Azathioprine and Prednisone in the Treatment of Idiopathic Pulmonary Fibrosis
Recruitment status was Recruiting
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Purpose
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.
| Condition | Intervention |
|---|---|
|
Idiopathic Pulmonary Fibrosis |
Drug: Placebo Drug: AZAPRED |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Azathioprine and Prednisone in the Treatment of Idiopathic Pulmonary Fibrosis: a Randomized, Double-Blind, Controlled Study |
- Progression-free survival, defined as free of death or a decrease from baseline in the FVC of at least 10%. [ Time Frame: 2 years ]
- Number of Acute Exacerbations of IPF. [ Time Frame: 2 years ]
- Health Related Quality of life, measured with the Chronic Questionnaire (CRQ). [ Time Frame: 2 years ]
- PO2 at rest and at exercise from baseline. [ Time Frame: 2 years ]
- P(A-a)O2 at rest and at exercise from baseline. [ Time Frame: 2 years ]
- Predicted FEV1 from baseline. [ Time Frame: 2 years ]
- Forced expiratory volume in one second (FEV1) to FVC from baseline. [ Time Frame: 2 years ]
- Plethysmographic lung volumes from baseline. [ Time Frame: 2 years ]
- Diffusion capacity for carbon monoxide (DLco) from baseline. [ Time Frame: 2 years ]
- Six-Minute Walk test, from baseline: resting and 6 minute SpO2, presence or absence of desaturation to 88% or lower at the end of the six minute walk, walked distance d. Pre and post modified Borg dyspnea scores [ Time Frame: 2 years ]
- Scoring of extent of lung fibrosis on HRCT, according to two independent chest radiologists, form baseline. [ Time Frame: 2 years ]
- Number and severity of adverse effects. [ Time Frame: 2 years ]
- Number of protocol drop outs. [ Time Frame: 2 years ]
| Estimated Enrollment: | 100 |
| Study Start Date: | May 2005 |
| Estimated Study Completion Date: | December 2008 |
| Arms | Assigned Interventions |
|---|---|
|
Placebo Comparator: 0
Placebo
|
Drug: Placebo |
|
Active Comparator: 1
Azathiprine Prednisone
|
Drug: AZAPRED
The initial dose of prednisone will be 0.5 mg/kg/day for 4 weeks, then 0.25 mg/kg/day for 8 weeks. The dose will continue to decrease at a rate of 5 to 10 mg per week, to a dose of 0.25 or 0.125 mg/kg/day. Azathioprine will be given at a dose of 2-3 mg/kg/day (max 100 mg).
|
Show Detailed Description Eligibility| Ages Eligible for Study: | 45 Years to 79 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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.
Contacts and Locations| Contact: Matias Florenzano, MD | 056 9 8294435 | mflorenzano@terra.cl |
| Contact: Alvaro Undurraga, MD | aundurragap@yahoo.com |
| Chile | |
| Instituto Nacional del Tórax | Recruiting |
| Santiago, RM, Chile | |
| Contact: Jeannie Hinrichsen, RN jhinrichsen@torax.cl | |
| Contact: Carmen L Naranjo cnaranjo@torax.cl | |
| Principal Investigator: Florenzano Matias, MD | |
| Principal Investigator: Undurraga Alvaro, MD | |
| Sub-Investigator: Juan C Rodríguez, MD | |
| Sub-Investigator: Jorge Navarro, MD | |
| Sub-Investigator: Carlos Inzunza, MD | |
| Sub-Investigator: Mariam Torres, Ph | |
| Sub-Investigator: Eduardo Sabbagh, MD | |
| Sub-Investigator: Juan C Díaz, MD | |
| Sub-Investigator: Gabriel Cavada, Stat | |
| Principal Investigator: | Florenzano Matías, MD | Clínica Las Condes |
More Information
No publications provided
| ClinicalTrials.gov Identifier: | NCT00518310 History of Changes |
| Other Study ID Numbers: | 10351 |
| Study First Received: | August 16, 2007 |
| Last Updated: | August 16, 2007 |
| Health Authority: | Chile: Comité Ético-Científico Servicio de Salud Metropolitano Oriente |
Keywords provided by Thorax National Institute:
|
Interstitial lung disease Idiopathic pulmonary fibrosis Usual interstitial pneumonia Cryptogenic fibrosing alveolitis Therapy |
Azathioprine Steroids Glucocorticoids Corticosteroids Prednisone |
Additional relevant MeSH terms:
|
Fibrosis Pulmonary Fibrosis Idiopathic Pulmonary Fibrosis Pathologic Processes Lung Diseases Respiratory Tract Diseases Idiopathic Interstitial Pneumonias Lung Diseases, Interstitial Azathioprine Prednisone Antimetabolites Molecular Mechanisms of Pharmacological Action Pharmacologic Actions |
Antimetabolites, Antineoplastic Antineoplastic Agents Therapeutic Uses Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Antineoplastic Agents, Hormonal Anti-Inflammatory Agents |
ClinicalTrials.gov processed this record on May 23, 2013