A Phase II, randomised, placebo-controlled, double-blind, parallel-group, efficacy and safety study of at least 48 weeks of oral BI 685509 treatment in adults with progressive systemic sclerosis
Trial Snapshot
- Phase
- Phase 2
- Status
- Active, not recruiting
- Sponsor
- Boehringer Ingelheim
- Enrollment
- 200
- Locations
- 10
- Primary Endpoint
- The primary objective is to demonstrate superiority of BI 685509 at a target dose of 3 mg TID over placebo based on the mean difference in annual rate of decline in FVC over 48 weeks. The treatment effect of primary interest will be based on all randomised patients including the effects of any changes of treatment, i.e., a treatment policy strategy will be used.
Study Overview
Brief Summary
This is a multi-centre,multi-national, prospective, randomised, placebo-controlled, double-blind, parallel-group, PhaseII clinical trial to investigate the efficacy and safety of oral BI 685509 at atarget dose of 3 mg TID, in adult patients with early progressive dcSSc andvasculopathy.
Patients will be enrolled in thetrial and screened for eligibility once they have signed the informed consent.The screening period has a maximum of 5 weeks. Eligible patients will proceedto the 48-week treatment period. BI 685509 versus placebo use will beestablished in a 1:1 randomisation after the screening period.
The treatment period includes a4-week up-titration of BI 685509 from 1 mg to 3 mg TID: BI 685509 1 mg will begiven TID for 2 weeks. If tolerated, BI 685509 2 mg TID will be given for 2weeks and then escalated to 3 mg TID. If the patient develops symptomatic orthostatichypotension on 2 mg TID, they will have to stop trial medication and contactthe site for dose adjustment. The same procedure will be followed afterescalation from 2 mg to 3mg. Every dose adjustment will require a patient visitat the site. It is anticipated that approximately 10% of patients may not beable to fully titrate up to the 3 mg TID dose.
The main efficacyanalysis will be assessed at Week 48. After completing the first 48 weeks oftreatment, patients may continue to receive their assigned trial treatment inthe extended treatment period, until the last patient has completed thetreatment period. Patients will then enter a 4-week follow-up period that doesnot include trial treatment, for ongoing safety and efficacy data collection.The patient’s trial participation is complete when they have completed the lastplanned visit (i.e., EOS, 4 weeks after EOT).
Study Design
- Study Type
- Interventional
- Allocation
- Other
- Masking
- Participant and Investigator Blinded
Eligibility Criteria
- Ages
- 18.00 Year(s) to 99.00 Year(s) (—)
- Sex
- All
Inclusion Criteria
- •Male or female patients aged ≥18 years at time of consent (or above legal age, e.g. UK ≥16 years).
- •Patients must fulfil the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for SSc.
- •Patients must be diagnosed with diffuse cutaneous SSc (widespread skin fibrosis with skin involvement proximal to elbows and/or knees) as defined by LeRoy et al.
- •SSc disease onset (defined by first non-RP symptom) must be within 5 years of Visit
- •Evidence of active disease, defined as having at least one of the following: New onset of SSc within the last 2 years of Visit 1 OR New skin involvement or worsening of two new body areas within 6 months of Visit 1 (out of the 17 body areas defined by mRSS assessment, documented in clinical files) OR New involvement or worsening of one new body area of either chest or abdomen within 6 months of Visit 1 OR Worsening of skin thickening (≥2 mRSS points) within 6 months of Visit 1 OR ≥1 tendon friction rub.
- •6.Elevated biomarkers on Visit 1 (screening) defined as at least one of the following: C-reactive protein (CRP) ≥6 mg/L (≥0.6 mg/dL), OR Erythrocyte sedimentation rate ≥28 mm/h, OR Krebs von den Lungen 6 (KL-6) ≥1000 U/mL
- •Evidence of significant vasculopathy, defined as: Active DU(s) on Visit 1 OR Documented history of DU(s), OR previous treatment of RP with prostacyclin analogues or ≥ 1 other medications, including Nitrates, NO donors in any form, including topical; phosphodiesterase 5 (PDE5) inhibitors (e.g. sildenafil, tadalafil, vardenafil); nonspecific PDE5 inhibitors (theophylline, dipyridamole) OR • RP with elevated CRP ≥6 mg/L If none of the four criteria above are met, the patient can be entered if the diagnosis of interstitial lung disease (ILD) has been confirmed
- •Evidence of early fibrosis at Visit 1, defined as a mRSS of ≥12 points, AND FVC ≥50% of predicted normal
- •If patients receive concomitant treatments for dcSSc, these need to be on stable doses for a predefined period.
- •Male patients able to father a child must be willing to use condoms if their sexual partner is a woman of childbearing potential (WOCBP).
- •WOCBP must be ready and able to use highly effective methods of birth control per ICH M3 (R2).
- •Such methods should be used throughout the trial.
- •A list of contraceptive methods meeting these criteria is provided in the CTP.
Exclusion Criteria
- •Any known form of pulmonary hypertension.
- •Limited cutaneous SSc at screening.
- •Other autoimmune connective tissue diseases, except for fibromyalgia, scleroderma-associated myopathy and secondary Sjogren syndrome.
- •Diffusing capacity for carbon monoxide (DLCO) (haemoglobin corrected) <40% of predicted at screening.
- •Any history of scleroderma renal crisis.
- •Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology [CKD-EPI] formula) or on dialysis at screening.
- •Cirrhosis of any Child-Pugh class (A, B or C).
- •Cholestasis at present, or alkaline phosphatase (ALP) > 4 x upper limit of normal (ULN), or ALP > 2 x ULN and gammaglutamyl transferase (GGT) > 3 x ULN at Screening.
- •Known, severe gastric antral telangiectasias (watermelon stomach).
- •Any history of bronchial artery embolization or massive hemoptysis.
- •(Massive hemoptysis is defined as acute bleeding >240 mL in a 24-hour period or recurrent bleeding >100 mL/day over consecutive days).
- •Active hemoptysis or pulmonary hemorrhage, including events managed by bronchial artery embolization.
- •Systolic blood pressure <100 mm Hg or known history of moderate or severe symptomatic orthostatic dysregulation as judged by the Investigator before start of trial treatment.
- •Sitting heart rate (HR) <50 beats per minute (BPM) at them Screening Visit.
- •Known heart failure with left ventricular ejection fraction <40% prior to screening.
- •A marked baseline prolongation of QT/QTc interval.
Outcomes
Primary Outcomes
The primary objective is to demonstrate superiority of BI 685509 at a target dose of 3 mg TID over placebo based on the mean difference in annual rate of decline in FVC over 48 weeks. The treatment effect of primary interest will be based on all randomised patients including the effects of any changes of treatment, i.e., a treatment policy strategy will be used.
Time Frame: 48 weeks
Secondary Outcomes
- Secondary objectives are to demonstrate superiority of BI 685509 over placebo for absolute change from baseline in mRSS, FVC (% predicted), patient and physician global assessment, HAQ-DI, RP activity and DU net burden at Week 48, the ACR-CRISS, revised CRISS and for time to treatment failure. Additional objectives are to evaluate safety, PK, and exploratory biomarkers.(48 weeks)