Proof-of-concept Trial of IVA337 in Diffuse Cutaneous Systemic Sclerosis

Diffuse Cutaneous Systemic Sclerosis Clinical Trial

— FASST  

Official title:

A Randomized, Double-blind, Placebo-controlled, Multicentre Proof-of-concept Trial of IVA337 in the Treatment of Diffuse Cutaneous Systemic Sclerosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02503644
• Other study ID #: IVA_01_337_HSSC_15_001
• Status: Completed
• Phase: Phase 2
• Start date: October 29, 2015
• Est. completion date: October 12, 2018

Study information

• Verified date: March 2019
• Source: Inventiva Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Systemic sclerosis (SSc), or scleroderma is a connective tissue disease of autoimmune origin. It is a life-threatening orphan disease with severe physical and psychosocial consequences. IVA337 has a novel mechanism of action and this study is designed to compare IVA337 at two dose levels with a placebo control treatment. Patients will be unaware of the treatment they are receiving and will be randomized to one of three treatment arms , either IVA337 400mg bid, IVA337 600mg bid or placebo bid. They will receive drug for 48 weeks and during that time assessments will be made to monitor both the efficacy and safety of the treatment.

Description:

Study design: randomized, double-blind, placebo-controlled, multicentre phase 2 proof-of-concept trial of IVA337 for the treatment DcSSc.

The treatments are randomly assigned. The randomisation is stratified for background therapy to ensure even distribution of background therapies among treatment groups.

There are 3 parallel treatment groups: placebo, IVA337 400mg bid and IVA337 600mg bid (identical capsules of 200mg IVA337 or placebo). Both, patient and investigator are blinded.

The treatment lasts 48 weeks. A follow-up assessment takes place 4 weeks after the last dose.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: October 12, 2018
• Est. primary completion date: October 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Informed Consent documented by signature

• Systemic sclerosis according to ACR/EULAR 2103 criteria (van de Hoogen 2013)

• Diffuse cutaneous SSc subset according to LeRoy's criteria

• Diagnosis within the past 3 years as defined by the first non-Raynaud's symptom

• MRSS between 10 and 25

• Age between 18 and 75, male or female

Patients on stable treatment (for >3 months) with prednisone = 10 mg, methotrexate= 20 mg/w, azathioprine = 150 mg/d, mycophenolate mofetil = 2g/d, or leflunomide = 20 mg/d may be included in the study; the therapy must be maintained as background therapy.

Exclusion Criteria:

• Cyclophosphamide during the past 3 months

• Requirement of IV prostanoids for pulmonary hypertension in the last 3 months

• Renal insufficiency defined by a creatinine clearance of less than 30 ml/min (CKD-EPI or MDRD formula) and/or past/current renal crisis

• Hepatic impairment i.e. primary biliary cirrhosis and unexplained persistent liver function abnormality,

• Gallbladder disease (Cholelithiasis is not an exclusion criterion)

• Diabetic ketoacidosis

• 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

• Known hypersensitivity or allergy to class of drugs or the investigational product

• Any condition or treatment, which in the opinion of the investigator, places the subject at unacceptable risk as a patient in the trial

• Co-therapy with biologics: Wash-out period: Any anti-TNF agent in the last 3-months:

adalimumab, certolizumab, etanercept, golimumab, infliximab; abatacept and tocilizumab in the last 3 months; rituximab in the last 6 months.

• Any other significant heart disease or any clinically significant ECG abnormality reported by central ECG reading.

Related Conditions & MeSH terms

• Diffuse Cutaneous Systemic Sclerosis
• Scleroderma, Diffuse
• Scleroderma, Systemic
• Sclerosis

Intervention

Drug:
• IVA337
Capsules of 200mg IVA337
• Placebo
Identical capsules without active substance

Locations

Country	Name	City	State
Bulgaria	University Multiprofile Hospital for Active Treatment - Dr. Georgi Stranski	Pleven
Bulgaria	Multiprofile Hospital for Active Treatment Plovdiv	Plovdiv
Bulgaria	University Multiprofile Hospital for Active Treatment -Kaspela	Plovdiv
Bulgaria	University Multiprofile Hospital for Active Treatment - "Sveti Ivan Rilski"	Sofia
France	Hôpital Pellegrin	Bordeaux
France	CHRU de Lille- Hôpital Claude Huriez	Lille
France	Hopital Cochin	Paris
France	University Hospital of Strasbourg	Strasbourg
Germany	Kerckhoff-Klinik	Bad Nauheim
Germany	Chaité-Universtätsmedezin Berlin	Berlin
Germany	Charité- Universitätsmedizin Berlin	Berlin
Germany	Univertaetsklinikum Carl Gustav Carus	Dresden
Germany	University of Erlangen-Nuremberg	Erlangen
Germany	CIRI GmbH Centrum für Innovative Diagnostik und Therapie	Frankfurt
Germany	University Medical Center Freiburg	Freiburg
Germany	Klinik fur Dermatologie und Venerologie der Universitat zu Köln	Köln
Germany	Kilinik für Hautkrankenheiten	Münster
Germany	Universtätsklinik Ulm	Ulm
Italy	Istituto di Clinica Medica Generale Polo Didattico	Ancona
Italy	Azienda Ospedalaria Spedali Civili di Brescia	Brescia
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	Ospedale San Salvatore ASL L'Aquila	L'Aquila
Italy	Azienda Ospedaliera Universitaria Federico II	Napoli
Italy	University of Padova	Padova
Italy	Ospedale di Alta Specializzazione "San Camillo"	Roma
Italy	Policlinico Umberto I	Roma
Italy	Universita degli Studi de Verona	Verona
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Erasmus MC Universitair Medisch Centrum Rotterdam	Rotterdam
Poland	Centrum Miriada Prywatny	Bialystok
Poland	University Hospital in Bydgoszcz	Bydgoszcz
Poland	CM Plejady	Krakow
Poland	Reumed	Lublin
Poland	Medycine Centrum Hetmanska Poznan	Poznan
Poland	Centrum Medyczne Oporow	Wroclaw
Slovenia	University Medical centre Ljubljana	Ljubljana
Slovenia	University Medical Centre Maribor	Maribor
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hopital 12 de Octubre	Madrid
Spain	Hopital Universitario Gregorio Marañon	Madrid
Spain	Hopital Universitario Sanchinarro	Madrid
Spain	Hospital La Paz	Madrid
Spain	Hospital La Princesa	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Dr Peset	Valencia
Switzerland	University Hospital Lausanne	Lausanne
Switzerland	University Hospital Zurich	Zurich
United Kingdom	Leeds Institut of Rheumatic and Musculoskeletal Medicine	Leeds
United Kingdom	Royal Free Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
Inventiva Pharma

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Raynaud attacks assessed by a diary and the Raynaud condition score (VAS)		Daily during week 9 and week 25
Other	Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the blood	Mean changes in activity biomarkers	12, 24, and 48 weeks
Other	Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the skin	Mean changes in activity biomarkers	48 weeks
Other	Population pharmacokinetics to confirm the pharmacokinetic profile, including Cmax, Tmax, AUC, half-life (t1/2), clearance (CL/F) and volume of distribution (Vd/F)		2, 24, and 48 weeks
Primary	Measurement of skin thickness by the Modified Rodnan Skin Score (MRSS)	Mean change of the MRSS from baseline	48 weeks
Secondary	Response rates based on MRSS improvement	MRSS response rates: Initial definition: improvers are defined by a reduction =5 points and =25 % of MRSS; Additional definition: improvers are defined by a reduction; = 4 points and = 20% of MRSS based on Quillinan et al. (2014, 2017)	12, 24, 32, 48 weeks
Secondary	Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement	Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement	28, 32,40, and 48 weeks
Secondary	Lung function measured by FVC% predicted	Change in pulmonary function	24 and 48 weeks
Secondary	Lung function by cDLCO% predicted	Change in pulmonary function	24 and 48 weeks
Secondary	Scleroderma Health Assessment Questionnaire (SHAQ)	Changes in patient reported outcomes	24 and 48 weeks
Secondary	Gastrointestinal tract symptoms severity and its impact on patients' well-being assessed by the UCLA SCTC GIT	Changes in patient reported outcomes	24 and 48 weeks
Secondary	Patient-reported health status assessed by PROMIS29	Changes in patient reported outcomes	24 and 48 weeks
Secondary	Physical and mental health assessed by SF36	Changes in patient reported outcomes	24 and 48 weeks
Secondary	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	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	12, 24, 32 and 48 weeks
Secondary	Hand function assessed by the Cochin Hand Function Scale	Hand function assessed by the Cochin Hand Function Scale	12, 24, 32 and 48 weeks
Secondary	Patient global assessment of disease activity assessed by a visual analogue scale	Patient global assessments of disease activity (VAS)	24 and 48 weeks
Secondary	Physician global assessment of disease activity assessed by a visual analogue scale	Physician global assessment of disease activity (VAS)	24 and 48 weeks
Secondary	Change in the Combined Response Index for Systemic Sclerosis (CRISS)	Composed of five variables: MRSS, FVC % predicted, physician and patient global assessments, and HAQ-DI score	24 and 48 weeks
Secondary	Percent of patients who need escape therapy	Need for escape therapy	28, 32,40, and 48 weeks
Secondary	Percent of patients who experience a new severe organ involvement	Severe organ involvement	2, 4, 8,12, 16, 24, 28, 32, 40, 48, and 52 weeks
Secondary	Number of participants with adverse events as a measure of safety and tolerability	Frequency and type of AEs	2, 4, 8, 12, 16, 20, 24, 28, 32, 40, 44, 48, and 52 weeks
Secondary	Routine and specific laboratory tests (composite) to assess safety and tolerability	creatine kinase, N-terminal pro-brain natriuretic peptide, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, ?-glutamyl transferase, total bilirubin, direct bilirubin,RBC and WBC count, reticulocytes, haemoglobin, haematocrit, albumin , Quick, aPTT, INR, BUN, plasma creatinine, microalbuminuria, homocysteine, urinalysis (dip stick), glycated haemoglobin, creatine phosphokinase increase, platelet counts, plasma osteocalcin, serum beta C-terminal telopeptide (ß-CTx or B-Crosslaps), Differential: neutrophils, eosinophils, basophils, monocytes, lymphocytes, cholesterol, triglycerides, albumin, total protein, C-reactive protein (CRP), adiponectin, serology HIV and hepatitis infection: Hep. A antibodies, B antibodies and antigen, C antibodies, serum b-HCG.	2, 12, 20, 24, 32, 36, 44, 48, and 52 weeks