To Compare the Efficacy of Combination Therapy vs Monotherapy for Pulmonary Arterial Hypertension in Systemic Sclerosis (BosSilSS)

Randomized Controlled Trial to Compare the Efficacy of Combination Therapy vs Monotherapy for Pulmonary Arterial Hypertension in Systemic Sclerosis

The study will be carried out on 50 consecutive consenting patients of systemic sclerosis with PAH recruited from outpatient department of internal medicine and rheumatology clinic of PGIMER, Chandigarh, India It is a single centre double blind randomised controlled trial evaluating the effect of upfront dual therapy (sildenafil and bosentan) vs monotherapy (sildenafil) Participants will be randomised in 1:1 ratio to one of treatment arms. Placebo and PDE-5 inhibitors 20 mg BD to 60 mg if patient tolerates the drug well to one study arm and PDE-5 inhibitors plus ER antagonist 62.5 to max of 125 to other study group

Study Overview

• Status: Unknown
• Conditions: Associated Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Sildenafil 20mg and Bosentan 62.5mg; Drug: Sildenafil 20mg and Placebo

Detailed Description

All patients fulfilling the SSc classification criteria of American College of Rheumatology during the study period will be screened for presence of PAH. Diagnosed cases of PAH based on CD echo with PAP >35mmHg based on echocardiography will be enrolled in study.Baseline NYHA functional class and 6 min walk distance in meters will be assessed. Heamogram and LFT will be measured Patients will be assessed at two weeks for side effects/safety issues. 6MWT and NYHA functional class will be reassessed at 3 months and 6 months.2D echo will be done at 6 months to measure mPAP RandomizationAll eligible patients will be randomized in a 1:1 ratio in blocks of ten between the two arms. Randomization will be stratified based on severity of PAH. The drugs will be labelled as A and B randomly by another staff member, who will not be involved in deciding the treatment of the study subjects. The randomization sequence will be generated using computer random number generator.

Blinding will be ensured by matching placebo for ERA in one group and will labelled one treatment arm as 'A' and other treatment arm as 'B'. Allocation concealment will be ensured by means of enclosing the randomization sequence in sealed opaque envelopes. Sealed opaque envelopes will contain Code 'A' or Code 'B'.

Intervention-The study consists of two treatment arms. The study drugs mainly Bosentan and Placebo will be packed into matching tablets at the dosage 62.5 mg. One treatment arm will contain Sildenafil and Placebo while other treatment arm will contain Sildenafil and Bosentan. Treatment will be initiated as 20 mg twice a day for Sildena-fil in combination with placebo once a day in one treatment arm and with Bosentan 62.5 mg once a day in other treatment arm .Dose of Sildenafil will be increased to 20 mg thrice a day at four weeks and that of Bosentan to 62.5 mg twice a day. Placebo will be also be provided twice a day.This will be continued till end of study period.. Dose adjustments in case of adverse events will be made depending on the severity of adverse events.

Statistical analysis- Intention to treat analysis will be carried for the primary and secondary outcomes. For continuous outcomes, unpaired t-test and for dichotomous outcomes chi-squares test with Yate's correction will be used. P<0.05 will be considered significant

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• India
  • Chandigarh, India, 160012
    • Recruiting
    • Dr Preksha Dwivedi
    • Contact: Preksha Dwivedi, MD; Phone Number: +91-8109492343; Email: drpreksha07@gmail.com
    • Contact: Shefali Sharma, MD; Phone Number: +91-9417372439; Email: Sharmashefali@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients aged 18 years
• Patients with systemic sclerosis
• PAH diagnosed as PAP>35mmHg
• NYHA functional class II,III,IV
• SSc disease duration >1years

Exclusion Criteria:

• Forced vital capacity <60% predicted
• Renal insufficiency
• Left heart disease and other relevant cardiac conditions
• Pregnant or breastfeeding female
• Patients on PAH specific therapy
• Liver disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Combination arm A-Sildenafil and Bosentan; Combination Arm A -Intervention- Drug; Tab Sildenafil 20 mg - three times a day for 6 months,and; Tab Bosentan 62.5mg - twice a day for 6 months	Drug: Sildenafil 20mg and Bosentan 62.5mg; Sildenafil 20 mg three times a day and bosentan 62.5mg two times a day
Placebo Comparator: Monotherapy arm-Sildenafil and Placebo; Monotherapy arm B Intervention-Drugs Tab Sildenafil 20mg- three times a day for 6 months, and Placebo tab (matched for bosentan) for 6 months	Drug: Sildenafil 20mg and Placebo; Sildenafil 20 mg three times a day and placebo (matched for bosentan)two times a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pulmonary artery pressures	Change in Pulmonary artery pressures measured by echocardiography at baseline and 6 months in patients of systemic sclerosis with PAH when treatment with Single(PDE-5inhibitors at dose of 20 mg maximum upto 60mg) versus Dual therapy(PDE-5inhibitors and ER antagonist 62.5 mg maximum upto 125mg) for 6 months	Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1.Change in 6 Minute walk distance	1. To compare change in 6 MWD at baseline, and 6 months when treated with single versus dual therapy.	Baseline and 6 months
Time To Clinical Worsening (TTCW)	To compare time to clinical worsening (TTCW) in SSc patients when treated with single versus dual therapy. TTCW is defined as first occurrence of all cause deaths, PAH related hospitalisation, worsening of symptoms defined as a decrease of >15% in 6 min walk distance and worsening of NYHA functional class.	Baseline and 6 months
Emergent side effects of Sildenafil and Bosentan	To compare the emergent side effects of sildenafil and bosentan by way of comparison of serious and nonserious side effects.	Baseline to 6 months

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research
• Investigators: Study Chair: Nandita Kakker, M.D, Institutional ethics committee,PGIMER Chandigarh,India

Study record dates

Study Major Dates

• Study Start: December 1, 2016
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: December 29, 2016
• First Submitted That Met QC Criteria: February 12, 2017
• First Posted (Actual): February 15, 2017

Study Record Updates

• Last Update Posted (Actual): February 15, 2017
• Last Update Submitted That Met QC Criteria: February 12, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Systemic sclerosis, Associated Pulmonary Arterial Hypertension
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Respiratory Tract Diseases; Lung Diseases; Connective Tissue Diseases; Hypertension, Pulmonary; Sclerosis; Hypertension; Scleroderma, Systemic; Scleroderma, Diffuse; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Endothelin Receptor Antagonists; Sildenafil Citrate; Bosentan
• Other Study ID Numbers: MK/2927/DM/9430

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No