria, phosphaturia. Physical examination A complete physical examination will be performed at the screening visit (V0), at the end of the treatment period (Week 24) and at the end of follow-up (week 28) or at the discontinuation visit. Vital signs Sitting systolic and diastolic blood pressure from the same arm, pulse (after 3 minutes sitting) and temperature will be measured at the screening visit, at the end of the treatment period (Week 24) and at the end of follow-up (week 28) or at the discontinuation

4 visit. Pregnancy Test A urine pregnancy test will be done locally, at each study site and at each study visit until the end of the treatment, to each woman of childbearing potential and to each menopausal woman (if menopause is less than one year) by means of a reagent stick. Severity Score of Skin Irritation Local tolerability at the application site will be assessed to rate the severity of any periungual irritation during the treatment period using the following Skin Irritation Severity Score: Score Dermal response 0 No evidence of irritation 1 Minimal erythema, barely perceptible 2 Definite erythema, readily visible; minimal edema or minimal papular response 3 Erythema and papules 4 Definite edema 5 Erythema, edema and papules 6 Vesicular eruption 7 Strong reaction spreading beyond test site Score A B C D F G Other effects Slight glazed appearance Marked glazing Glazing with peeling and cracking Glazing with fissures Film of dried serous exudate covering all or part of the patch site Small petechial erosions or scabs Efficacy Measurements Nail Psoriasis Severity Index (NAPSI) To assign a score to each nail for nail bed and nail matrix psoriasis, the Nail Psoriasis Severity Index (NAPSI) will be used. The nail plate is divided into four quadrants by imaginary longitudinal and horizontal lines. Nail matrix psoriasis is assessed by the presence of any feature of nail matrix psoriasis, including nail pitting, leukonychia, red spots in the lunula, and crumbling in each quadrant of the nail. Nail bed psoriasis is assessed by the presence of any features of nail bed psoriasis, including onycholysis, oil drop (salmon patch) dyschromia, splinter haemorrhages, and nail

5 bed hyperkeratosis in each quadrant of the nail. The score is 0 if the findings are not present, 1 if they are present in 1 quadrant of the nail, 2 if present in 2 quadrants of a nail, 3 if present in 3 quadrants of a nail, and 4 if present in 4 quadrants of a nail. Thus each nail has a matrix score (0-4) and a nail bed score (0-4), and the total nail score is the sum of those two (0-8). The sum of the scores from all involved fingernails is 0-80 (Total NAPSI score for that patient at that time) and represents the total score 11. Nail Physician Global Assessment (PGA) Each fingernail bed and matrix is scored on a 5-point scale, from clear (0) to severe-markedly involved (4) which correlates with the percentage of fingernail area affected (from no visible sign to signs involving greater than 51% of the nail). The highest of either score (bed or matrix) corresponds to the Nail PGA score for that nail.. VAS of discomfort A Visual Analogue Scale (VAS) is an instrument that is used to measure the amount of discomfort that the patient feels in the nail and ranges from no discomfort to worst possible discomfort. The VAS is a horizontal line, 100 mm in length, with descriptive words at each end. The patients mark on the line the point that they feel represents their perception of their current state of discomfort. The VAS score is determined by measuring in millimeters from the left side of the line to the point that has been marked by the patient. Quality of life and Health Outcomes At the screening visit (Visit -1, Baseline), and every postrandomization visit, patients will complete the Dermatology Life Quality Index (DLQI) 13 the EuroQoL-5D (EQ-5D) 14, SF and NPQ10 16 questionnaires. The DLQI is designed to evaluate quality-of-life in dermatological patients affected by chronic diseases. The EQ-5D is a measure of health outcome applicable to a wide range of health conditions. The Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) is an indicator of overall health status. The Nail Psoriasis Quality of Life Index (NPQ10) was developed to measure life quality impairment due to nail psoriasis and its modification in the course of treatment. Patient Acceptance of Study Therapy At the End of Treatment (V6 or at an early discontinuation), patients will evaluate the acceptability of the study therapy on a 4- point scale from 1 (Poor) to 4 (Very Good).

6 Inclusion criteria Written informed consent before starting any study-related procedure. Patients aged 18 and 80 years old. Men or women. Outpatients. Patients with mild to moderate psoriastic fingernail(s) defined as fingernail/s with matrix psoriasis NAPSI score and/or bed psoriasis NAPSI score 1 and 3 at baseline. The sum of the scores for each nail should range between 1 and 6. In case of skin involvement, patients with established clinical diagnosis of mild-to-moderate psoriasis (BSA involvement 8% or PASI 10). Exclusion criteria Use of any systemic treatment for psoriasis and/or nail psoriasis during the last six months before the screening visit. Use of any topical treatment for nail psoriasis on fingernail during the last six months before the screening visit. Use of photochemotherapy (phototherapy is allowed) or other forms of radiotherapy during the last four weeks before the screening visit. Positive mycology findings (KOH evaluation or culture) obtained in the three months before the screening visit or positive KOH evaluated at the screening visit. Patients using nail polish or other nail cosmetic products during last 72 hours prior to study drug application. Systemic use of the following therapies for any reason during last three months before the screening visit: immunosuppressives, chemotherapy and corticosteroids (topical use for plaque psoriasis is allowed).consumption of oral Vitamin D or its analogues for any reason during the last three months before the screening visit (calcipotriene topical use for plaque psoriasis is allowed). Patients with a clinically significant history of cardiovascular, renal, neurologic, liver, immunologic or endocrine dysfunction. A clinically significant disease is defined as one that in the opinion of the investigator may either put the patient at risk because of participation in the study or is a disease that may influence the results of the study or the patient s ability to participate in the study. Patients with a recent history (< 1 year) of myocardial infarction and/or (< 3 years) of heart failure or patients with any cardiac arrhythmia requiring drug therapy. History of hypercalcaemia or hypercalciuria. History of previous or current malignancy; in particular lymphoma, melanoma and/or basal cell carcinoma.

7 Randomization Product application and removal Study visits History of allergic reactions to Calcipotriene or [STUDY DRUG] excipients. Patients unable to understand the procedures and purposes of the study. Patients unable or unwilling to accept and meet study requirements. Use of an investigational drug or participation in an investigational study within 30 days prior to application of study medication. Alcohol or substance abuse. AIDS symptoms or any other immunodeficiency. Additional exclusion criteria for females only: Breast-feeding patients. Positive urine pregnancy test at screening (performed for all females of child bearing potential or for those in non- surgical post-menopause for less than 1 year). Female of childbearing potential having unprotected sexual intercourse with any non-sterile male partner (i.e., a male who has not been sterilized by vasectomy at least 6 months prior to drug application) within 14 days prior to study drug application. Acceptable methods of contraception are the following: condom, diaphragm, intrauterine contraceptive device (placed at least 4 weeks prior to study drug application), pill + condom. Eligible patients will be randomized to either [STUDY DRUG] or vehicle, in a 1:1 ratio according to a computer-generated randomization list. Randomization will be performed using permuted blocks. The randomization process will be managed centrally through the e-crf. All patients shall apply the allocated treatment once daily, preferably at bedtime, on clean and dry nail(s). The solution dries in approximately 30 seconds. A single layer of the product will be applied over the entire nail plate and 5 mm of surrounding skin. If possible, it will be applied to the nail bed, nail matrix and under the free edge of the nail. The nails shall not be washed for at least six hours after application, therefore, it will be recommended to preferably apply the product at bedtime. To remove the product it is sufficient to wash the nails. No solvent is needed. Eight visits are scheduled for each patient. The following are expected: screening: Visit 0 randomization: Visit 1 treatment: Visits 2, 3, 4, 5 and 6 (four weeks between visit 1

8 Not Allowed Medication Sample Size Analysis Populations and 2, eight weeks between Visits 2 and 3, the other visits during treatment are every four weeks) follow-up: Visit 7 (4 weeks after the end of treatment) Any systemic treatment for psoriasis and/or nail psoriasis (topical treatments on skin are allowed). Any topical product on fingernails (cosmetic or topical treatment for nail psoriasis). Photochemotheraphy (phototherapy is allowed) or other forms of radiotherapy. Systemic immunosuppressives, chemotherapy, corticosteroids. Oral Vitamin D or its analogues for any reason. At least 470 patients should be randomized, 235 patients in each treatment group. A total sample size of 390 evaluated patients (195 patients per treatment arm) will provide a power of at least 90% to detect a difference of 12% in the percentage of patients with Target nail NAPSI = 0 at the endpoint visit (24 weeks), 10% vehicle arm versus 22% in active treatment arm. A 0.05 two-sided significance level was set (nquery Advisor, two-sided Chi-Square Test). The primary analyses of efficacy will be based on a Full Analysis Set (FAS) consisting of all randomized patients to whom investigational drug is dispensed. Following the intent-to-treat principle, patients in the FAS population will be analyzed according to the treatment to which they were randomized. A Per Protocol (PP) population will consist of all patients in the FAS population who complete the study fully compliant with the protocol and without any major deviation likely to affect the nail bed or nail matrix assessments. Patients in the PP population will be analyzed according to the treatment they actually received. Efficacy analyses based on PP population will be performed in order to confirm the robustness of the results. The Safety population will consist of all randomized patients with at least one documented application of any study drug. It will be the basis for the analyses of safety. Patients in the Safety population will be analyzed according to the treatment they actually received. Of note, a statement that a patient experienced no adverse events also constitutes a safety assessment.

9 Statistical Methods All efficacy analyses will be performed on the FAS population. Also, analysis of the primary and secondary efficacy variables will be carried out on the Per Protocol population to assess the robustness of the findings. Safety outcomes will be analysed on the Safety population. The primary efficacy endpoint Proportion of patients with clear target nail (NAPSI = 0) at Week 24 will be analysed on the FAS population by means of a generalized linear model parameterized with logit link function, binomial distribution and with treatment and center as factors. Hypothesis testing of active treatment versus placebo and two-sided 95% confidence intervals for the odds ratios will be calculated based on previous described model, using the Wald statistic. Same approach will be used for Proportion of patients with clear target nail bed (bed NAPSI =0) at Week 24, Proportion of patients with clear target nail matrix (matrix NAPSI =0) at Week 24 and Proportion of patients with target nail reaching NAPSI- 75% at Week 24. The Proportion of affected nails at baseline with NAPSI = 0 at Week 24 and the Proportion of affected nails at baseline reaching NAPSI-75% at Week 24 will be analysed by a generalized linear mixed effects model for repeated measures with the identity link function and binomial distribution for the proportion of affected nails that become completely cleared of psoriatic signs will be estimated with treatment group, center, visit and treatment-by-visit interaction as fixed effects and with an unstructured variance-covariance matrix to take into account correlations among repeated measures within patient. A maximum likelihood estimate of the treatment difference in the proportions at Week 24 will be reported together with its associated two-tailed 95% CI. For the changes from baseline in continuous variables, a linear mixed effects model for repeated measures will be estimated with treatment group, center, visit and treatment-by-visit interaction as fixed effects, baseline value as covariate, and with an unstructured variance-covariance matrix to take into account correlations among repeated measures within patient. A maximum likelihood estimate of the difference between the least squares treatment means at Week 24 will be reported together with its associated two-tailed 95% CI. Missing data on the primary endpoint ( Proportion of patients with clear target nail (NAPSI=0) at Week 24 ) will be imputed as treatment failures (MVTF) as the primary imputation method and

10 using multiple imputation (MI) and last observation carried forward (LOCF) as sensitivity analyses. Stratified Wilcoxon Rank Sum test blocking for center will compare the treatments with respect to Patient acceptance of study therapy at Week 24. The overall type I family-wise error rate for testing the primary and the secondary efficacy parameters will be controlled at the 0.05 significance level using a 3-step serial gatekeeping multiple comparisons procedure (MCP). This procedure will be fully described in the protocol.