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Original Research |

Thalidomide for the Treatment of Cough in Idiopathic Pulmonary Fibrosis: A Randomized Trial

Maureen R. Horton, MD; Victoria Santopietro; Leena Mathew, BS; Karen M. Horton, MD; Albert J. Polito, MD; Mark C. Liu, MD; Sonye K. Danoff, MD; and Noah Lechtzin, MD
[+] Article, Author, and Disclosure Information

From Johns Hopkins University School of Medicine and Mercy Medical Center, Baltimore, Maryland.

Financial Support: Celgene Corporation.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0255.

Reproducible Research Statement:Study protocol: Available from Dr. M.R. Horton (e-mail, mhorton2@jhmi.edu). Statistical code and data set: Available from Dr. Lechtzin (e-mail, nlechtz1@jhmi.edu).

Requests for Single Reprints: Maureen R. Horton, MD, 1830 East Monument Street, 5th Floor, Baltimore, MD 21205; e-mail, mhorton2@jhmi.edu.

Current Author Addresses: Drs. M.R. Horton, Danoff, and Lechtzin: 1830 East Monument Street, 5th Floor, Baltimore, MD 21205.

Ms. Santopietro, Ms. Mathew, and Dr. Liu: 5501 Hopkins Bayview Circle, Asthma and Allergy Center, Baltimore, MD 21224.

Dr. K.M. Horton: JHOC 3253, 601 North Caroline Street, Baltimore, MD 21287.

Dr. Polito: 301 St. Paul Place, McAuley Tower Building, 4th Floor, Baltimore, MD 21202.

Author Contributions: Conception and design: M.R. Horton, A.J. Polito, N. Lechtzin.

Analysis and interpretation of the data: M.R. Horton, K.M. Horton, M.C. Liu, S.K. Danoff, N. Lechtzin.

Drafting of the article: M.R. Horton, S.K. Danoff, N. Lechtzin.

Critical revision of the article for important intellectual content: M.R. Horton, K.M. Horton, M.C. Liu, N. Lechtzin.

Final approval of the article: M.R. Horton, V. Santopietro, K.M. Horton, M.C. Liu, S.K. Danoff, N. Lechtzin.

Provision of study materials or patients: L. Mathew, A.J. Polito, M.C. Liu, S.K. Danoff, N. Lechtzin.

Statistical expertise: N. Lechtzin.

Obtaining of funding: M.R. Horton, L. Mathew.

Administrative, technical, or logistic support: L. Mathew, A.J. Polito, M.C. Liu, N. Lechtzin.

Collection and assembly of data: M.R. Horton, V. Santopietro, K.M. Horton.

Ann Intern Med. 2012;157(6):398-406. doi:10.7326/0003-4819-157-6-201209180-00003
Text Size: A A A

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder of unknown cause with no effective treatment. Cough affects up to 80% of patients with IPF, is frequently disabling, and lacks effective therapy.

Objective: To determine the efficacy of thalidomide in suppressing cough in patients with IPF.

Design: 24-week, double-blind, 2-treatment, 2-period crossover trial. (ClinicalTrials.gov registration number: NCT00600028)

Setting: 1 university center.

Participants: 98 participants were screened, 24 were randomly assigned, 23 received treatment (78.3% men; mean age, 67.6 years; mean FVC, 70.4% predicted), and 20 completed both treatment periods.

Measurements: The primary end point was cough-specific quality of life measured by the Cough Quality of Life Questionnaire (CQLQ). Secondary end points were visual analogue scale of cough and the St. George's Respiratory Questionnaire (SGRQ). For all measures, lower scores equaled improved cough or respiratory quality of life.

Results: CQLQ scores significantly improved with thalidomide (mean difference vs. placebo, −11.4 [95% CI, −15.7 to −7.0]; P < 0.001). Thalidomide also significantly improved scores on the visual analogue scale of cough (mean difference vs. placebo, −31.2 [CI, −45.2 to −17.2]; P < 0.001). In participants receiving thalidomide, scores from the total SGRQ, SGRQ symptom domain, and SGRQ impact domain improved compared with those of participants receiving placebo. Adverse events were reported in 74% of patients receiving thalidomide and 22% receiving placebo; constipation, dizziness, and malaise were more frequent with thalidomide.

Limitation: This was a single-center study of short duration and small sample size focused on symptom-specific quality of life.

Conclusion: Thalidomide improved cough and respiratory quality of life in patients with IPF. A larger trial is warranted to assess these promising results.

Primary Funding Source: Celgene Corporation.


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Figure 1.

Study flow diagram.

We collected data for all planned study visits from 20 participants and incomplete data on 3 participants who received placebo first but withdrew before completion of the thalidomide group. Analysis included all available data.

* One participant signed consent but was found to be ineligible because of an FVC >90% predicted.

† One participant withdrew because of hospitalization and inability to attend visits due to worsening health.

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Figure 2.

Cough-specific quality-of-life scores after thalidomide and placebo treatments.

Cough-specific quality-of-life scores for each participant after 12 wk of treatment with thalidomide or placebo. Shaded areas represent the mean CQLQ scores. CQLQ = Cough Quality of Life Questionnaire. Top. Participants who received thalidomide in the first period. Bottom. Participants who received placebo in the first period.

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Figure 3.

Cough VAS and respiratory-specific quality-of-life scores after thalidomide and placebo treatments.

Cough VAS and SGRQ scores for each participant after 12 wk of thalidomide or placebo treatments. Shaded areas represent mean values. SGRQ = St. George's Respiratory Questionnaire; VAS = visual analogue scale. Left. Participants who received thalidomide in the first period. Right. Participants who received placebo in the first period.

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Study Results Are Exciting
Posted on September 27, 2012
Jeffrey J. Swigris, DO, MS, Associate Professor of Medicine, Kevin K. Brown, MD, Professor of Medicine, Amanda Belkin, MPH
Autoimmune Lung Center and Interstitial Lung Disease Program, National Jewish Health
Conflict of Interest: None Declared

Dear Editor:We read with interest the article by Horton and colleagues on thalidomide for IPF-related cough.(1) Besides dyspnea and fatigue, cough is a hallmark symptom—for a significant minority of IPF patients, cough is most debilitating. IPF patients describe an ever-present “nagging” sensation but “never feeling relieved after coughing.”(2) In our unpublished work, IPF patients describe cough when they “talk too long,” breathe “hard” and/or “fast” or when their oxygen saturation is low. Cough can occur in frightening paroxysms, cause significant oxygen desaturation and leave patients “wiped out.” The potential for cough to profoundly affect IPF patients’ lives makes these investigators’ results all the more impressive. Their statistical models would suggest effect sizes > 0.6—and > 0.9 for the primary outcome. While recognizing the goal was to test thalidomide and not necessarily to elucidate how cough impacts IPF patients, their data could prove useful there. On the face of it, many items from the CQLQ appear relevant to IPF patients, but many do not. Might the authors provide more detail on scores from specific CQLQ domains? Did one or more of the six CQLQ domains drive the change scores in response to thalidomide? We are also curious about the wording for the cough VAS? Did it ask about cough “frequency”? “Affects on daily life?” “Impact on quality of life?” Data for the SGRQ are interesting. In most IPF trials that included SGRQ, the Activity domain—which assesses physical activities that either cause or are limited by dyspnea(2)—is most impaired. Possibly because this cohort consisted largely of self-referred subjects, presumably because their coughs were so distressing; here, the Symptoms domain—items on cough, phlegm, wheezing and others—was most impaired. It may prove informative to drill into the Symptoms domain to see where thalidomide had its effects. The absence of change in Activity domain would suggest thalidomide had no effect on dyspnea. The baseline score from the Impacts domain—assesses effects of respiratory disease on daily life, including psycho-social functioning—suggests greater impairment than in other IPF treatment trials. Presumably, when responding to Impacts items, subjects focused on the effects of cough.Whatever the case, the results of this study are exciting. They pave the way for investigation into the mechanistic pathways of IPF-related cough, into discerning more precisely how cough impacts IPF patients’ lives and they provide the impetus for large-scale, systematic assessments of therapies for this vexing symptom.


1. Horton MR, Santopietro V, Mathew L, Horton KM, Polito AJ, Liu MC, et al. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med. 2012;157(6):398-406.

2. Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir Med. 1991;85 Suppl B:25-31; discussion 3-7.

Author's Response
Posted on October 31, 2012
Noah Lechtzin, MD MHS, Maureen R. Horton, MD
Johns Hopkins University School of Medicine
Conflict of Interest: None Declared

We appreciate Dr. Swigris and colleagues’ interest in our article and would like to respond to their questions regarding the Cough Quality of Life Questionnaire (CQLQ)(1), the visual analog scale (VAS) of cough, and the St. George’s Respiratory Questionnaire (SGRQ)(2). The CQLQ is a 28-item instrument developed and validated in a cohort of patients with idiopathic cough, and as such contains some questions that are not relevant to patients with IPF. However, the CQLQ contains many questions that are applicable to virtually anyone with a severe cough. There are six subscales of the CQLQ; Physical Complaints, Psychosocial Issues, Functional Abilities, Emotional Well-Being, Extreme Physical Complaints, and Personal Safety Fears. In our study four of the subscales improved significantly after treatment with thalidomide. The two subscales that did not improve significantly were the Emotional Well-Being and Personal Safety Fears subscales, which both contain statements that are not pertinent to patients with IPF, such as “I want to be reassured that I do not have anything seriously the matter with me.” The cough VAS we used was meant to be broad and was worded “Considering all the ways your cough affects you, on the average, how have you been doing in the past week?” The anchors on the VAS were “No Cough” and “Worst Cough.” Therefore it does little to assess cough frequency or its impact on QOL. The SGRQ is respiratory specific QOL instrument developed for use in asthma and COPD, but it has been used in a wide variety of lung diseases. Many of the items in the SGRQ are dichotomous and therefore are therefore not particularly sensitive to subtle changes in symptoms. Additionally, our study was not designed to look at individual questions from the SGRQ. With these limitations in mind, there were several questions that showed statistically significant improvement in dyspnea after thalidomide treatment. The proportion of people who stated that sitting or lying still made them feel breathless decreased from 10% to 5%, (p=0.002). The proportion who felt breathless when bending over decreased from 68% to 42%, (p=0.012). Unfortunately, looking into responses on the CQLQ and SGRQ in more detail does little to further our understanding of the mechanistic pathways of IPD-related cough. Nevertheless, we share Dr. Swigris’ excitement about the ability of thalidomide to reduce IPF-related cough and hope to see a subsequent, larger clinical trial of thalidomide for IPF.

Reference List

(1) French CT, Irwin RS, Fletcher KE, Adams TM. Evaluation of a cough-specific quality-of-life questionnaire. Chest 2002; 121(4):1123-1131.

(2) Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir Med 1991; 85 Suppl B:25-31.

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Summary for Patients

Thalidomide Treatment for Cough in Patients With Idiopathic Pulmonary Fibrosis

The full report is titled “Thalidomide for the Treatment of Cough in Idiopathic Pulmonary Fibrosis. A Randomized Trial.” It is in the 18 September 2012 issue of Annals of Internal Medicine (volume 157, pages 398-406). The authors are M.R. Horton, V. Santopietro, L. Mathew, K.M. Horton, A.J. Polito, M.C. Liu, S.K. Danoff, and N. Lechtzin.


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