A Trial of Tadalafil in Interstitial Lung Disease of Scleroderma

• Status: Completed
• Trial end date: 2014-05-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Sanjay Gandhi Postgraduate Institute of Medical Sciences
• Treatments: Tadalafil

Criteria

Inclusion Criteria:

1. Fulfillment of the criteria for systemic sclerosis (SSc) by American College or Rheumatology (ACR) criteria (Subcommittee for Scleroderma Criteria, 1980)

2. Forced vital capacity (FVC) ≤ 70% predicted.

3. DLCO ≤ 70 % of predicted

3. Presence of dyspnea on exertion (grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index) 4. Evidence of ILD on HRCT

Exclusion Criteria:

1. Those that cannot perform PFT or 6 min walk test

2. High dose prednisolone (1 mg/kg) or cyclophosphamide (> 500 mg) or MMF (> 500mg/d) or (azathioprine > 1 mg/kg) for more than 4 weeks anytime within previous 6 months

3. SBP < 90 mmHg or history of orthostatic hypotension

4. Current smokers

5. Women who are pregnant or lactating

6. Those receiving nitrates, alpha blockers, or both, other phosphodiesterase inhibitors

7. Current use of captopril (because of sulfhydryl group). If ACE- inhibitors are indicated, an ACE-inhibitor other than captopril should be used.

8. Serum creatinine ≥ 2.0 mg/dl.

9. Obstructive lung disease (FEV1/FVC ratio < 0.6)

10. Prostacyclins or endothelin antagonists or who had received any investigational drug within the prior month

11. Acute coronary or cerebrovascular event within 3 months

12. Evidence of malignancy

13. Peptic ulcer

14. Hepatic dysfunction.