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…
ID
Source
Brief title
Condition
- Connective tissue disorders (excl congenital)
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome is the mean change of the MRSS from baseline to week 48
Secondary outcome
At the time points specified in the Schedule of Study Procedures:
EFFICACY
• 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 ischaemia of the extremities promoting necrosis and/or gangrene OR
• New development of pulmonary hypertension associated with pulmonary fibrosis
- defined by a mean pulmonary arterial pressure of 25 mmHg or more at right
heart catheterization
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 4 weeks after completion of the treatment. The performed
assessments listed in the Schedule of Study Procedures refer to safety.
• Evaluate the changes of Ssc activity index.
Background 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. There is currently no cure for this debilitating
disease.
IVA337 has strong potential for becoming a breakthrough therapeutic option for
SSc patients. IVA337 has been shown in several preclinical models of fibrotic
disorders that it can prevent the development of skin fibrosis and reverse
established skin fibrosis in curative settings
Study 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.
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.
Study design
Randomized, double-blind, placebo-controlled, multicentre proof-of-concept
trial of IVA337 in the treatment of early DcSSc.
Intervention
Patients take 6 capsules per day (3 capsules twice daily with food) and thus
receive either 800 mg or 1200 mg IVA337 or placebo, the control intervention.
Study burden and risks
The flow chart of the study is described on page 12 of the Protocol. The
duration of the study is as follows: screening period of 1 to 4 weeks prior to
the administration of medication; treatment period of 60 weeks. A total of 15
visits are performed. The screeningvisit may take more than 2 hours, but
thereafter each visit will not take more than 1 hour. If optional PK blood
samples are taken then it is possible that the patient is admitted to the
hospital. This differs per center. The patient will otherwise stay in the
hospital during the day.
Bloodsamples for safety analysis are taken during 11 visits. In addition,
during 4 visits blood samples will be collected for biomarker analysis.
Optional pharmacokinetics samples are taken during 2 visits. Physical
examination will take place during each visit, a total of 15 times. The patient
will also be asked whether he wants to undergo a skinbiopsy during visit 1 and
14. The biopsy takes place on the forearm and is voluntary.
At visit 1, 8, 14 and 15 patients are requested to answer questionnaires. The
patient could perceive these as confrontational. The questionnaires are : SHAQ,
PROMIS29, GIT and SF36. On visit 0, 4 and 8, the patient is asked to write down
the symptoms of Raynaud's in a patient diary during one week.The Cochin hand
function scale is carried on Visit 0, visit 1, visit 5, visit 8, visit 10,
visit 14 and visit 15.
The risk-benefit analysis of IVA337 in the current study is as follows:
IVA337 potentially offers a new therapeutic approach for SSc for which no
curative treatment is available: patients with SSc suffer from a high risk of
premature mortality and have considerable morbidity from their disease due to
skin fibrosis and excessive collagen deposition in various organs including the
lungs, kidney, heart and gastrointestinal tract. There is no cure for SSc,
there are only treatments for some of the symptoms. Hence there is a high unmet
medical need for new treatments.
IVA337 has been shown in non-clinical models to inhibit the effects of the main
fibrogenic cytokines, TGFβ and PDGF in vitro on fibroblasts
trans-differentiation into myofibroblasts and on fibroblasts proliferation
respectively. In vivo, IVA337 displayed antifibrotic activity in
bleomycin-induced fibrosis in the skin or lung and in CCL4-induced fibrosis in
the liver. In the skin, IVA337 was active in both preventive as well as
curative mode, thus providing evidence for an anti-fibrotic effect in
established fibrotic disease.
Risks
IVA337 has not yet been evaluated in systemic sclerosis and therefore there are
no expected events for IVA337 in this indication.
IVA337 has been evaluated in healthy volunteers and diabetic patients, and the
following adverse reactions have been observed:
Table 1: Frequencies of adverse reactions (AEs considered by the investigator
as related to IVA337) in healthy volunteers and diabetic patients who received
IVA337.
System Organ Class Description Severity Frequency
Healthy volunteers N=100
Gastrointestinal disorders:
constipation-Severity;mild, Frequency;1
epigastric discomfort-Severity;mild, Frequency;1
dysphagia-Severity; moderate, Frequency;1
nausea-Severity;mild, Frequency;2
vomiting-Severity;moderate, Frequency;1
General disorders
feeling hot-Severity; mild, Frequency;1
Nervous system disorders
dizziness-Severity;mild, Frequency;3
dizziness postural-Severity;mild, Frequency;7
lethargy-Severity;mild, Frequency;3
headache -Severity;mild, Frequency;3
somnolence-Severity;mild, Frequency;2
Psychiatric disorders
abnormal dreams-Severity;mild, Frequency;1
Renal and urinary disorders
pollakiuria-Severity;mild, Frequency;1
Vascular disorders
hot flush-Severity;mild, Frequency;1
Diabetes mellitus N=47
Blood and lymphatic system disorders
hypochromic anaemia-Severity;mild, Frequency;1
Nervous system disorders
headache -Severity; severe, Frequency;1
Gastrointestinal disorders
constipation-Severity;mild, Frequency;1
Urinary tract infections
urinary tract infection-Severity;mild, Frequency;1
IVA337 belongs to the group PPAR agonists. Even though it differs from other
PPARγ and PPARα agonists, one cannot yet exclude the following risks known for
some of these products:
- Hypoglycaemia, especially when combined with hypoglycaemic agents of
sulfonylurea class or insulin therapy,
- Fluid retention, pedal oedema and congestive heart failure , a risk shared by
the PPARγ and dual PPARα/γ agonists that cannot be excluded at this stage of
the clinical development of IVA337 despite an improved preclinical profile,
- Weight gain,
- Haematological changes i.e. small reductions in mean haemoglobin and
haematocrit,
- Liver enzyme increases,
- Myalgia and creatine phosphokinase increase,
- Ovulation resumption in special population,
- Bone fractures, increase of incidence in particular in women,
- Macular oedema,
- Cholelithiasis,
- Carcinogenicity: A review of the data on rodent carcinogenicity studies on
PPAR agonists by the European authorities has shown that epithelial cell
carcinomas in the bladder of rats and haemangiosarcomas in mice can occur. It
is not possible to determine the relevance of this data to humans.
The risks are mitigated by comprehensive and frequent monitoring of the
patients.
Conclusion
There is a positive risk-benefit balance in favour of IVA337. The serious
nature of systemic sclerosis, the unmet medical need, and the good tolerability
of IVA337 so far, justify further investigation of IVA337 in this rare disease.
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Age
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
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; therapy to be maintained as background therapy.
A complete list of criteria is provided in Section 7.1 of the protocol.
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 (see 7.1.3)
• History of malignancy within the last 5 years, except for resected basal or squamous cell carcinoma of the skin, 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 the past 4 weeks or during the study
• 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-001617-27-NL |
| CCMO | NL56540.078.16 |
| Other | NTC02503644 |