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Evaluating the Effectiveness of Prednisone, Azathioprine, and N-acetylcysteine in Patients With IPF (PANTHER-IPF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00650091
Recruitment Status : Completed
First Posted : April 1, 2008
Results First Posted : June 2, 2015
Last Update Posted : June 2, 2015
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Duke University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Pulmonary Fibrosis
Interventions Drug: N-acetylcysteine (NAC)
Drug: Placebo
Enrollment 264
Recruitment Details

Initial Study Design: Subjects are randomly assigned to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo.

Amended Study Design: The three-drug regimen was removed from the protocol due to safety concerns on 10/14/2011. Subjects are randomly assigned to acetylcysteine or placebo.
Pre-assignment Details Participants in the Pred/AZA/NAC group were discontinued and not re-randomized in the amended study.
Arm/Group Title N-Acetylcysteine Placebo Pred/AZA/NAC
Hide Arm/Group Description

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

N-acetylcysteine (NAC): Participants will receive 600 mg of NAC three times a day.

Participants will receive placebo for 60 weeks.

Placebo: Participants will receive placebo each day.

The prednisone dose was started at 0.5 mg per kilo- gram of ideal body weight and was tapered to 0.15 mg per kilogram during a period of 25 weeks.

The azathioprine dose (maximum, 150 mg per day) was based on the patient's ideal weight, concurrent use of allopurinol, and thiopurine methyl-transferase (TPMT) activity. NAC was prescribed at 600 mg orally three times a day.
Period Title: Initial Study Design - Interim Analysis
Started 81 78 77
Completed 81 78 77
Not Completed 0 0 0
Period Title: Amended Study Design
Started 133 131 0 [1]
Completed 110 111 0
Not Completed 23 20 0
Reason Not Completed
Withdrawal by Subject             12             11             0
Physician Decision             5             0             0
Adverse Event             1             4             0
Lung transplantation             4             2             0
Other             1             3             0
[1]
Study Drug was discontinued for all subjects due to safety concerns.
Arm/Group Title N-Acetylcysteine Placebo Total
Hide Arm/Group Description

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

N-acetylcysteine (NAC): Participants will receive 600 mg of NAC three times a day.

Participants will receive placebo for 60 weeks.

Placebo: Participants will receive placebo each day.

 Total of all reporting groups
Overall Number of Baseline Participants 133 131 264
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 133 participants 131 participants 264 participants
68.3  (6.4) 67.2  (8.2) 67.8  (8.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 133 participants 131 participants 264 participants
Female
26
  19.5%
33
  25.2%
59
  22.3%
Male
107
  80.5%
98
  74.8%
205
  77.7%
1.Primary Outcome
Title Overall Change in Forced Vital Capacity
Hide Description Change from Baseline in Forced Vital Capacity at 60 weeks (units in liters)
Time Frame Measured as the estimated change from baseline to Week 60
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population includes participants from the amended study design only.
Arm/Group Title N-Acetylcysteine Placebo
Hide Arm/Group Description:

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

N-acetylcysteine (NAC): Participants will receive 600 mg of NAC three times a day.

Participants will receive placebo for 60 weeks.

Placebo: Participants will receive placebo each day.
Overall Number of Participants Analyzed 133 131
Mean (95% Confidence Interval)
Unit of Measure: liters
-0.18
(-0.23 to -0.12)
-0.19
(-0.24 to -0.14)
2.Secondary Outcome
Title Disease Progression
Hide Description

The time-to-death or a 10% decline in FVC will be defined as the time-to-disease progression.

The 10% decline in FVC from enrollment must be confirmed on 2 consecutive visits no less than 6 weeks apart. For subjects with 2 consecutive visits with a 10% decline in FVC, the time-to-disease progression will be defined as the time interval between enrollment and the initial visit with a 10% FVC decline.
Time Frame Measured at Week 60
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population includes participants from the amended study design only.
Arm/Group Title N-Acetylcysteine Placebo
Hide Arm/Group Description:

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

N-acetylcysteine (NAC): Participants will receive 600 mg of NAC three times a day.

Participants will receive placebo for 60 weeks.

Placebo: Participants will receive placebo each day.
Overall Number of Participants Analyzed 133 131
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
27.1
(20.1 to 36.0)
26.5
(19.5 to 35.4)
3.Secondary Outcome
Title Acute Exacerbations
Hide Description

The following 3 criteria will define acute exacerbations in subjects with acute worsening of their respiratory conditions:

1. Clinical (all of the following required): A) Unexplained worsening of dyspnea or cough within 30 days, triggering unscheduled medical care (e.g., emergency room, clinic, study visit, hospitalization). B) No clinical suspicion or overt evidence of cardiac event, pulmonary embolism, or deep venous thrombosis to explain acute worsening of dyspnea. C) No pneumothorax.
Time Frame Measured at Week 60
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population includes participants from the amended study design only.
Arm/Group Title N-Acetylcysteine Placebo
Hide Arm/Group Description:

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

N-acetylcysteine (NAC): Participants will receive 600 mg of NAC three times a day.

Participants will receive placebo for 60 weeks.

Placebo: Participants will receive placebo each day.
Overall Number of Participants Analyzed 133 131
Measure Type: Number
Unit of Measure: events
3 3
4.Secondary Outcome
Title Respiratory Infections
Hide Description [Not Specified]
Time Frame Measured at Week 60
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population includes participants from the amended study design only.
Arm/Group Title N-Acetylcysteine Placebo
Hide Arm/Group Description:

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

N-acetylcysteine (NAC): Participants will receive 600 mg of NAC three times a day.

Participants will receive placebo for 60 weeks.

Placebo: Participants will receive placebo each day.
Overall Number of Participants Analyzed 133 131
Measure Type: Number
Unit of Measure: events
6 6
5.Secondary Outcome
Title Number of Participants With Maintained Forced Vital Capacity Response
Hide Description Maintained forced vital capacity response was a binary variable taking on a value of 1 for participants with higher FVC % predicted at week 60 compared to baseline.
Time Frame Measured at Week 60
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population includes participants from the amended study design only.
Arm/Group Title N-Acetylcysteine Placebo
Hide Arm/Group Description:

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

N-acetylcysteine (NAC): Participants will receive 600 mg of NAC three times a day.

Participants will receive placebo for 60 weeks.

Placebo: Participants will receive placebo each day.
Overall Number of Participants Analyzed 133 131
Measure Type: Number
Unit of Measure: participants
29 35
6.Post-Hoc Outcome
Title Change in Forced Vital Capacity
Hide Description Change from Baseline in Forced Vital Capacity at 15, 30, 45, and 60 weeks (units in liters)
Time Frame Baseline, 15, 30, 45, 60 week
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis population includes participants from the amended study design only.
Arm/Group Title N-Acetylcysteine Placebo
Hide Arm/Group Description:

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

N-acetylcysteine (NAC): Participants will receive 600 mg of NAC three times a day.

Participants will receive placebo for 60 weeks.

Placebo: Participants will receive placebo each day.
Overall Number of Participants Analyzed 133 131
Mean (Standard Deviation)
Unit of Measure: liters
15 week -0.07  (0.19) -0.04  (0.19)
30 week -0.07  (0.20) -0.08  (0.25)
45 week -0.15  (0.25) -0.15  (0.30)
60 week -0.16  (0.26) -0.15  (0.30)
Time Frame Adverse events are reported for amended study only.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title N-Acetylcysteine Placebo Initial Study: Pred/AZA/NAC Initial Study: Placebo
Hide Arm/Group Description

Participants will receive N-acetylcysteine (NAC) for 60 weeks.

N-acetylcysteine (NAC): Participants will receive 600 mg of NAC three times a day.

Participants will receive placebo for 60 weeks.

Placebo: Participants will receive placebo each day.

 Participants will receive prednisone, azathioprine, and N-acetylcysteine (NAC) for 60 weeks. Placebo: Participants will receive placebo each day.
All-Cause Mortality
N-Acetylcysteine Placebo Initial Study: Pred/AZA/NAC Initial Study: Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Hide Serious Adverse Events
N-Acetylcysteine Placebo Initial Study: Pred/AZA/NAC Initial Study: Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   25/133 (18.80%)      20/131 (15.27%)      24/77 (31.17%)      8/78 (10.26%)    
Cardiac disorders         
Coronary artery disease *  2/133 (1.50%)  2 2/131 (1.53%)  2 0/77 (0.00%)  0 0/78 (0.00%)  0
Angina pectoris *  2/133 (1.50%)  2 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Myocardial infarction *  2/133 (1.50%)  2 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Arteriosclerosis coronary artery *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Cardiac arrest *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Coronary artery stenosis *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Right ventricular failure *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Non-cardiac chest pain *  2/133 (1.50%)  2 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Chest pain *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Atrial Fibrillation *  0/133 (0.00%)  0 0/131 (0.00%)  0 2/77 (2.60%)  2 0/78 (0.00%)  0
Acute Myocardial infarction *  0/133 (0.00%)  0 0/131 (0.00%)  0 2/77 (2.60%)  2 0/78 (0.00%)  0
Gastrointestinal disorders         
Diarrhoea *  0/133 (0.00%)  0 3/131 (2.29%)  3 0/77 (0.00%)  0 0/78 (0.00%)  0
Abdominal pain *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Intestinal obstruction *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 1/78 (1.28%)  1
Rectal haemorrhage *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 1/78 (1.28%)  1
Upper gastrointestinal haemorrhage *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 1/78 (1.28%)  1
Vomiting *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
General disorders         
Adverse Drug Reaction *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Death *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Hepatobiliary disorders         
Cholecystitis *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Infections and infestations         
Pneumonia *  4/133 (3.01%)  4 5/131 (3.82%)  5 4/77 (5.19%)  4 1/78 (1.28%)  1
Bacteraemia *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Bronchitis *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Diverticulitis *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Fungal skin infection *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Gastroenteritis viral *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Oral candidiasis *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Pneumonia streptococcal *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Respiratory Tract Infection *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Injury, poisoning and procedural complications         
Femur fracture *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Investigations         
Drug Fever *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Metabolism and nutrition disorders         
Diabetes mellitus *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Dehydration *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Musculoskeletal and connective tissue disorders         
Intervertebral disc protrusion *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 1/78 (1.28%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Breast cancer *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Colon cancer *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Lung Squamous Cell Carcinoma *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Prostate Cancer *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Nervous system disorders         
Presyncope *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
Transient ischaemic attack *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
syncope *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Reproductive system and breast disorders         
prostatitis *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Idiopathic pulmonary fibrosis *  8/133 (6.02%)  10 4/131 (3.05%)  6 8/77 (10.39%)  9 2/78 (2.56%)  3
pulmonary oedema *  0/133 (0.00%)  0 2/131 (1.53%)  2 0/77 (0.00%)  0 0/78 (0.00%)  0
Dyspnoea *  1/133 (0.75%)  1 0/131 (0.00%)  0 1/77 (1.30%)  1 1/78 (1.28%)  1
Pleural effusion *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Pulmonary embolism *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 1/78 (1.28%)  1
Respiratory failure *  0/133 (0.00%)  0 1/131 (0.76%)  1 0/77 (0.00%)  0 0/78 (0.00%)  0
Atelectasis *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Intersticial Lung Disease *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
pneumothorax *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Exacerbation of Idiopathic Pulmonary Fibrosis *  0/133 (0.00%)  0 0/131 (0.00%)  0 1/77 (1.30%)  1 0/78 (0.00%)  0
Vascular disorders         
Hypertension *  1/133 (0.75%)  1 0/131 (0.00%)  0 0/77 (0.00%)  0 0/78 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
N-Acetylcysteine Placebo Initial Study: Pred/AZA/NAC Initial Study: Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   123/133 (92.48%)      117/131 (89.31%)      68/77 (88.31%)      61/78 (78.21%)    
Gastrointestinal disorders         
Diarrhoea †  18/133 (13.53%)  19 15/131 (11.45%)  18 6/77 (7.79%)  7 7/78 (8.97%)  8
Nausea †  14/133 (10.53%)  14 7/131 (5.34%)  9 10/77 (12.99%)  14 4/78 (5.13%)  4
Constipation †  12/133 (9.02%)  13 4/131 (3.05%)  4 2/77 (2.60%)  2 4/78 (5.13%)  4
General disorders         
Fatigue †  9/133 (6.77%)  9 9/131 (6.87%)  9 8/77 (10.39%)  9 6/78 (7.69%)  6
Oedema peripheral †  9/133 (6.77%)  11 6/131 (4.58%)  6 2/77 (2.60%)  3 3/78 (3.85%)  3
Infections and infestations         
Upper respiratory tract infection †  27/133 (20.30%)  31 26/131 (19.85%)  31 10/77 (12.99%)  11 10/78 (12.82%)  11
Bronchitis †  15/133 (11.28%)  26 13/131 (9.92%)  15 6/77 (7.79%)  6 6/78 (7.69%)  8
Sinusitis †  17/133 (12.78%)  22 10/131 (7.63%)  12 4/77 (5.19%)  6 5/78 (6.41%)  5
Nasopharyngitis †  10/133 (7.52%)  13 11/131 (8.40%)  15 4/77 (5.19%)  6 7/78 (8.97%)  10
Musculoskeletal and connective tissue disorders         
Arthralgia †  10/133 (7.52%)  10 10/131 (7.63%)  13 2/77 (2.60%)  2 5/78 (6.41%)  8
Nervous system disorders         
Headache †  12/133 (9.02%)  14 12/131 (9.16%)  12 3/77 (3.90%)  3 3/78 (3.85%)  3
Dizziness †  8/133 (6.02%)  9 8/131 (6.11%)  10 5/77 (6.49%)  7 6/78 (7.69%)  8
Respiratory, thoracic and mediastinal disorders         
Cough †  37/133 (27.82%)  44 32/131 (24.43%)  39 13/77 (16.88%)  15 18/78 (23.08%)  20
Dyspnea †  22/133 (16.54%)  25 26/131 (19.85%)  29 11/77 (14.29%)  12 10/78 (12.82%)  11
Idiopathic Pulmonary Fibrosis †  12/133 (9.02%)  14 8/131 (6.11%)  10 9/77 (11.69%)  12 4/78 (5.13%)  5
Epistaxis †  6/133 (4.51%)  6 11/131 (8.40%)  12 1/77 (1.30%)  1 5/78 (6.41%)  5
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Kevin J Anstrom
Organization: Duke Clinical Research Institute
Phone: 919-668-8902
EMail: kevin.anstrom@duke.edu
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT00650091    
Other Study ID Numbers: Pro00020066
U10HL080413-03 ( U.S. NIH Grant/Contract )
First Submitted: March 28, 2008
First Posted: April 1, 2008
Results First Submitted: July 31, 2014
Results First Posted: June 2, 2015
Last Update Posted: June 2, 2015