A Trial of Tadalafil in Interstitial Lung Disease of Scleroderma
Condition: Lung Diseases, Interstitial
MeSH terms: Lung Diseases; Lung Diseases, Interstitial; Scleroderma, Systemic; Scleroderma, Diffuse
Study type: Interventional
Phase: Phase 3

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.
    

Detailed description: 
      Systemic sclerosis (SSc, scleroderma) is a multisystem autoimmune rheumatic disease that
      causes inﬂammation, vascular damage and ﬁbrosis. Besides involvement of skin, fibrosis also
      affects many internal organ involving blood vessel, lungs, heart, kidney etc. 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. But there is a significant change in pattern of cause of mortality
      over these years. 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). The frequency of
      pulmonary hypertension, independent of PF, also significantly increased during this time
      period (p<0.05)1. Presently PAH and interstitial lung disease accounts for majority of
      scleroderma related deaths. This emphasizes the need of novel therapies for interstitial lung
      disease in scleroderma, in order to improve the mortality and morbidity outcome of these
      patients.

      The ﬁbrosis of the skin and internal organs in SSc is believed to be caused by the transition
      of quiescent ﬁbroblasts to activated myofibroblasts, which characteristically overproduce
      dermal ﬁbrillar collagen (type I, III, V), collagen-modifying enzymes and other extracellular
      matrix (ECM) components2. One of the major cytokines involved in this process is transforming
      growth factor TGF β1 3. TGF-β is normally secreted as a latent complex, which is required to
      be activated in extracellular regions before binding its receptors and exerting its
      biological effects. In dermal ﬁbroblasts, several membrane proteins, including integrin αVβ5
      and thrombospondin 1(TSP1), catalyze the activation of latent TGF-β in the local
      microenvironment4,5. Binding of TGF-β to type II receptors (TRII) recruits type I receptors
      (TRI) and activates a series of signaling transduction pathways including the core Smad
      pathway (canonical pathway) and the non-Smad pathways (mitogen-activated protein kinase
      [MAPK], Rho, etc). TRI phosphorylates Smad3 at the S423/S425 within the C-terminal MH2. The
      activated pSmad3 binds with Smad4 to form the activated heteromeric Smad complex. The
      pSmad3/Smad4complexes enter the nucleus and associate with other transcription factors to
      regulate transcriptions of target genes required for collagen synthesis, myofibroblasts
      transformation and synthesis of matrix metalloproteinases6.

      Studies of cyclophosphamide have shown inconsistent result on pulmonary function and
      survival. In the Scleroderma Lung Study (oral cyclophosphomide), there was only modest
      improvement in dyspnoea score, stabilization (no improvement) of FVC and no effect on DLCO at
      1 year 7. At 2 years, there is no significant difference between any of these parameters
      between placebo and treatment group8. In a decision analysis using the Markov model to assess
      quality-adjusted life years (QALYs), authors conclude that there is no survival or quality of
      life benefit with oral cyclophosphamide9. Subsequent, Fibrosing Alveolitis in Scleroderma
      Trial (FAST) [intravenous cyclophosphamide followed by azathioprine] did not demonstrate
      significant improvement in the primary or secondary end points in the active treatment group
      versus the group receiving placebo10. A recent meta-analysis concluded that although previous
      trials with cyclophosphamide show a statistically significant improvement in lung function,
      they do not show a clinically significant improvement (>10% change in lung function)10.
      Considering the risk of infection and other serious adverse effects of oral cyclophosphamide,
      the risk benefit ratio may not be favorable for long term use of this drug. The experience
      with other immunosuppressive agents like mycophenolate moeftil11, azathioprine (as single
      agent)12,rituximab13 are limited to case studies or open label studies and lack double blind
      randomized control studies. Nonetheless, the potential adverse effects associated with these
      agents raise concern regarding their long term administration in a chronic disease like SSc
      -ILD.

      Therefore, the focus of treatment of SSc associated ILD gradually shifting from non- specific
      immunosuppressive drugs to specific targeted therapy. Many attempts have been made to use
      drugs which target the molecular pathways responsible for causing fibrosis. Imatinib mesylate
      is a small molecule that blocks specific tyrosine kinases, including c-Abl and
      platelet-derived growth factor receptor (PDGFR) kinase. Incubation of cultured fibroblasts
      from patients with SSc and healthy volunteers with imatinib strongly inhibited the synthesis
      of col 1a1, col 1a2 and fibronectin-1 on the mRNA as well as protein level by up to 90% at
      concentrations of 1.0 mg/ml14. Treatment with imatinib completely prevented the development
      of fibrosis in the mouse model of Bleomycin-induced dermal fibrosis and tight-skin-1 (tsk-1)
      mouse model of SSc15. But clinical trials in patients failed to reproduce this effect. In a
      randomized, placebo-controlled trial of patients with mild to moderate Idiopathic pulmonary
      fibrosis followed for 96 weeks, imatinib did not affect survival or lung function16. The
      major adverse events include edema, muscle cramps and creatine kinase elevations,
      uncontrollable diarrhea and bone marrow toxicity, congestive heart failure17. These adverse
      effects need particular attention in clinical trials with patients with SSc because these
      patients often present with cardiac involvement, diarrhea and coexisting myositis with
      creatine kinase elevations. In addition, mild to moderate edema might be less well tolerated
      by patients with SSc with existing skin diseases than by patients with cancers 18.

      Recently, endothelin1 (ET-1), is implicated in the pathophysiology of lung fibrosis.
      Endothelin 1(ET-1) is known to induce fibroblast chemotaxis and proliferation19, promote
      deposition of collagen20, decrease collagenase activity, and increase levels of
      fibronectin21. But Bosentan, a nonselective Endothelin receptor antagonist, in randomized
      placebo controlled trial failed to have any significant impact on 6-min walk distance or in
      lung function parameters 22.

      PDE5 enzyme degrades cyclic guanosine monophosphate (c-GMP), a molecule responsible for
      nitric oxide-mediated vasodilatation. Recently PDE 5 inhibitors have shown to have novel
      antifibrotic effect by increasing level of CGMP. Cyclic GMP in turn activates the
      cGMP-dependent protein kinase G (PKG). Phosphorylation of Smad3 at S309 and T368 within MH2
      by PKG prevents its heterodimerization with Smad4 and thus disrupts their nuclear
      translocation, resulting in repression of transcriptional activation23. TSP1 (thrombospondin
      -1) is a molecule catalyzing latent TGF-b activation and is expressed at high levels in
      cultured SSc ﬁbroblasts (in vitro) and in activated ﬁbroblasts in lesional skin of SSc (in
      vivo). Blockade of TSP1 by cyclic GMP partially abolishes the autocrine TGF-b signaling in
      SSc ﬁbroblasts24. Increase in level of cGMP blocks ca2+ pump and thereby improves endothelial
      disruption which is the initiating event in pathogenesis of fibrosis. Increase in NO level
      also helps in mopping up reactive oxygen species which are implicated in pathogenesis of
      fibrosis. In a Bleomycin induced pulmonary fibrosis model, PDE5 inhibition alters pulmonary
      and right ventricular (RV) response to intratracheal Bleomycin and that this inhibition acts
      through suppression of tissue free radicals and the Rho kinase pathway25. Dunkern et al
      showed that predominant PDE activities in lung fibroblasts are attributed to PDE5, PDE1 and
      to a smaller extent to PDE4 and PDE inhibitors prevent the formation of myofibroblasts from
      fibroblast 26.

      The evidence that PDE 5 inhibitors are antifibrotic have mainly came from its effectiveness
      in prevention and treatment of Peyronie's disease (PD). In a rat model of TGF-β1-induced PD,
      Valente and associates, demonstrated that both oral sildenafil, a PDE5 inhibitor that
      protects cGMP from breakdown, and oral pentoxifylline, a predominantly PDE4 inhibitor that
      increases cAMP synthesis, counteract the development of the PD-like plaque27. In the case of
      pentoxifylline, it was proposed that the well-known cAMP-cGmP signaling crosstalk may be
      responsible for its antifibrotic effects. In a subsequent study in the same rat model, it was
      shown that another PDe5 inhibitor, vardenafil, given orally and in different dosing regimens,
      not only prevented but partially reversed the formation of the PD-like plaque. Preventive
      treatment at the higher dose reduced the overall collagen content, collagen iii/i ratio and
      the number of myofibroblasts and tGF-β1-positive cells, and selectively increased the
      apoptotic index of cells (presumably including myofibroblasts), in the PD-like plaque28. The
      antifibrotic effect although initially demonstrated in penile tissue, now proved in other
      tissues like heat, kidney and lungs. These antifibrotic effects of PDE5 inhibitors were also
      seen in rat models of diabetic nephropathy29, experimental glomerulonephritis24, myocardial
      infarction and hypertrophy30, and pulmonary fibrosis. So as scleroderma patients have
      fibrosis in multiple organs, the beneficial effect of PDE5 inhibitor may become manifold. It
      has also found to be very effective in treating other clinical manifestation of systemic
      sclerosis like PAH and digital ulcer. In a double-blind, randomized, placebo-controlled trial
      of sildenafil in idiopathic pulmonary fibrosis, there were significant differences in
      arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of
      life in patients treated with sildenafil in comparison to placebo group31. Tadalafil is a
      PDE5 inhibitor which is longer acting than sildenafil. It is safe and not associated with any
      serious life threatening side effect in the recently concluded study of effect of tadalafil
      in digital ulcer of scleroderma patients from our center32. In the same trial, Patients
      reported improvement of skin tightening and they can move their limb and joint more freely.
      Those patients with ILD had improvement or at least stabilization of lung function
      (Unpublished). Besides, FMD (flow mediated vasodilation as marker of endothelial dysfunction)
      significantly improved in these patients so providing another basis for using this drug for
      treatment of pulmonary fibrosis.

      Hypothesis:

      Tadalafil, a PDE5 inhibitor, by virtue of its stabilizing effect on endothelial dysfunction
      and anti-fibrotic effect, may have efficacy in reducing symptoms due to interstitial lung
      disease in scleroderma.
    

Intervention name(s): Tadalafil; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Tab. Tadalafil 20 mg every other day for 6 months; Shape , size, color and odor matched Tab. of inert material every other day for 6 months
Intervention MeSH terms: Tadalafil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Interstitial lung disease; Scleroderma