Study to Evaluate Safety and Efficacy of Oral MP1032 in Psoriasis Patients

Study Overview
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Brief Summary
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This Phase IIa study is designed to assess the safety, tolerability and pharmacokinetics of oral MP1032 in patients with moderate to severe psoriasis over a period of 6 weeks. Secondary endpoints to evaluate clinical parameters for psoriasis during the 6 week treatment period and a 4-week follow up will provide an opportunity to perform a first assessment of oral MP1032's clinical efficacy in the treatment of moderate to severe psoriasis. The study population will consist of 44 enrolled (40 completed) patients with moderate to severe chronic plaque psoriasis. Patients must be able to provide written consent and meet all the inclusion criteria and none of the exclusion criteria.

Detailed Description
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This study is a randomized, double-blind, parallel, placebo-controlled exploratory pilot study to evaluate safety, pharmacokinetics and efficacy of systemic oral (po) administration of 100 mg MP1032 bid in adult patients with moderate to severe chronic plaque psoriasis. The study design consists of a 28-day screening/run-in period, a 42-day treatment period, 1 day for the End of Treatment visit, and a 28-day follow-up period. Forty-four patients who meet the entry criteria will be randomized on Day 1 in a 1:1 ratio to receive either 100 mg MP1032 or placebo orally twice daily for 42 days. The goal is to have 40 patients (20 in each treatment group) complete the study. Pharmacokinetic sampling will occur on 3 designated study days. Safety will be monitored from the signing of the informed consent form (ICF) until the last follow-up visit on Day 71. Efficacy will be assessed on 6 designated study days using the following assessments: PASI, PGA, DLQI, mNAPSI, and EQ-5D 5L (VAS).

Official Title
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A Randomized (1:1), Double-blind, Parallel, Placebo-controlled Exploratory Pilot Study to Evaluate the Safety, Pharmacokinetics and Efficacy of Systemic (po) Application of MP1032 in Patients With Moderate to Severe Chronic Plaque Psoriasis

Conditions
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Psoriasis, Plaque Psoriasis

Intervention / Treatment
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* Drug: MP1032
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants legally competent to sign and give informed consent. Adult male and female patients aged 18 to 65 years with chronic plaque psoriasis: PASI score > 10 at screening and Disease duration of ≥ 6 months at the initiation of study medication. Body Mass Index (BMI) between 18.5 and 34.9 kg/m2. Diagnosis of chronic plaque psoriasis confirmed by a dermatologist/physician. Women of childbearing potential (WCBP) must have a negative urine pregnancy test at Screening (Visit 1). In addition, sexually active WCBP must agree to use 2 forms of adequate contraception throughout the trial. Post-menopausal women with spontaneous amenorrhea for at least 12 months and serum levels follicle stimulating hormone (FSH) Levels indicating post-menopausal state as per local laboratory reference ranges. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study. Sterilized women may be included. Patients must meet the following clinical laboratory criteria: White blood cell count ≥ 3.5 x 10^9/L Platelet count ≥ 100 x 10^9/L Serum creatinine ≤ 1.5 x upper limit of normal (ULN); estimated glomerular filtration rate > 60 mL/min Total bilirubin ≤ 1.5 x ULN Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 1.5 x ULN Hemoglobin ≥ lower limit of normal as per local laboratory reference ranges for women and men accordingly No coagulopathy (International Normalized Ratio [INR] < 1.5). Patients agree not to increase normal sun exposure during the course of the study. Patients are able to swallow 2 small capsules during each administration. Patients are considered reliable and capable of adhering to the protocol (eg, able to understand and complete diaries), visit schedule, or medication intake according to the judgment of the Investigator. Exclusion Criteria: Patients with non-plaque form of psoriasis (erythrodermic, guttate, pustular or palmo plantar psoriasis; severe form of psoriasis arthritis, inverse form of psoriasis). Mild to moderate cases of psoriasis arthritis are allowed provided there is no impact on study objectives as determined by the Investigator. Patients with drug-induced psoriasis. Evidence of skin conditions at the time of screening visit other than psoriasis that would interfere with evaluations of the effect of study medication on psoriasis. Patients with any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form. Pregnant or lactating females or females planning to become pregnant during the study and/or within 28 days following the last dose of study medication. Male patients planning a partner pregnancy or sperm donation during the study or within 3 months following the last dose of study medication. Known allergies to mannitol, macrophage modulators, and gelatin. Patients with a recent history or current signs or symptoms, as determined by the Investigator, of severe, progressive viral or bacterial infections, of clinically significant cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic insufficiency disease (excluding psoriasis) requiring systemic treatment or other major diseases, which are not well controlled and may interfere with the conduct of the trial. Patients with active malignancy or history of malignancy, except for basal cell or squamous cell carcinoma and actinic keratosis. Basal cell carcinoma and small squamous cell carcinoma of the skin which have been excised according to guidelines within the last 5 years or in situ cervical carcinoma that has been fully treated and shows no evidence of recurrence are allowed. Clinically significant abnormality on 12-lead electrocardiogram (ECG) at screening. Positive human immunodeficiency virus (HIV), hepatitis B or hepatitis C laboratory result. Previous strong sun exposure (eg, sea holiday) within the 28 days before study medication initiation. Known photo allergy and/or experienced drug-induced photo toxicity. Elective (planned) hospitalization or medical intervention preventing patient from following the protocol requirements. Prior Treatment: Drug class >> Last dose prior to study medication initiation (washout period) Topical psoriasis medications (including, but not limited to corticosteroids, calcipotriene, topical vitamin D derivates, retinoids, coal tar) >> 14 days Topical immunosuppressive drugs (tacrolimus, pimecrolimus, or anthralin) >> 14 days (Exception: Non-medicated emollients, moisturizers and sunscreens will be allowed), Use of low potency topical steroids for critical areas such as the face, genitalia, and scalp may be allowed until 24 hours prior to randomization. Systemic treatment (non-biologic): Systemic immunosuppressant agents (eg: methotrexate, cyclosporine, azathioprine), Systemic fumarate, Systemic corticosteroids >> 28 days Phototherapy or photochemotherapy/photosensitizing drugs >> 28 days Systemic retinoids >> 12 weeks Any investigational drug >> 24 weeks (systemic); 4 weeks (topical) Any Anti-TNFs: Infliximab, adalimumab, golimumab, etanercept, etc. >> 12 weeks Other Biologics and other systemic therapies: ustekinumab, alefacept, apremilast, Efalizumab, certolizumab pegol, secukinumab, etc. >> 24 weeks Rituximab >> 12 months Drinking or ingesting grapefruit, pomegranate, grapefruit juice or grapefruit containing products within 14 days of study medication initiation. Planned use of any ultraviolet (UV) phototherapy or photochemotherapy/photosensitizing drugs during the course of the study and within 28 days following the last dose of the study medication. Patients with a history of chronic alcohol or drug abuse within 6 months of study medication initiation. Patients employed by MetrioPharm or a contract research organization (CRO) involved in the clinical study. Vulnerable patients (eg, patients kept in detention). Patients who are unable to communicate, read and understand the local language, or who display any other condition, which, in the Investigator's opinion, makes them unsuitable for clinical study participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MP1032<br>Test Product: 100 mg MP1032 (= 2 capsules a 50 mg) are provided orally twice daily for 42 days | Drug: MP1032<br>* hard gelatine capsules containing 50 mg MP1032 as active ingredient<br>|
| Experimental: Placebo<br>Placebo to MP1032: 2 capsules of Placebo are provided orally twice daily for 42 days | Drug: Placebo<br>* hard gelatine capsules without active ingredient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - Treatment Emergent Adverse Events (TEAEs) - Number of TEAEs | Number of TEAEs (Treatment Emergent Adverse Events) occured was determined by treatment group. Furthermore, the absolute and relative frequencies for patients with a given AE, as well as the number of events of the individual AEs that have occurred throughout the study (inclusive screening), were determined within each treatment group and system organ class. Results thereto are provided in the section Reported Adverse Events. AEs are collected throughout the study. Abnormal values received from Clinical Laboratory Safety Testing (hematology, biochemistry and urinalysis on Study Days 1, 15, 29, 43, 57 and 71), Vital Signs (Systolic blood pressure, diastolic blood pressure, heart rate, tympanic body temperature and respiration rate on Study Days 1, 15, 29, 43, 57 and 71), ECG (Study Days 1, 43 and 71) and Physical Examination (Study Days 1, 43 and 71) were also handled as AE. | Continuously from Treatment Start until the last follow-up visit on Study Day 71 | 
| Safety - Treatment Emergent Adverse Events (TEAEs) - Number of Related TEAEs by SOC | Number of related TEAEs (Treatment Emergent Adverse Events) occured by SOC (System Organ class) was determined by treatment group. Furthermore, the absolute and relative frequencies for patients with a given AE, as well as the number of events of the individual AEs that have occurred throughout the study (inclusive screening), were determined within each treatment group and system organ class. Results thereto are provided in the section Reported Adverse Events. AEs are collected throughout the study. Abnormal values received from Clinical Laboratory Safety Testing (hematology, biochemistry and urinalysis on Study Days 1, 15, 29, 43, 57 and 71), Vital Signs (Systolic blood pressure, diastolic blood pressure, heart rate, tympanic body temperature and respiration rate on Study Days 1, 15, 29, 43, 57 and 71), ECG (Study Days 1, 43 and 71) and Physical Examination (Study Days 1, 43 and 71) were also handled as AE. | Continuously from Treatment Start until the last follow-up visit on Study Day 71 | 
| Safety - Treatment Emergent Adverse Events (TEAEs) - Number of Patients With TEAEs | Number of patients with TEAEs (Treatment Emergent Adverse Events) was determined by treatment group. Furthermore, the absolute and relative frequencies for patients with a given AE, as well as the number of events of the individual AEs that have occurred throughout the study (inclusive screening), were determined within each treatment group and system organ class. Results thereto are provided in the section Reported Adverse Events. AEs are collected throughout the study. Abnormal values received from Clinical Laboratory Safety Testing (hematology, biochemistry and urinalysis on Study Days 1, 15, 29, 43, 57 and 71), Vital Signs (Systolic blood pressure, diastolic blood pressure, heart rate, tympanic body temperature and respiration rate on Study Days 1, 15, 29, 43, 57 and 71), ECG (Study Days 1, 43 and 71) and Physical Examination (Study Days 1, 43 and 71) were also handled as AE. | Continuously from Treatment Start until the last follow-up visit on Study Day 71 | 
| Safety - Treatment Emergent Adverse Events (TEAEs) - Number of Patients With Related TEAEs by SOC | Number of patients with related TEAEs (Treatment Emergent Adverse Events) occured by SOC (System Organ class) was determined by treatment group. Furthermore, the absolute and relative frequencies for patients with a given AE, as well as the number of events of the individual AEs that have occurred throughout the study (inclusive screening), were determined within each treatment group and system organ class. Results thereto are provided in the section Reported Adverse Events. AEs are collected throughout the study. Abnormal values received from Clinical Laboratory Safety Testing (hematology, biochemistry and urinalysis on Study Days 1, 15, 29, 43, 57 and 71), Vital Signs (Systolic blood pressure, diastolic blood pressure, heart rate, tympanic body temperature and respiration rate on Study Days 1, 15, 29, 43, 57 and 71), ECG (Study Days 1, 43 and 71) and Physical Examination (Study Days 1, 43 and 71) were also handled as AE. | Continuously from Treatment Start until the last follow-up visit on Study Day 71 | 
| Pharmacokinetics (PK) - Plasma Concentrations | Study Day 1 - sampling 15 minutes, 30 minutes, 1 hour and 2 hours postdose Study Days 15, 29 and 43 - only one sample was taken any time postdose (time of the last dose was recorded). No statistical Evaluation has been performed. | Study Days 1, 15, 29 and 43 | 
| Pharmacokinetics (PK) - Maximum Observed Concentration (Cmax) | Maximum observed plasma concentration (Cmax)as observed on Day 1 with sampling times of 15 minutes, 30 minutes, 1 hour, and 2 hours postdose | Study Day 1 | 
| Pharmacokinetics (PK) - Time | Sampling 15 minutes, 30 minutes, 1 hour, and 2 hours postdose t max = Time corresponding to occurence of Cmax t last = Time of last quantifiable concentration | Study Day 1 | 
| Pharmacokinetics (PK) - Area Under the Curve (AUC) | AUC (lin-log) - Sampling 15 minutes, 30 minutes, 1 hour, and 2 hours postdose AUC 2h = area under the plasma concentration-time curve from time zero to 2 hours AUC t = area under the plasma concentration-time curve from time zero to the last quantifiable concentration. | Study Day 1 | 
| Pharmacokinetics (PK) - Area Under the Curve (AUC) - Subgroups | AUC (lin-log) - Sampling 15 minutes, 30 minutes, 1 hour, and 2 hours postdose AUC 2h = area under the plasma concentration-time curve from time zero to 2 hours AUC t = area under the plasma concentration-time curve from time zero to the last quantifiable concentration. | Study Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psoriasis Area Severity Index (PASI) - Observed PASI Values | Observed PASI values. PASI is a total score computed over 4 body regions with 4 assessments ranging from 0 (no symptoms) to 4 (very marked). The total score ranges from 0 to 72. No formal hypothesis testing, variables are summarized by descriptive statistics (n, mean, SD, ). | Study Day 1, 43, 57 and 71 | 
| Psoriasis Area Severity Index (PASI) - Change From Baseline | Change from Baseline (PASI value Day 43 - PASI value at Day 1) / Treatment difference on Day 43 PASI is a total score computed over 4 body regions with 4 assessments ranging from 0 (no symptoms) to 4 (very marked). The total score ranges from 0 to 72. Variables will be summarized by descriptive statistics (n, mean, SD), difference between groups is analyzed via non-parametric statistical testing. | Study Day 1 and 43 | 
| Psoriasis Area Severity Index (PASI) - PASI Percentage Change - Including Subgroup Analysis AUC2h | The PASI percentage change in % at Day 29 is calculated as PASI of (Day 29 - Baseline)/Baseline*100). The PASI percentage change in % at Day 43 is calculated as PASI of (Day 43 - Baseline)/Baseline*100). Baseline = Study Day 1 PASI is a total score computed over 4 body regions with 4 assessments ranging from 0 (no symptoms) to 4 (very marked). The total score ranges from 0 to 72. No formal hypothesis testing, variables are summarized by descriptive statistics (n, mean, SD). | Study Day 1, 29 and 43 | 
| Psoriasis Area Severity Index (PASI) - PASI Percentage Change - Including Subgroup Analysis AUCt | The PASI percentage change in % at Day 29 is calculated as PASI of (Day 29 - Baseline)/Baseline*100). The PASI percentage change in % at Day 43 is calculated as PASI of (Day 43 - Baseline)/Baseline*100). Baseline = Study Day 1 PASI is a total score computed over 4 body regions with 4 assessments ranging from 0 (no symptoms) to 4 (very marked). The total score ranges from 0 to 72. No formal hypothesis testing, variables are summarized by descriptive statistics (n, mean, SD). | Study Day 1, 29 and 43 | 
| Psoriasis Area Severity Index (PASI) - PASI 30 and PASI 50 - Number of Patients | PASI is a total score computed over 4 body regions with 4 assessments ranging from 0 (no symptoms) to 4 (very marked). The total score ranges from 0 to 72. PASI 30 and PASI 50 are related to the number of patients who had at least 30% (PASI 30) or 50% (PASI 50) reduction in PASI score compared to baseline (Study Day 1). Variables are summarized by descriptive statistics (n, mean, SD, ). Difference between groups has been analyzed via Fisher exact test. | Study Day 1, 29 and 43 | 
| Psoriasis Area Severity Index (PASI) - PASI 30 and PASI 50 - Responder Frequency | PASI is a total score computed over 4 body regions with 4 assessments ranging from 0 (no symptoms) to 4 (very marked). The total score ranges from 0 to 72. PASI 30 and PASI 50 are related to the number of patients (responder frequency (%)) who had at least 30% (PASI 30) or 50% (PASI 50) reduction in PASI score compared to baseline (Study Day 1). Variables are summarized by descriptive statistics (n, mean, SD, ). | Study Day 1, 29 and 43 | 
| Physician's Global Assessment (PGA) - Observed Values and Change From Baseline | PGA is the physician's global assessment of the severity of psoriasis using a 7-point scale from 0 (clear) to 6 (severe). No formal hypothesis testing, variables will be summarized by descriptive statistics (n, mean, SD) for absolute values and changes from baseline (Study Day 1) at Study Day 43 (End of Treatment). | Study Day 1 and 43 | 
| Dermatology Life Quality Index (DLQI) - Observed Values and Change From Baseline. | DLQI is a total score ranging from 0 (life quality is not affected) to 30 (deep impact on life quality) computed from answers to 10 questions, with each answer scored from 0 (not at all) to 3 (very much). No formal hypothesis testing, variables will be summarized by descriptive statistics (n, mean, SD) for absolute values and changes from baseline (Study Day 1) on end of treatment (Day 43). | Study Day 1 and 43 | 
| EQ-5D 5L Visual Analogue Scale (VAS) | EQ-5D (VAS) is a total score which records the patients' self-rated health status with the scale numbered 0 (worst imaginable) to 100 (best imaginable) No formal hypothesis testing, variables will be summarized by descriptive statistics (n, mean, SD) for absolute values and changes from baseline (Study Day 1) at end of Treatment (Study Day 43). | Study Day 1 and 43 | 
| Modified Nail Psoriasis Severity Index (mNAPSI) - Observed Values and Change From Baseline | mNAPSI score is a total score computed from answers to 7 questions, 3 of which can be answered with a score ranging from 0 to 3, and 4 of which can be answered with a score ranging from 0 to 1. The total score ranges from 0 to 13, the higher the score the worse the outcome. No formal hypothesis testing, variables will be summarized by descriptive statistics (n, mean, SD) for absolute values and changes from baseline (Study Day 1) at end of Treatment (Study Day 43). | Study Day 1 and 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plaque psoriasis, chronic, moderate, severe, Plaque