Well, the press-release was today so it is public info: the phase 3 trial testing IFN-gamma vs. placebo in patients with IPF has been discontinued. The independent data monitoring committee did an interim analysis and found no difference between IFN-gamma and placebo for mortality (14.5% in the Actimmune group as compared to 12.7% in the placebo). The adverse reactions were consistent with prior clinical experience(constitutional symptoms, neutropenia and possibly pneumonia).
“The interim results of the INSPIRE trial and our decision to discontinue the trial are disappointing,” said Steve Porter, M.D., Ph.D., Chief Medical Officer at InterMune.
I'm not sure what this means for the company, but they are also running the perfenidone trial, but not so sure this will fare any better...
To me, this is not so surprising, but it really does illustrate the importance of being careful not to read too much into sub group analysis before the next study is done- the original study found that patients with more "mild" IPF (FVC 55-90% predicted) might have a survival advantage and the current study was powered to test that hypothesis. Ultimately it was found not to be the case after all.
People currently taking the IFN-g as part of the study will be instructed to stop it, and everyone will then pack up their bags and move on to the next latest and greatest...
Does anyone have any patients enrolled int his trial?
Showing posts with label pulmonary fibrosis. Show all posts
Showing posts with label pulmonary fibrosis. Show all posts
Monday, March 05, 2007
Monday, February 27, 2006
IPF recap
I thought it would be fun to highlight some of the previous cases. This is also useful because occasionally we'll get a comment long after the case was posted so it may get lost as new cases bump the old ones back.
Recently there was some interesting discussion about the treatment for IPF. There was the article on Acetylcysteine and pulmonary fibrosis (IPF). More often than not, we read a high impact journal and take what it finds at face value. As busy physicians we might not have the time or patience to read an article critically, and we sometimes "trust" that the peer reviewers read it critically for us. This may be especially true in a high impact journal like the New England Journal of Medicine. It seemed like a straight forward question: "where do I get acetylcysteine to prescribe for my patents?" But the comments highlight the fallacy of believing everything we read. As Jeff H pointed out, I think it's critical to point out that NAC was used IN ADDITION to Azathioprine and Prednisone. There are no trials that have evaluated NAC as monotherapy. Moreover, there was no "placebo" group included in the NEJM paper. So, there are NO DATA that oral NAC, as monotherapy, is any better (or worse) than nothing. Doug (and others) highlighted this, pointing out that NAC may have merely had a protective effect on the harmful effects of prednisone. And jgiustino's comments are interesting: All I can say is that this was a bad study! The data from patients that actually completed the study did not show ANY significant change in lung function between the two groups. The authors then needed to resort to "last observation carry forward" to show significance ....this is a highly controversial statistical method. I am very surprised that this has not been questioned by more people. I think that this study proved that NAC prevent bone marrow toxicity from imuran (they did not need "last observation carry forward" to prove this. All else is very suspect as far as I'm concerned and I wish they had the foresight to get a larger patient population into the study so they would not have to resort to such statistical games.
The diagnosis of UIP can also be challenging. What's more important, a biopsy showing UIP or typical CT findings of honeycombing at the bases with minimal ground glass? What about a biopsy with UIP and previous CTs showing LOTS of ground glass? I posted a case where a patient had an open lung biopsy that was consistent with UIP but with chest CT's back 6 years showed that there has been lots of ground glass (and upper lobe to boot). My question was, does the biopsy trump the atypical CT findings, OR do the previous CT findings make us question the assumption that UIP makes the diagnosis of IPF? I'm not sure the question has been adequately answered but the comments shed some light on the controversy. More than one pointed out that the diagnosis of UIP is also dependent of the pathologist.
And if we have a diagnosis of UIP by biopsy, would we withhold treatment with immunosuppressives? What if the pathologist read it wrong and it is truly a steroid-responsive disease? One commented that this is also the best argument on why we should "treat" our UIP patients with a 3 to 6 month course of prednisone and imuran..not to treat UIP but to definatively rule out other treatable diagnosis."
So the same research group showing that UIP trumps all other biopsy specimens (in terms of prognosis) also found that the dignosis of UIP is pathologist-dependent. In other words, if you are not at a major university specializing in IPF, ignore the biopsy report and treat everyone with prednisone for 6 months to see if they get better!
But seriously, it sure is strange that a pathologist would have difficulty with the diagnosis. After all, all you need is a biopsy showing fibroblastic foci, areas of normal parenchyma, areas of fibrosis and honeycombing in the periphery, and a paucity of inflammatory cells. What's the problem?
Recently there was some interesting discussion about the treatment for IPF. There was the article on Acetylcysteine and pulmonary fibrosis (IPF). More often than not, we read a high impact journal and take what it finds at face value. As busy physicians we might not have the time or patience to read an article critically, and we sometimes "trust" that the peer reviewers read it critically for us. This may be especially true in a high impact journal like the New England Journal of Medicine. It seemed like a straight forward question: "where do I get acetylcysteine to prescribe for my patents?" But the comments highlight the fallacy of believing everything we read. As Jeff H pointed out, I think it's critical to point out that NAC was used IN ADDITION to Azathioprine and Prednisone. There are no trials that have evaluated NAC as monotherapy. Moreover, there was no "placebo" group included in the NEJM paper. So, there are NO DATA that oral NAC, as monotherapy, is any better (or worse) than nothing. Doug (and others) highlighted this, pointing out that NAC may have merely had a protective effect on the harmful effects of prednisone. And jgiustino's comments are interesting: All I can say is that this was a bad study! The data from patients that actually completed the study did not show ANY significant change in lung function between the two groups. The authors then needed to resort to "last observation carry forward" to show significance ....this is a highly controversial statistical method. I am very surprised that this has not been questioned by more people. I think that this study proved that NAC prevent bone marrow toxicity from imuran (they did not need "last observation carry forward" to prove this. All else is very suspect as far as I'm concerned and I wish they had the foresight to get a larger patient population into the study so they would not have to resort to such statistical games.
The diagnosis of UIP can also be challenging. What's more important, a biopsy showing UIP or typical CT findings of honeycombing at the bases with minimal ground glass? What about a biopsy with UIP and previous CTs showing LOTS of ground glass? I posted a case where a patient had an open lung biopsy that was consistent with UIP but with chest CT's back 6 years showed that there has been lots of ground glass (and upper lobe to boot). My question was, does the biopsy trump the atypical CT findings, OR do the previous CT findings make us question the assumption that UIP makes the diagnosis of IPF? I'm not sure the question has been adequately answered but the comments shed some light on the controversy. More than one pointed out that the diagnosis of UIP is also dependent of the pathologist.
And if we have a diagnosis of UIP by biopsy, would we withhold treatment with immunosuppressives? What if the pathologist read it wrong and it is truly a steroid-responsive disease? One commented that this is also the best argument on why we should "treat" our UIP patients with a 3 to 6 month course of prednisone and imuran..not to treat UIP but to definatively rule out other treatable diagnosis."
So the same research group showing that UIP trumps all other biopsy specimens (in terms of prognosis) also found that the dignosis of UIP is pathologist-dependent. In other words, if you are not at a major university specializing in IPF, ignore the biopsy report and treat everyone with prednisone for 6 months to see if they get better!
But seriously, it sure is strange that a pathologist would have difficulty with the diagnosis. After all, all you need is a biopsy showing fibroblastic foci, areas of normal parenchyma, areas of fibrosis and honeycombing in the periphery, and a paucity of inflammatory cells. What's the problem?
Thursday, February 09, 2006
Acetylcysteine for IPF
S.F. poses the following:
I tried to prescribe acetylcysteine for pulmonary fibrosis, based on the recent article suggesting some benefit. I was called by the pharmacist who had never heard of it in PO form. The article by Demedts in NEJM 11/2005 used 600 mg PO tid. If the average pharmacist is unable to find any info about the drug, it makes me wonder what to do next. Has anyone been able to find a pharmacist who is familiar with this rare and magical medicine? I didn't know PO was such a strange route. Isn't that what we give for acetaminophen overdose?
I tried to prescribe acetylcysteine for pulmonary fibrosis, based on the recent article suggesting some benefit. I was called by the pharmacist who had never heard of it in PO form. The article by Demedts in NEJM 11/2005 used 600 mg PO tid. If the average pharmacist is unable to find any info about the drug, it makes me wonder what to do next. Has anyone been able to find a pharmacist who is familiar with this rare and magical medicine? I didn't know PO was such a strange route. Isn't that what we give for acetaminophen overdose?
Thursday, January 12, 2006
Therapy for IPF
I had seen this 76 y/o man about 18 months ago for "abnormal CxR". He had "dry" crackles, a mild restrictive defect (FVC, FEV1 and TLC all around 70%) and a HRCT very typical for IPF. I had discussed prognosis and treatment options and suggested a referral to the nearby University center for possible enrollment in a trial. He felt fine and declined the referral. He continued to see his PCP but had cancelled his follow-up with me. He then came back because of worsening dyspnea and hypoxemia (he is now on 3L/min O2) and his FVC is down to 45%.
I have attached a recent CT image below. He is obviously not a transplant candidate and he does not want to enroll in clinical trials. What medical therapy (if any) would you offer him?
I have attached a recent CT image below. He is obviously not a transplant candidate and he does not want to enroll in clinical trials. What medical therapy (if any) would you offer him?
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