Evaluation of Safety, Tolerability and Preliminary Efficacy of EHP-101 in Diffuse Cutaneous Systemic Sclerosis

Study Overview
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Brief Summary
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The purpose of this trial is to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of EHP-101 in adult subjects with diffuse cutaneous Systemic Sclerosis (dcSSc).

Detailed Description
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An interventional, double-blind, randomized, intracohort placebo-controlled design will be used to test safety, tolerability, pharmacokinetics, and preliminary efficacy of EHP-101 in 36 patients ≥ 18 and ≤ 74 years of age with documented dcSSc. There is a screening period of 28 days, 84 days treatment period, and 28 days follow-up.

Official Title
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A Phase IIa, Double-Blind, Randomised, Intracohort Placebo-Controlled, Multicentre Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of EHP-101 in Patients With Diffuse Cutaneous Systemic Sclerosis

Conditions
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Diffuse Cutaneous Systemic Sclerosis

Intervention / Treatment
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* Drug: Patients will be randomized to receive EHP-101 or Placebo
* Drug: Patients will be randomized to receive EHP-101 or Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients male and female ≥18 years and ≤74 years at the time of consent; American College of Rheumatology/ European League Against Rheumatism 2013 Criteria for SSc; dcSSc (skin thickening on upper arms, upper legs, or trunk); Documented SSc for up to 6 years from the first non-Raynaud's phenomenon with a total mRSS of ≥15; No new or increased doses of immunosuppressants medications within 3 months prior to Screening; Effective method of contraception for participants and their partners. Exclusion Criteria: Severe or unstable Systemic Sclerosis (SSc) or SSc with end-stage organ failure; Patient with FVC <60%; History of clinically significant medical condition or concurrent medical therapies that would exclude the patient, preclude participation in the clinical trial, influence response to study product, or interfere with study assessments; History of gastrointestinal dysmotility requiring total parenteral nutrition or hospitalization within 6 months before Visit 1; Any one of the following values for laboratory tests at screening: Haemoglobin <9 g/dL; Neutrophils <1.0 x 10^9/L; Platelets <75 x 10^9/L; Estimated creatinine clearance <50 mL/min according to the Cockcroft-Gault equation; Serum transaminases >2.0 x upper normal limit; Total bilirubin ≥1.5 x upper limit of normal.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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
Interventional Model Description: This is a dose escalation double-blind intracohort trial starting with Cohorts 1 and 2 commencing in parallel and then Cohorts 3 and 4 commencing in parallel
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EHP-101 low dose once a day<br> | Drug: Patients will be randomized to receive EHP-101 or Placebo<br>* EHP-101 or placebo will be taken once a day<br>|
| Experimental: EHP-101 low dose twice a day<br> | Drug: Patients will be randomized to receive EHP-101 or Placebo<br>* EHP-101 or placebo will be taken twice a day<br>|
| Experimental: EHP-101 high dose once a day<br> | Drug: Patients will be randomized to receive EHP-101 or Placebo<br>* EHP-101 or placebo will be taken once a day<br>|
| Experimental: EHP-101 high dose twice a day<br> | Drug: Patients will be randomized to receive EHP-101 or Placebo<br>* EHP-101 or placebo will be taken twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of Treatment Emergent Adverse Events | This safety outcome combines the measure of the number of subjects experiencing adverse events (AEs), the nature and severity of those AEs and their relationship to the study treatments. | Day 113 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment effect of EHP-101 compared to placebo as measured by the American College of Rheumatology composite response index in diffuse cutaneous Systemic Sclerosis | The ACR CRISS exponential algorithm determines the predicted probability of improvement from baseline, incorporating change in modified Rodnan Skin Score (mRSS), Forced Vital Capacity (FVC) % predicted, physician and patient global assessments, and Scleroderma Health Assessment Questionnaire Disability Index (S-HAQ-DI). The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). Subjects are not considered improved (ACR CRISS score = 0) if they develop new: 1) renal crisis; 2) decline in FVC% predicted by 15% (relative) from baseline and confirmed after 1 month; or 3) left ventricular failure (systolic ejection fraction < 45%); or 4) new pulmonary artery hypertension on right heart catheterization requiring treatment. | Day 85 and Day 113 | 
| Treatment effect of EHP-101 compared to placebo in modified Rodnan Skin Score | The mRSS consists of an evaluation of patient's skin thickness rated by clinical palpation using a 0-3 scale (0 = normal skin; 1 = mild thickness; 2 = moderate thickness; 3 = severe thickness with inability to pinch the skin into a fold for each of 17 surface anatomic areas of the body: face, anterior chest, abdomen, and, with right and left sides of the body separately evaluated, the fingers, forearms, upper arms, thighs, lower legs, dorsum of hands and feet. Individual values are summed and defined as the total skin score. Total score is 0 to 51. | Day 85 and Day 113 | 
| Treatment effect of EHP-101 compared to placebo in forced vital capacity percent predicted | Forced vital capacity (FVC) is a standard pulmonary function test used to quantify respiratory muscle weakness . FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted forced vital capacity is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (observed value)/(predicted value) * 100% | Day 85 and Day 113 | 
| Treatment effect of EHP-101 compared to placebo in physician global assessment score | The Physician Global Assessment of disease activity will be performed using a segmented numerical version of the visual analogue scale in which the physician selects a whole number (0-10 integers) that best reflects the overall disease activity. The numerical rating score is anchored by 2 verbal descriptors, one of no disease activity (score of 0) and one of worse imaginable disease activity (score of 10), with numbers 1-9 spaced equidistance in between. The physician will select an integer to describe disease activity. The recall period is one week. | Day 85 and Day 113 | 
| Treatment effect of EHP-101 compared to placebo in patient global assessments score | The Patient Global Assessment will be performed with a segmented numerical version of the visual analogue scale in which the subject selects a whole number (0-10 integers) that best reflects the overall disease activity. The numerical rating score is anchored by two verbal descriptors, one of no disease activity (score of 0) and one of worse imaginable disease activity (score of 10), with numbers 1-9 spaced equidistance in between. The subject will select an integer to describe disease activity. The recall period is one week. | Day 85 and Day 113 | 
| Treatment effect of EHP-101 compared to placebo in Scleroderma Health Assessment Questionnaire - Disability Index | S-HAQ-DI includes 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and activities. There are two or three questions for each section. Scoring within each section is from 0 (without any difficulty) to 3 (unable to do). The eight scores of the eight sections are summed and divided by 8. If one section is not completed by a subject, the summed score is divided by 7. As such, maximum scores can vary with a min of 0. The result is the DI, the disability index or functional disability index. The recall period is one week. | Day 85 and Day 113 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Scleroderma, Systemic sclerosis, EHP-101 Oral Solution, dcSSc, diffuse, pathological processes, connective tissue disease, skin disease