Safety, Tolerability, Efficacy, and Pharmacokinetics of JBT-101 in Systemic Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and efficacy of JBT-101 in adult subjects with diffuse cutaneous systemic sclerosis.

Detailed Description
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Part A of the study is an interventional, double-blind, randomized, placebo-control design will be used to test safety, tolerability, pharmacokinetics, and efficacy of JBT-101 in subjects ≥ 18 and ≤ 70 years of age with active diffuse cutaneous systemic sclerosis. The screening period is up to 28 days, with 84 days treatment period and 28 days follow-up off active treatment. Part B of the study is an interventional, open-label design will be used. All subjects who complete dosing in Part A without permanent discontinuation of study drug and who pass repeat safety screening will be eligible for enrollment. The screening period is up to 28 days, with a 364 day treatment period and 28 day follow up after last dose of JBT-101.

Official Title
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A Phase 2, Double-blind, Randomized, Placebo-controlled Multicenter Study to Evaluate Safety, Tolerability, Efficacy, and Pharmacokinetics of JBT-101 in Diffuse Cutaneous Systemic Sclerosis

Conditions
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Diffuse Cutaneous Systemic Sclerosis

Intervention / Treatment
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* Drug: JBT-101
* Drug: Placebo
* Drug: Part B Open-Label Extension


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A Diffuse cutaneous systemic sclerosis Have skin thickening from SSc in a body area suitable for repeat biopsy Disease duration ≤ 3 years from the first non-Raynaud's phenomenon or >3 years and ≤ 6 years from the first non-Raynaud's phenomenon and high sensitivity C-reactive protein > 3 mg/L, high sensitivity interleukin-6 > 5 pg/mL, or increase in mRSS ≥ 5 points over the last 6 months with total RSS ≥ 12. Stable treatment for SSc for at least 28 days before Visit 1 Part B •Completion of dosing in Part A without permanent discontinuation of study product because of safety or tolerability reasons. Exclusion Criteria (Part A and B): Severe or unstable systemic sclerosis Significant diseases or conditions other than systemic sclerosis that may influence response to the study product or safety; Any one of the following values for laboratory tests at Screening: A positive pregnancy test (or at Visit 1); Hemoglobin < 10 g/dL Neutrophils < 1.0 x 10^9/L Platelets < 75 x 10^9/L Creatinine clearance < 50 ml/min according to modified Cockcroft-Gault equation Serum transaminases > 2.0 x upper normal limit Total bilirubin ≥ 1.5 x upper limit of normal Any other condition that, in the opinion of the Principal Investigator, is clinically significant and may put the subject at greater safety risk, influence response to study product, or interfere with study assessments.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JBT-101 5 mg/20 mg bid<br>JBT-101 5 mg q am and placebo q pm on Days 1-28, then JBT-101 20 mg twice a day (bid) on Days 29-84. | Drug: JBT-101<br>* JBT-101 5 mg q am, 20 mg q am, or 20 mg bid on Days 1-28. JBT-101 20 mg bid on Days 29-84.<br>Drug: Placebo<br>* Placebo q pm (with JBT-101 5 or 20 mg q AM) or placebo bid on Days 1-28. Placebo bid on Days 29-84.<br>|
| Experimental: JBT-101 20 mg/20 mg bid<br>JBT-101 20 mg q am and placebo q pm on Days 1-28, then JBT-101 20 mg bid on Days 29-84. | Drug: JBT-101<br>* JBT-101 5 mg q am, 20 mg q am, or 20 mg bid on Days 1-28. JBT-101 20 mg bid on Days 29-84.<br>Drug: Placebo<br>* Placebo q pm (with JBT-101 5 or 20 mg q AM) or placebo bid on Days 1-28. Placebo bid on Days 29-84.<br>|
| Experimental: JBT-101 20 mg bid/20 mg bid<br>JBT-101 20 mg bid on Days 1-84. | Drug: JBT-101<br>* JBT-101 5 mg q am, 20 mg q am, or 20 mg bid on Days 1-28. JBT-101 20 mg bid on Days 29-84.<br>|
| Placebo Comparator: Placebo<br>Placebo bid on Days 1-84. | Drug: Placebo<br>* Placebo q pm (with JBT-101 5 or 20 mg q AM) or placebo bid on Days 1-28. Placebo bid on Days 29-84.<br>|
| Experimental: Part B Open-label<br>JBT-101 20 mg bid on Days 1-364 | Drug: Part B Open-Label Extension<br>* JBT-101 20mg bid on Days 1-364<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events From Baseline at Day 113 | The overall number of subjects with TEAE's per treatment group during active dosing (Days 1-84) plus the 28 day follow-up. | Part A: Day 113 | 
| Combined Response Index in Diffuse Cutaneous Systemic Sclerosis (CRISS) at Day 85 and 113 | CRISS components included the following domains: modified Rodnan skin score, forced vital capacity percent predicted, Physician Global Assessment, Patient Global Assessment, and Health Assessment Questionnaire Disability-Index. An algorithm determines the predicted probability of improvement from baseline by incorporating change in the mRSS, FVC percent predicted, Physician and Patient Global Assessments, and HAQ-DI. The outcome is a continuous variable between 0.0 and 1.0 (0 - 100%). A cut-off at 0.6 in the predicted probability of being improved has yielded the smallest misclassification error. Subjects are not considered improved if, between Visit 1 and 6, 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 pulmonary artery hypertension. Higher CRISS scores indicates improvement. | Day 85 and Day 113 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CRISS Individual Components (mRSS Total Score) Change From Baseline. | The LS mean change from baseline (CFB) at Visit 5 (Day 85) and 6 (Day 113) is provided for mRSS total score. Change from Change from Baseline was calculated as Visit 5 - Baseline and independently Visit 6 - Baseline. 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 with higher scores indicating worse symptomology | Day 85 and 113 | 
| CRISS Individual Component (FVC Percent Predicted) Change From Baseline | The LS mean change from baseline (CFB) at Visit 5 (Day 85) and 6 (Day 113) is provided for FVC percent predicted. Change from Baseline was calculated as Visit 5 - Baseline and independently Visit 6 - Baseline. | Day 85 and 113 | 
| CRISS Individual Component (Physician Global Assessment Score) Change From Baseline | The LS mean change from baseline (CFB) at Visit 5 (Day 85) and 6 (Day 113) is provided for physician global assessment. Change from Baseline was calculated as Visit 5 - Baseline and independently Visit 6 - Baseline. 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 113 | 
| CRISS Individual Component (Patient Global Assessment Score) Change From Baseline | The LS mean change from baseline (CFB) at Visit 5 (Day 85) and 6 (Day 113) is provided for patient global assessment. Change from Baseline was calculated as Visit 5 - Baseline and independently Visit 6 - Baseline. The assessment at each specified visit 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 113 | 
| CRISS Individual Component (HAQ-DI Score) Change From Baseline. | Change from Baseline was calculated as Visit 5 - Baseline and independently Visit 6 - Baseline. Health Assessment Questionnaire - Disability Index 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. Higher scores indicate worse symptomology | Day 85 and 113 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JBT-101, Lenabasum, Systemic Sclerosis