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Proof-of-concept Trial of IVA337 in Diffuse Cutaneous Systemic Sclerosis (FASST)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02503644
Recruitment Status : Completed
First Posted : July 21, 2015
Last Update Posted : March 4, 2019
Sponsor:
Information provided by (Responsible Party):
Inventiva Pharma

Tracking Information
First Submitted Date  ICMJE June 30, 2015
First Posted Date  ICMJE July 21, 2015
Last Update Posted Date March 4, 2019
Actual Study Start Date  ICMJE October 29, 2015
Actual Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 20, 2015)
Measurement of skin thickness by the Modified Rodnan Skin Score (MRSS) [ Time Frame: 48 weeks ]
Mean change of the MRSS from baseline
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2018)
  • Response rates based on MRSS improvement [ Time Frame: 12, 24, 32, 48 weeks ]
    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)
  • Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement [ Time Frame: 28, 32,40, and 48 weeks ]
    Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement
  • Lung function measured by FVC% predicted [ Time Frame: 24 and 48 weeks ]
    Change in pulmonary function
  • Lung function by cDLCO% predicted [ Time Frame: 24 and 48 weeks ]
    Change in pulmonary function
  • Scleroderma Health Assessment Questionnaire (SHAQ) [ Time Frame: 24 and 48 weeks ]
    Changes in patient reported outcomes
  • Gastrointestinal tract symptoms severity and its impact on patients' well-being assessed by the UCLA SCTC GIT [ Time Frame: 24 and 48 weeks ]
    Changes in patient reported outcomes
  • Patient-reported health status assessed by PROMIS29 [ Time Frame: 24 and 48 weeks ]
    Changes in patient reported outcomes
  • Physical and mental health assessed by SF36 [ Time Frame: 24 and 48 weeks ]
    Changes in patient reported outcomes
  • 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 [ Time Frame: 12, 24, 32 and 48 weeks ]
    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
  • Hand function assessed by the Cochin Hand Function Scale [ Time Frame: 12, 24, 32 and 48 weeks ]
    Hand function assessed by the Cochin Hand Function Scale
  • Patient global assessment of disease activity assessed by a visual analogue scale [ Time Frame: 24 and 48 weeks ]
    Patient global assessments of disease activity (VAS)
  • Physician global assessment of disease activity assessed by a visual analogue scale [ Time Frame: 24 and 48 weeks ]
    Physician global assessment of disease activity (VAS)
  • Change in the Combined Response Index for Systemic Sclerosis (CRISS) [ Time Frame: 24 and 48 weeks ]
    Composed of five variables: MRSS, FVC % predicted, physician and patient global assessments, and HAQ-DI score
  • Percent of patients who need escape therapy [ Time Frame: 28, 32,40, and 48 weeks ]
    Need for escape therapy
  • Percent of patients who experience a new severe organ involvement [ Time Frame: 2, 4, 8,12, 16, 24, 28, 32, 40, 48, and 52 weeks ]
    Severe organ involvement
  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: 2, 4, 8, 12, 16, 20, 24, 28, 32, 40, 44, 48, and 52 weeks ]
    Frequency and type of AEs
  • Routine and specific laboratory tests (composite) to assess safety and tolerability [ Time Frame: 2, 12, 20, 24, 32, 36, 44, 48, and 52 weeks ]
    creatine kinase, N-terminal pro-brain natriuretic peptide, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, γ-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 (β-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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2015)
  • Response rates based on MRSS improvement [ Time Frame: 12, 24, 32, 48, and 60 weeks ]
    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 [ Time Frame: 28, 32,40, and 48 weeks ]
    Overall progression of the disease: defined as absence of rescue therapy and absence of severe organ involvement
  • Lung function measured by FVC% predicted [ Time Frame: 24 and 48 weeks ]
    Change in pulmonary function
  • Lung function by cDLCO% predicted [ Time Frame: 24 and 48 weeks ]
    Change in pulmonary function
  • Scleroderma Health Assessment Questionnaire (SHAQ) [ Time Frame: 24, 48, and 60 weeks ]
    Changes in patient reported outcomes
  • Gastrointestinal tract symptoms severity and its impact on patients' well-being assessed by the UCLA SCTC GIT [ Time Frame: 24, 48, and 60 weeks ]
    Changes in patient reported outcomes
  • Patient-reported health status assessed by PROMIS29 [ Time Frame: 24, 48, and 60 weeks ]
    Changes in patient reported outcomes
  • Physical and mental health assessed by SF36 [ Time Frame: 24, 48, and 60 weeks ]
    Changes in patient reported outcomes
  • 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 [ Time Frame: 12, 24, 32, 48, and 60 weeks ]
    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
  • Hand function assessed by the Cochin Hand Function Scale [ Time Frame: 12, 24, 32, 48, and 60 weeks ]
  • Patient global assessment of disease activity assessed by a visual analgue scale [ Time Frame: 24, 48, and 60 weeks ]
    Patient global assessments of disease activity (VAS)
  • Physician global assessment of disease activity assessed by a visual analgue scale [ Time Frame: 24, 48, and 60 weeks ]
    Physician global assessment of disease activity (VAS)
  • Change in the Combined Response Index for Systemic Sclerosis (CRISS) [ Time Frame: 24, 48, and 60 weeks ]
    Composed of five variables: MRSS, FVC % predicted, physician and patient global assessments, and HAQ-DI score
  • Percent of patients who need escape therapy [ Time Frame: 28, 32,40, and 48 weeks ]
    Need for escape therapy
  • Percent of patients who experience a new severe organ involvement [ Time Frame: 2, 4, 8,12, 16, 24, 28, 32, 40, 48, and 60 weeks ]
    Severe organ involvement
  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: 2, 4, 8,12, 16, 24, 28, 32, 40, 48, and 60 weeks ]
    Frequency and type of AEs
  • Routine and specific laboratory tests (composite) to assess safety and tolerabiltiy [ Time Frame: 2, 12, 24, 32, 48, and 60 weeks ]
    creatine kinase, troponin I, N-terminal pro-brain natriuretic peptide, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, γ-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 (β-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.
Current Other Pre-specified Outcome Measures
 (submitted: July 20, 2015)
  • Raynaud attacks assessed by a diary and the Raynaud condition score (VAS) [ Time Frame: Daily during week 9 and week 25 ]
  • Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the blood [ Time Frame: 12, 24, and 48 weeks ]
    Mean changes in activity biomarkers
  • Progression of the disease assessed by changes of the activity of specific SSc biomarkers in the skin [ Time Frame: 48 weeks ]
    Mean changes in activity biomarkers
  • Population pharmacokinetics to confirm the pharmacokinetic profile, including Cmax, Tmax, AUC, half-life (t1/2), clearance (CL/F) and volume of distribution (Vd/F) [ Time Frame: 2, 24, and 48 weeks ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Proof-of-concept Trial of IVA337 in Diffuse Cutaneous Systemic Sclerosis
Official Title  ICMJE A Randomized, Double-blind, Placebo-controlled, Multicentre Proof-of-concept Trial of IVA337 in the Treatment of Diffuse Cutaneous Systemic Sclerosis
Brief 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.
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Scleroderma, Diffuse
  • Diffuse Cutaneous Systemic Sclerosis
Intervention  ICMJE
  • Drug: IVA337
    Capsules of 200mg IVA337
    Other Name: lanifibranor
  • Drug: Placebo
    Identical capsules without active substance
    Other Name: No other names at present
Study Arms  ICMJE
  • Active Comparator: IVA337 800mg
    Patients receive twice daily 400mg IVA337.
    Intervention: Drug: IVA337
  • Active Comparator: IVA337 1200mg
    Patients receive twice daily 600mg IVA337.
    Intervention: Drug: IVA337
  • Placebo Comparator: Placebo
    Patients receive twice daily placebo.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 21, 2018)
145
Original Estimated Enrollment  ICMJE
 (submitted: July 20, 2015)
105
Actual Study Completion Date  ICMJE October 12, 2018
Actual Primary Completion Date October 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Bulgaria,   France,   Germany,   Italy,   Netherlands,   Poland,   Slovenia,   Spain,   Switzerland,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02503644
Other Study ID Numbers  ICMJE IVA_01_337_HSSC_15_001
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Inventiva Pharma
Study Sponsor  ICMJE Inventiva Pharma
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Yannick Allanore, Professor Université Paris Descartes, Hôpital Cochin, Service de Rhumatologie A & INSERM, Paris, France,
Principal Investigator: Christopher Denton, Professor Royal Free Hospital NHS Foundation Trust
PRS Account Inventiva Pharma
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP