Azathioprine and Prednisone in the Treatment of Idiopathic Pulmonary Fibrosis

• Status: Unknown status
• Trial end date: 2008-12-01
• Target enrollment: 0
• Participant gender: All

Summary

Idiopathic pulmonary fibrosis (IPF) is a diffuse lung disease, associated with the histological appearance of usual interstitial pneumonia (UIP), with an inexorably deteriorating clinical course. Prognosis is poor, reported median survival is less than 3 years. The prevalence is estimated as being 3 to 10 per 100.000 in different Western populations. To date, no pharmacological therapy has been proven to alter or reverse the pathogenic process of IPF. Most treatments trials have been observational case series of small patient populations and very few have been randomized, prospective and placebo-controlled.

Two recent Cochrane reviews investigated the role of corticosteroids and other immunomodulatory agents and concluded that there is no evidence for their use in IPF. Most current therapies are targeted to suppress the inflammatory component of the disease, based on the theory that it would be chronic alveolar inflammation which leads to parenchymal remodeling and fibrosis. Recently, a hypothesis that has gained acceptance suggests that fibrosis may result directly from alveolar injury, promoting an abnormal fibrogenic repair mediated by fibroblasts and myofibroblasts.

One of the cytotoxic agents most widely used and better tolerated in the management of IPF is azathioprine. Based upon limited data available and from a single small high quality randomized controlled trial (RCT), this drug appears to confer, given in conjunction with prednisone, a marginal long term survival advantage. Since this combination therapy is associated serious adverse effect, we planned to design a trial of low dose corticosteroid and azathioprine versus placebo in management of IPF, evaluating progression-free survival.

Our study hypothesis is: Combined therapy with azathioprine and corticosteroids improves progression-free survival in patients with the diagnosis of IPF.

• Phase: N/A
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Thorax National Institute
• Collaborators: Servicio de Salud Metropolitano Oriente, Ministerio de Salud de Chile; Sociedad Chilena de Enfermedades Respiratorias
• Treatments: Azathioprine; Prednisone

Criteria

Inclusion Criteria:

• 45 and 79 years of age.

• Clinical symptoms of IPF for at least 3 months.

• Forced vital capacity (FVC) between 50 to 90% of the predicted value.

• DLco at least 35% of the predicted value.

• PaO2 > 55 mm Hg while breathing ambient air at rest.

• High-resolution computed tomography (HRCT) showing definite or probable criteria of IPF.

Exclusion Criteria:

• Clinically significant exposure to known fibrogenic agents (birds, molds, hot tubes, asbestos, radiation and drugs known to cause pulmonary fibrosis (amiodarone, nitrofurantoin, bleomicin,etc)).

• History of neurofibromatosis, Hermansky-Pudlak syndrome, metabolic storage disorders, etc.

• History of fever, weight loss, myalgias, arthralgias, skin rash, arthritis.

• Active infection within one week before enrollment.

• Alternative cause of interstitial lung disease.

• Ratio of the forced expiratory volume in one second (VEF1) to FVC of less than 0.6 after the use of a bronchodilator.

• Residual volume more than 120% of the predicted value (when available).

• More than 20% of lymphocytes or eosinophils in bronchoalveolar lavage (BAL) (when available).

• Granulomas, infection or malignancy in the transbronchial or surgical biopsy (when available).

• Previous therapy with azathioprine, prednisolone (>0.5 mg/kg/day or more for at least 3 months), cyclophosphamide or novel biotech drugs.

• Unstable cardiovascular or neurologic disease.

• Uncontrolled diabetes.

• Pregnancy.

• Lactation.

• Likelihood of death, as predicted by the investigator, within the next year.

• White cell blood count < 4000/mm3.

• Platelet count < 100000/mm3.

• Hematocrit < 30% or > 59%.

• Liver enzymes more than 3 times the upper limit of the normal range.

• Creatinine level > 1.5 mg/dL.

• Albumin level < 3 g/dL.

• Refusal to sign informed consent by patient or guardian.