A Trial of Tadalafil in Interstitial Lung Disease of Scleroderma

Summary

Systemic sclerosis (SSc, scleroderma) is a multisystem autoimmune rheumatic disease that causes inflammation, vascular damage and fibrosis. Besides involvement of skin, fibrosis also affects lung and heart. Although advances in understanding in pathophysiology and use of immunosuppressive therapy has brought significant improvement in outcome of other autoimmune diseases, scleroderma still remains as a disease with high mortality and 10 yr survival rate has improved only from 54% to 66% during last 25 years1. The frequency of deaths due to renal crisis significantly decreased (mainly due to effectiveness of ACE Inhibitors), from 42% to 6% of scleroderma-related deaths (p 0.001), whereas the proportion of patients with scleroderma who died of pulmonary fibrosis increased (due to lack of significant treatment) from 6% to 33% (p 0.001). However, presently, trials with immunosuppressive drugs including cyclophosphamide and other targeted molecules like Bosentan and Imatinib mesylate have shown very modest results at the best and given the risk of toxicity. The investigators have conducted three clinical trials with PDE5 inhibitor Tadalafil in the refractory Raynaud's phenomenon (RP) in SSc over last 3 years and had found good response in RP, healing of digital ulcers, prevention of new digital ulcers and also observed improvement in skin tightening, endothelial dysfunction and improvement of quality of life. The investigators therefore hypothesize that tadalafil may have an efficacy in improving the ILD of SSc.

The investigators therefore design this double-blind, randomized, placebo-controlled trial of oral Tadalafil (20 mg alternate day) in patients with SSc having ILD. Patients will be randomly assigned in a 1:1 ratio to receive either Tadalafil or matched placebo and will be followed up for 6 months. Prednisolone (if required for indications other than ILD) will be allowed up to 10 mg/d in all patients. Patient/s requiring more than 10 mg/d of prednisolone or equivalent dose of steroid will be excluded from the study. Patients who will fail on therapy during the study will be excluded from the study and will be asked to choose any therapeutic option from the rescue protocol.

Patients with FVC ≤ 70% predicted or DLCO ≤ 70 % of predicted, Evidence of ILD on HRCT will be enrolled. The primary objective of the study will be the change in FVC (expressed as a percentage of the predicted value) from baseline values at the end of 6-months of treatment. The secondary objectives will be improvement in dyspnea, improvement in 6 min walk distance, change in DLCO, change in total lung capacity, change in the disability index of the Health Assessment Questionnaire (S HAQ), and change quality of life (SF-36), levels of NT pro-BNP and fibrosis markers.

Conditions

• Lung Diseases, Interstitial

Interventions

DRUG

Tadalafil

Tab. Tadalafil 20 mg every other day for 6 months

DRUG

Placebo

Shape , size, color and odor matched Tab. of inert material every other day for 6 months

Sponsors & Collaborators

• Sanjay Gandhi Postgraduate Institute of Medical Sciences

  lead OTHER_GOV

Principal Investigators

• Vikas Agarwal, MD, DM · SGPGIMS

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2012-03-31

Primary Completion

2014-04-30

Completion

2014-05-31

Countries

• India

Study Locations