A randomized, double-blind, placebo-controlled, multicentre proof-of-concept trial of IVA337 in the treatment of diffuse cutaneous systemic sclerosis - IVA337 SSC POC

• Register: EUCTR
• Last refreshed on: 21 December 2021
• Main ID: EUCTR2015-001617-27-IT
• Date of registration: 17/06/2015
• Prospective Registration: Yes
• Primary sponsor: Inventiva SAS
• Public title: A randomized, double-blind, placebo-controlled, multicentre proof-of-concept trial of IVA337 in the treatment of diffuse cutaneous systemic sclerosis - IVA337 SSC POC
• Scientific title: A randomized, double-blind, placebo-controlled, multicentre proof-of-concept trial of IVA337 in the treatment of diffuse cutaneous systemic sclerosis - IVA337 SSC POC
• Date of first enrolment: 18/09/2015
• Target sample size: 105
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001617-27
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Germany, Italy, Netherlands, Slovenia, Spain, Switzerland, United Kingdom

Contacts

• Name: Manager
• Affiliation: Inventiva

• Name: Manager
• Affiliation: Inventiva

Key inclusion & exclusion criteria

Inclusion criteria:
• Systemic sclerosis according to ACR/EULAR 2013 criteria
• Diffuse cutaneous SSc subset (LeRoy’s criteria)
• Diagnosis within the past 3 years as defined by the first non-Raynaud’s symptom
• MRSS between 10 and 25
• Aged between 18 and 75 years
• Informed consent documented by signature
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 85
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

Exclusion criteria:
• Unstable treatment with corticosteroids or immunosuppressive agents (stable therapy for more than 3 months with prednisone = 10 mg, methotrexate= 20 mg/w, azathioprine = 150 mg/d, mycofenolate mofetil = 2g/d, or leflunomide = 20 mg/d is acceptable)
• Cyclophosphamide during the past 6 months
• Requirement of IV prostanoids for critical ischemia or pulmonary hypertension in the last 3 months
• Renal insufficiency defined by a creatinine clearance of less than 30 ml/min and/or past/current renal crisis
• Hepatic impairment i.e. primary biliary cirrhosis and unexplained persistent liver function abnormality,
• Gallbladder disease
• Severe cardiac (LVEF <45%) and/or pulmonary disease (FVC < 50% or pulmonary hypertension proven by right heart catheterisation)
• History of heart failure, symptomatic coronary artery disease, significant ventricular tachyarrhythmia, stent placement, coronary artery bypass surgery, and/or myocardial infarction.
• Recipient of solid organ transplant
• Gastrointestinal involvement preventing oral administration of study drug
• Chronic infections, positive serology for infection with hepatitis B or C.
• Pregnancy, Lactation. Woman of childbearing potential unwilling to use a medically acceptable form of birth control
• History of malignancy within the last 5 years, except for resected basal or squamous cell carcinoma, treated cervical dysplasia, or treated in situ cervical cancer
• A recent history of alcohol or drug abuse, non-compliance with other medical therapies
• Participation in a clinical study involving another investigational drug or device within 4 weeks before the Pre-treatment Visit
• Laboratory parameters at the pre-treatment visit showing any of the following abnormal results: transaminases > 2x the upper limit of normal (ULN) and/or bilirubin > 2x ULN; neutrophil count < 1,500/mm3; platelet count < 100,000/mm3; haemoglobin < 9 g/dL
• Contraindications to the class of drugs under study (PPAR agonists), e.g. known hypersensitivity or allergy to class of drugs or the investigational product (see IB 2015)
• Any condition or treatment, which in the opinion of the investigator, places the subject at unacceptable risk as a patient in the trial (Please consider the precautions and warnings described in the IB 2015)


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Systemic sclerosis (scleroderma) (SSc) is a chronic connective tissue disorder of unknown aetiology characterized by widespread microvascular damage and excessive deposition of collagen in the skin and internal organs . Pulmonary fibrosis and pulmonary hypertension appear as the leading causes of mortality and patients with SSc have considerable morbidity from their disease due to skin fibrosis, Raynaud’s phenomenon and damage to the gastrointestinal tract, lungs, heart and kidneys.
MedDRA version: 18.0 Level: LLT Classification code 10012941 Term: Diffuse scleroderma System Organ Class: 100000004859
MedDRA version: 18.0 Level: LLT Classification code 10074034 Term: Generalised scleroderma System Organ Class: 100000004859

Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

Intervention(s)

Product Name: IVA337
Product Code: IVA337
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: IVA337
CAS Number: 927961-18-0
Current Sponsor code: IVA337
Other descriptive name: 1-(6-BENZOTHIAZOLYLSULFONYL)-5-CHLORO-1H-INDOLE-2-BUTANOIC ACID
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: Secondary objectives include additional efficacy evaluations (details in the protocol), assessment of adverse events (AEs), and determination of population PK parameters of IVA337 in patients.

Timepoint(s) of evaluation of this end point: 48 weeks

Main Objective: The primary objective of this study is to evaluate in patients suffering from diffuse cutaneous SSc (DcSSc) the effect of 800mg and 1200mg IVA337 daily on the skin compared to placebo. The modified Rodnan Skin Score (MRSS) will be used to determine the changes in skin.

Primary end point(s): Primary outcome is the mean change of the Modifed Rodnan Skin Score (MRSS) from baseline to week 48

Secondary Outcome(s)

Secondary end point(s): • MRSS response rates; improvers are defined by a reduction =5 points and =25 % of MRSS
• Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement (see definition below)
• Change in pulmonary function (FVC% predicted and cDLCO% predicted)
• Changes in patient reported outcomes (SHAQ, UCLA SCTC GIT, PROMIS29, SF36)
• Digital ulcer net burden (defined as total number of ulcers at a certain time point minus number of ulcers at baseline) and proportion of patients who do not develop new ulcers
• Cochin Hand Function Scale
• Physician and patient global assessments of disease activity over the past week (VAS)
• Change in the Combined Response Index for Systemic Sclerosis (CRISS), consisting of five variables: MRSS, FVC % predicted, physician and patient global assessments, and HAQ-DI score (from SHAQ patient reported outcome)
• Need for escape therapy (% patients)
• Severe organ involvement (% patients) defined by
• New renal crisis OR
• New or worsened clinically symptomatic and significant heart disease, considered secondary to DcSSc OR
• Relative decline in FVC % predicted by = 10% or relative decline in FVC % predicted between 5 to < 10% with associated relative decline in DLCO % predicted by = 15%, provided that the decline in FVC results in FVC <75% of predicted OR
• New or worsening of gastrointestinal disease requiring hospitalization or new requirement for parenteral nutrition OR
• Critical digital ischemia of the extremities promoting the necrosis or gangrene
• Active polyarthritis defined by tender joints > 8 and swollen joints > 6 OR
• New onset of tendon friction rubs
SAFETY
• Frequency and type of AEs
• Lab tests: mean change and frequency of values outside the normal range
OTHER
• Changes in Raynaud phenomenon (Raynaud’s condition score)
• Mean changes in activity biomarkers
• Population pharmacokinetics
• Follow-up: There is a follow-up visit to evaluate any changes that might occur within 12 weeks after completion of the treatment. The performed assessments listed in the Schedule of Study Procedures refer to safety and efficacy.

Timepoint(s) of evaluation of this end point: Throughout the study at weeks, 2, 4, 8, 12, 16, 24, 28, 32, 40, 48, 60

Secondary ID(s)

IVA_01_337_HSSC_15_001

Source(s) of Monetary Support

Inventiva SAS

Ethics review

Status: Approved
Approval date: 07/09/2015
Contact:

Results

• Results available: Yes
• Date Posted: 24/04/2021
• Date Completed: 12/10/2018
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-001617-27/results