The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, has stopped one arm of a clinical trial studying treatments for the lung-scarring disease, idiopathic pulmonary fibrosis (IPF). The trial, called PANTHER-IPF, found that a currently used triple-drug therapy consisting of prednisone, azathioprine, and N-acetylcysteine (NAC) is a potentially harmful combination to people with IPF.
- What is the purpose of the PANTHER-IPF study and what questions does it plan to answer?
PANTHER-IPF was designed to answer important questions about the safety and benefits of widely used treatments for idiopathic pulmonary fibrosis (IPF). The trial tests prednisone, azathioprine, and N-acetylcysteine (NAC) triple therapy vs. placebo, and NAC alone vs. placebo, on lung function and other health outcomes in patients with newly-diagnosed Idiopathic Pulmonary Fibrosis.
- Why did NHLBI feel it was important to conduct this study?
Despite being a widely used regimen for IPF, prednisone, azathioprine, and N-acetylcysteine (NAC) triple therapy has never been studied against placebo for all three drugs in a randomized controlled trial. Previously published official guidelines on management of IPF sponsored by the joint American Thoracic and European Respiratory Societies (AJRCCM 2000) had recommended treatment with prednisone plus azathioprine for patients with IPF. This was based on the consensus of an expert panel and not on information from a randomized clinical trial.
- Why did the study choose to include an NAC-only study arm but not other one- and two-drug combinations (like prednisone only, NAC + prednisone, etc.)?
A previously published IPF study called IFIGENIA showed that prednisone, azathioprine, and NAC in combination preserved lung function in IPF better than prednisone and azathioprine in combination. This raised the possibility that NAC was providing the benefit, which the investigators in PANTHER-IPF wanted to study in the absence of the other two drugs.
In addition, NAC is available over the counter as a standalone supplement or an ingredient in other supplements. With the increased awareness of the potential treatment benefits of NAC following the publication of the IFIGENIA study, and the liberal access to NAC over the counter, increasing numbers of patients with IPF are using the over the counter. Thus, it was prudent to determine the safety and efficacy of NAC alone for patients with IPF
- How many people participated in the study, and what were the criteria for participation?
As of October 2011, the PANTHER-IPF study has enrolled 238 of the 390 expected participants with newly-diagnosed mild-to-moderate IPF.
- Why was the triple therapy arm stopped early? Who made the decision to stop?
NHLBI stopped the study arm based upon the recommendation of the Data and Safety Monitoring Board (DSMB), an independent panel of experts chosen by the NHLBI to monitor the PANTHER-IPF study for safety and effectiveness. After a review and analysis of interim data, the DSMB recommended halting enrollment and study drug administration in the prednisone, azathioprine, and N-acetylcysteine (triple therapy) arm of the study because of safety concerns. Participants treated with triple therapy had more mortality, more serious adverse events, and more drug discontinuations, without evidence of benefit.
- How many people died, and what were the causes of death?
Eight (11%) died in the triple therapy arm and one (1%) in the placebo arm. The deaths have been due to a variety of causes with about half appearing to be due to respiratory disease.
- What is prednisone? What other conditions is this drug used for? What are its side effects?
Prednisone is a corticosteroid that has anti-inflammatory properties. Prednisone is also used to treat other chronic lung diseases, arthritis, lupus and other autoimmune diseases, severe allergic reactions, multiple sclerosis, certain types of cancer and to prevent rejection of transplanted organs.
Common side effects include rounding of the upper back, puffiness of the face, elevated cholesterol, fluid retention (swelling), growth of facial hair, headache, hyperglycemia, impaired wound healing, insomnia, muscle weakness, osteoporosis, weight gain, excessive thirst or hunger, mood changes and skin rash.
- What is azathioprine? What other conditions is this drug used for? What are its side effects?
Azathioprine is in a class of medications called immunosuppressants. It is used to treat a variety of inflammatory, connective tissue, and autoimmune diseases, and to prevent rejection of transplanted organs. It works by weakening the body's immune system so it will not attack a transplanted organ or the joints.
Common side effects of azathioprine include fever and chills, nausea, vomiting, liver function abnormalities, bone marrow toxicity (anemia, decreased white blood cell count and decreased platelets), skin rash or hives, and stomach discomfort.
- What is N-acetylcysteine (NAC)? What other conditions is this drug used for? What are its side effects?
N-acetyl cysteine comes from the amino acid L-cysteine. Amino acids are the building blocks of proteins. In laboratory experiments, it has been found to slow the growth of the type of fibrous tissue that causes disease in IPF. It is also an antioxidant. It is available over the counter and is used by people as a dietary supplement. N-acetyl cysteine has many uses as medicine. As a physician-prescribed inhaled medication, it is used to 'thin' thick mucus.
Common side effects include nausea, stomach pain, vomiting, diarrhea, rash, hives, itching, fever, drowsiness, headache, migraine, reduced blood pressure, rapid heart rate, and ringing in the ears.
- Were any of the known side effects of these drugs related to the adverse effects and mortality seen in the study participants?
Based on a preliminary review of study data, although some of the expected drug side effects were seen as adverse events in study participants, the most common causes of the adverse events and mortality seem more related to the worsening respiratory disease and the general health of the participants in the study. The investigators will continue to study the data for any links between the side effects and the drugs used in the study.
- Which drug of the three caused the harm?
The decision of the DSMB is based upon data seen when all three drugs are used together in mild to moderate IPF. The data do not give any information on whether the harm was caused by one of the medications or two of the three in combination. The DSMB has not indicated any safety concern regarding the NAC only arm and has recommended the continuation of enrollment of that arm as well as the placebo arm. These two continuing arms will provide information on the safety and benefits of NAC compared to placebo upon study completion.
- NAC is available over-the-counter as a nutritional supplement. Is it unsafe to take as a supplement?
The PANTHER-IPF study does not address the safety or efficacy of over-the-counter formulations of NAC. The NAC used in the study may not be equivalent to over-the-counter formulations of NAC.
- What drug doses were used in this study and how do they compare with recommended doses of these medications for other conditions?
The dosage of azathioprine was consistent with usual use for the drug and its use in treating rheumatologic diseases; this azathioprine dosing was also consistent with earlier studies in IPF patients. The dosage of prednisone was consistent with the recommendations of an expert panel and was lower than dosing used in earlier studies of IPF. The dosing of NAC was based on previous data, including an earlier IPF study (IFIGENIA).
- If I am currently taking one or more of these medications for IPF, should I stop because of the results for PANTHER-IPF?
Patients taking a combination of all three medications should see their doctor. Patients currently taking prednisone, azathioprine, or combinations of the two, with or without NAC for IPF should see their physician to discuss whether the results of this study apply to them and treatment options. Prednisone should not be stopped abruptly; consult your doctor to get instructions on management of prednisone therapy.
- If I am currently taking one or more of these medications (prednisone/azathioprine/NAC) for a condition other than IPF, should I stop because of the results of PANTHER-IPF?
The PANTHER-IPF study only looked at prednisone/azathioprine/NAC therapy in well defined IPF patients with mild to moderate disease. Patients with other conditions may want to discuss treatment options with their physician.
- What do these study results mean for people with IPF? What do they mean for people with related lung diseases like COPD or sarcoidosis?
Based on these data, prednisone/azathioprine/NAC triple therapy is not considered a safe and effective treatment option for patients with mild to moderate IPF.
Prednisone/azathioprine/NAC triple therapy is not a typically used treatment for COPD or sarcoidosis. Patients with related lung diseases on prednisone and azathioprine combination regimens may want to discuss treatment options with their physician.
- Has the NHLBI notified study participants and study sites of its decision to stop the three-drug study arm?
Yes, all study sites and participants on the three drug study arm have been notified of the study change. All participants in the three drug study arm are being given instructions on how to discontinue therapy safely. Since the study will continue the NAC-only and placebo arms, all participants in those treatment arms will be notified, and if they choose to continue study participation, they will be given new consent forms.
- Will study investigators be conducting any participant follow-up? If so, how long will participants be followed?
Participants in the NAC only and placebo arms will be followed for 60 weeks according to original study protocol. Participants in the three drug study arm will discontinue their azathioprine and NAC treatments immediately and taper prednisone over a few weeks (approximately 6-8 weeks); these patients will continue to be followed for safety monitoring and for an extended period to monitor health outcomes.
- Did any participants in the study arm benefit? Can participants choose to remain on the three-drug regimen if they want to?
As a group, the patients in the prednisone/azathioprine/NAC arm did not benefit from the therapy. Due to the safety concerns, participants in the study should not remain on the three drug regimen.
- When was the increase in deaths and adverse events discovered and when did NHLBI shut down one arm of the study?
The DSMB met the evening of October 12, 2011, to review the interim data and made a recommendation late that night to stop the triple therapy arm. NHLBI accepted the recommendation and most participants had been notified by the end of the day on October 14
- Did anyone else besides NHLBI support this study?
The study is primarily funded by the NHLBI, with additional financial support from the Cowlin Family Fund of the Chicago Community Trust. In addition, the NAC and its matching placebo were provided by Zambon Group. The prednisone and azathioprine and matching placebos were purchased.
- Are there other studies similar to PANTHER-IPF currently underway? Will they have to be shut down early as well?
There are no other studies in IPF patients testing prednisone/azathioprine/NAC combination therapy.
- When will the data from the PANTHER-IPF study be available?
The results of PANTHER-IPF prednisone/azathioprine/NAC combination therapy arm are expected to be available in spring 2012. The final PANTHER-IPF study results are expected to be published in 2013.
- Where can I get more information on the PANTHER-IPF study?
Information about the IPFnet clinical trials network and the PANTHER-IPF study is available at https://www.ipfnet.org/ and http://www.clinicaltrials.gov/ct2/show/NCT00650091?term=PANTHER-IPF&rank=1
- Where can I learn more about idiopathic pulmonary fibrosis?
More information about idiopathic pulmonary fibrosis is available at http://www.nhlbi.nih.gov/health/health-topics/topics/ipf/ and http://www.pulmonaryfibrosis.org/ipf