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Azathioprine and Prednisone in the Treatment of Idiopathic Pulmonary Fibrosis

Primary Purpose

Idiopathic Pulmonary Fibrosis

Status
Unknown status
Phase
Not Applicable
Locations
Chile
Study Type
Interventional
Intervention
Placebo
AZAPRED
Sponsored by
Thorax National Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Idiopathic Pulmonary Fibrosis focused on measuring Interstitial lung disease, Idiopathic pulmonary fibrosis, Usual interstitial pneumonia, Cryptogenic fibrosing alveolitis, Therapy, Azathioprine, Steroids, Glucocorticoids, Corticosteroids, Prednisone

Eligibility Criteria

45 Years - 79 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Instituto Nacional del TóraxRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

0

1

Arm Description

Placebo

Azathiprine Prednisone

Outcomes

Primary Outcome Measures

Progression-free survival, defined as free of death or a decrease from baseline in the FVC of at least 10%.

Secondary Outcome Measures

Number of Acute Exacerbations of IPF.
Health Related Quality of life, measured with the Chronic Questionnaire (CRQ).
PO2 at rest and at exercise from baseline.
P(A-a)O2 at rest and at exercise from baseline.
Predicted FEV1 from baseline.
Forced expiratory volume in one second (FEV1) to FVC from baseline.
Plethysmographic lung volumes from baseline.
Diffusion capacity for carbon monoxide (DLco) from baseline.
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
Scoring of extent of lung fibrosis on HRCT, according to two independent chest radiologists, form baseline.
Number and severity of adverse effects.
Number of protocol drop outs.

Full Information

First Posted
August 16, 2007
Last Updated
August 16, 2007
Sponsor
Thorax National Institute
Collaborators
Sociedad Chilena de Enfermedades Respiratorias, Servicio de Salud Metropolitano Oriente, Ministerio de Salud de Chile
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1. Study Identification

Unique Protocol Identification Number
NCT00518310
Brief Title
Azathioprine and Prednisone in the Treatment of Idiopathic Pulmonary Fibrosis
Official Title
Azathioprine and Prednisone in the Treatment of Idiopathic Pulmonary Fibrosis: a Randomized, Double-Blind, Controlled Study
Study Type
Interventional

2. Study Status

Record Verification Date
August 2007
Overall Recruitment Status
Unknown status
Study Start Date
May 2005 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
December 2008 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
Thorax National Institute
Collaborators
Sociedad Chilena de Enfermedades Respiratorias, Servicio de Salud Metropolitano Oriente, Ministerio de Salud de Chile

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed Description
We will evaluate all adult patients consecutively referred from March 2005 to the Instituto Nacional del Tórax (Thorax National Institute), Santiago, Chile for diagnostic evaluation of Pulmonary Fibrosis. The routine evaluation will include, when indicated, the following steps: History: Age Genre Duration of symptoms before first consultation Smoking status Search for collagen vascular disease Family history of pulmonary fibrosis Occupational exposures Drug ot toxic exposures Physical examination: search of crackles and finger clubbing. Laboratory data: Complete blood bell count BUN Creatinine Liver enzymes Antinuclear antigens Erythrocyte sedimentation rate Rheumatoid factor HIV Antineutrophil cytoplasmic antibody (in appropiate clinical setting) Antiglomerular basement antibody (in appropiate clinical setting) Modified Medical Research Council Dyspnea Scale (MMRC) (10) Chronic Respiratory Questionnaire (CRQ) (11) Pulmonary function tests: Spirometry Plethismographic lung volumes DLco Composite physiologic index (12) Exercise testing: Six-Minute Walk Test (6MWT) Resting and 6 minute SpO2 Presence or absence of desaturation to 88% or lower at the end of the six minute walk (13) Walked distance Pre and post modified Borg dyspnea scores Timed walk test (14) Arterial blood gas analysis in rest and exercise, calculating the difference between alveolar and arterial oxygen tension (P(A-a)O2) at rest and after exercise. Radiologic studies: Chest radiography HRCT: Definite or probable idiopathic pulmonary fibrosis (15): Definitive criteria: presence of lung volume reduction, reticular abnormalities, traction bronchiectasis, or both, with a basal and peripheral predominance; the presence of honeycombing with a basal and peripheral predominance; and the absence of atypical features of usual interstitial pneumonia - micronodules, peribronchovascular nodules, consolidation, isolated (nonhoneycombing) cysts, ground-glass attenuation (or if present, less extensive than the reticular opacity), and mediastinal adenopathies (or if present, too limited to be visible on a chest radiography). Probable criteria: presence of a bilateral, predominantly basal and subpleural reticular pattern with subpleural cysts (honeycombing), traction bronchiectasis, or both in the absence of atypical features of UIP. Scoring of the extent of lung fibrosis (16). Bronchoscopy: Bronchoalveolar lavage: cellular analysis and CD4/CD8 ratio. Transbronchial biopsy. Surgical lung biopsy: Number Site/Side Type of surgery: open vs thoracoscopic Histologic features (3) Those patients with IPF diagnosed on the basis of clinical and radiographic criteria alone according to the ATS/ERS consensus committee (3), and/or with a biopsy proven histological pattern of UIP, will be selected to the randomization process, after they have signed the written informed consent.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Idiopathic Pulmonary Fibrosis
Keywords
Interstitial lung disease, Idiopathic pulmonary fibrosis, Usual interstitial pneumonia, Cryptogenic fibrosing alveolitis, Therapy, Azathioprine, Steroids, Glucocorticoids, Corticosteroids, Prednisone

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
0
Arm Type
Placebo Comparator
Arm Description
Placebo
Arm Title
1
Arm Type
Active Comparator
Arm Description
Azathiprine Prednisone
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Type
Drug
Intervention Name(s)
AZAPRED
Intervention Description
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).
Primary Outcome Measure Information:
Title
Progression-free survival, defined as free of death or a decrease from baseline in the FVC of at least 10%.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Number of Acute Exacerbations of IPF.
Time Frame
2 years
Title
Health Related Quality of life, measured with the Chronic Questionnaire (CRQ).
Time Frame
2 years
Title
PO2 at rest and at exercise from baseline.
Time Frame
2 years
Title
P(A-a)O2 at rest and at exercise from baseline.
Time Frame
2 years
Title
Predicted FEV1 from baseline.
Time Frame
2 years
Title
Forced expiratory volume in one second (FEV1) to FVC from baseline.
Time Frame
2 years
Title
Plethysmographic lung volumes from baseline.
Time Frame
2 years
Title
Diffusion capacity for carbon monoxide (DLco) from baseline.
Time Frame
2 years
Title
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
Title
Scoring of extent of lung fibrosis on HRCT, according to two independent chest radiologists, form baseline.
Time Frame
2 years
Title
Number and severity of adverse effects.
Time Frame
2 years
Title
Number of protocol drop outs.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
79 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Matias Florenzano, MD
Phone
056 9 8294435
Email
mflorenzano@terra.cl
First Name & Middle Initial & Last Name or Official Title & Degree
Alvaro Undurraga, MD
Email
aundurragap@yahoo.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Florenzano Matías, MD
Organizational Affiliation
Clínica Las Condes
Official's Role
Principal Investigator
Facility Information:
Facility Name
Instituto Nacional del Tórax
City
Santiago
State/Province
RM
Country
Chile
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeannie Hinrichsen, RN
Email
jhinrichsen@torax.cl
First Name & Middle Initial & Last Name & Degree
Carmen L Naranjo
Email
cnaranjo@torax.cl
First Name & Middle Initial & Last Name & Degree
Florenzano Matias, MD
First Name & Middle Initial & Last Name & Degree
Undurraga Alvaro, MD
First Name & Middle Initial & Last Name & Degree
Juan C Rodríguez, MD
First Name & Middle Initial & Last Name & Degree
Jorge Navarro, MD
First Name & Middle Initial & Last Name & Degree
Carlos Inzunza, MD
First Name & Middle Initial & Last Name & Degree
Mariam Torres, Ph
First Name & Middle Initial & Last Name & Degree
Eduardo Sabbagh, MD
First Name & Middle Initial & Last Name & Degree
Juan C Díaz, MD
First Name & Middle Initial & Last Name & Degree
Gabriel Cavada, Stat

12. IPD Sharing Statement

Learn more about this trial

Azathioprine and Prednisone in the Treatment of Idiopathic Pulmonary Fibrosis

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