Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT
Background: Idiopathic pulmonary fibrosis is an irreversible fibrosing lung disorder with a poor prognosis. Current treatments slow the rate of decline in lung function and may influence survival, but they have a significant side-effect profile and so additional therapeutic options are required. Peo...
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| Format: | Article |
| Language: | English |
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NIHR Journals Library
2021-07-01
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| Series: | Efficacy and Mechanism Evaluation |
| Subjects: | |
| Online Access: | https://doi.org/10.3310/eme08090 |
| _version_ | 1818061029113856000 |
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| author | Andrew M Wilson Allan B Clark Anthony Cahn Edwin R Chilvers William Fraser Matthew Hammond David M Livermore Toby M Maher Helen Parfrey Ann Marie Swart Susan Stirling David Thickett Moira Whyte |
| author_facet | Andrew M Wilson Allan B Clark Anthony Cahn Edwin R Chilvers William Fraser Matthew Hammond David M Livermore Toby M Maher Helen Parfrey Ann Marie Swart Susan Stirling David Thickett Moira Whyte |
| author_sort | Andrew M Wilson |
| collection | DOAJ |
| description | Background: Idiopathic pulmonary fibrosis is an irreversible fibrosing lung disorder with a poor prognosis. Current treatments slow the rate of decline in lung function and may influence survival, but they have a significant side-effect profile and so additional therapeutic options are required. People with idiopathic pulmonary fibrosis have altered innate immunity and altered lung microbiota, with the bacterial burden relating to mortality. Two randomised controlled trials have demonstrated beneficial effects with co-trimoxazole (SEPTRIN®; Essential Generics Ltd, Egham, UK; Chemidex Generics Ltd, Egham, UK), with the suggestion of an improvement in rates of survival. Objectives: To determine the clinical efficacy of co-trimoxazole in people with moderate to severe idiopathic pulmonary fibrosis. Design: A Phase II, double-blind, placebo-controlled, parallel-group, randomised multicentre study. Setting: UK specialist interstitial lung disease centres. Participants: Patients who were randomised had idiopathic pulmonary fibrosis diagnosed by a multidisciplinary team. In addition, patients had significant breathlessness (i.e. a Medical Research Council Dyspnoea Scale score of > 1) and impaired lung function (i.e. a forced vital capacity of < 75% predicted). Patients could be taking licensed medication for idiopathic pulmonary fibrosis, but were excluded if they had significant comorbidities, including airflow obstruction. Intervention: Oral co-trimoxazole, 960 mg twice per day (two 480-mg tablets twice per day), compared with placebo tablets (two tablets twice per day) for a median of 27 months (range 12–42 months). Otherwise, both trial groups had standard care. Main outcome measures: The primary outcome was the time to death (all causes), transplant or first non-elective hospital admission. Secondary outcomes were the individual components of the primary end point and the number of respiratory-related events. Questionnaires (the King’s Brief Interstitial Lung Disease questionnaire; the Medical Research Council Dyspnoea Scale; EuroQol-5 Dimensions, five-level version; the Leicester Cough Questionnaire; and the Cough Symptom Score) and lung function tests (forced vital capacity and diffusing capacity for carbon monoxide) were undertaken at baseline and at 12 months. Results: The trial randomised a total of 342 (295 male) patients (active treatment group, n = 170; placebo group, n = 172), using minimisation for hospital and receipt of licensed antifibrotic medication, from 39 UK hospitals. The patients had a mean (standard deviation) age of 71.3 years (7.47 years) and a mean forced vital capacity of 2.25 l (0.56 l). A total of 137 (40%) patients were taking pirfenidone (Esbriet, Roche Holding AG, Basel, Switzerland) and 116 (34%) were taking nintedanib (Ofev®, Boehringer Ingelheim, Brackness, UK). There was one post-randomisation exclusion from the co-trimoxazole group, but no withdrawals. There was no difference in the time to event for the composite primary end point (co-trimoxazole: hazard ratio 1.2, 95% confidence interval 0.9 to 1.6; p = 0.319). Likewise, there was no difference in other event outcomes, lung function measurements or patient-reported outcomes, other than a beneficial effect on the total Leicester Cough Questionnaire score, the social domain of the Leicester Cough Questionnaire score and the chest domain of the King’s Brief Interstitial Lung Disease questionnaire in the adjusted analysis. The repeated-measures analysis showed a significant overall difference in Cough Symptom Score. There were significantly more reports of nausea, but fewer reports of diarrhoea, with co-trimoxazole; however, differences in frequency of hyperkalaemia, rash and headache were not significant. The limitations of the trial were that it was not possible to evaluate the lung microbiota, there were missing data for secondary end points and there was no health economic analysis. Conclusion: These results suggest that co-trimoxazole does not reduce the likelihood of death or number of hospitalisations among people with idiopathic pulmonary fibrosis with moderate to severe idiopathic pulmonary fibrosis. Further work is required to evaluate the effect in subgroups of individuals with idiopathic pulmonary fibrosis or the effect of antibiotics with different antibacterial properties. Trial registration: Current Controlled Trials ISRCTN17464641. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 9. See the NIHR Journals Library for further project information. |
| first_indexed | 2024-12-10T13:41:49Z |
| format | Article |
| id | doaj.art-eac2fcbe27b44ad5b2fc818f25be3374 |
| institution | Directory Open Access Journal |
| issn | 2050-4365 2050-4373 |
| language | English |
| last_indexed | 2024-12-10T13:41:49Z |
| publishDate | 2021-07-01 |
| publisher | NIHR Journals Library |
| record_format | Article |
| series | Efficacy and Mechanism Evaluation |
| spelling | doaj.art-eac2fcbe27b44ad5b2fc818f25be33742022-12-22T01:46:41ZengNIHR Journals LibraryEfficacy and Mechanism Evaluation2050-43652050-43732021-07-018910.3310/eme0809012/206/09Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCTAndrew M Wilson0Allan B Clark1Anthony Cahn2Edwin R Chilvers3William Fraser4Matthew Hammond5David M Livermore6Toby M Maher7Helen Parfrey8Ann Marie Swart9Susan Stirling10David Thickett11Moira Whyte12Norwich Medical School, University of East Anglia, Norwich, UKNorwich Medical School, University of East Anglia, Norwich, UKDepartment of Respiratory Medicine, Bedford Hospitals NHS Trust, Bedford, UKICTEM building, Hammersmith Campus, Imperial College London, London, UKNorwich Medical School, University of East Anglia, Norwich, UKNorwich Clinical Trials Unit, University of East Anglia, Norwich, UKNorwich Medical School, University of East Anglia, Norwich, UKDepartment of Respiratory Medicine, Royal Brompton & Harefield NHS Foundation Trust, Royal Brompton Hospital, London, UKDepartment of Respiratory Medicine, Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UKNorwich Clinical Trials Unit, University of East Anglia, Norwich, UKNorwich Clinical Trials Unit, University of East Anglia, Norwich, UKBirmingham Acute Care Research Group, University of Birmingham, Birmingham, UKMedical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, UKBackground: Idiopathic pulmonary fibrosis is an irreversible fibrosing lung disorder with a poor prognosis. Current treatments slow the rate of decline in lung function and may influence survival, but they have a significant side-effect profile and so additional therapeutic options are required. People with idiopathic pulmonary fibrosis have altered innate immunity and altered lung microbiota, with the bacterial burden relating to mortality. Two randomised controlled trials have demonstrated beneficial effects with co-trimoxazole (SEPTRIN®; Essential Generics Ltd, Egham, UK; Chemidex Generics Ltd, Egham, UK), with the suggestion of an improvement in rates of survival. Objectives: To determine the clinical efficacy of co-trimoxazole in people with moderate to severe idiopathic pulmonary fibrosis. Design: A Phase II, double-blind, placebo-controlled, parallel-group, randomised multicentre study. Setting: UK specialist interstitial lung disease centres. Participants: Patients who were randomised had idiopathic pulmonary fibrosis diagnosed by a multidisciplinary team. In addition, patients had significant breathlessness (i.e. a Medical Research Council Dyspnoea Scale score of > 1) and impaired lung function (i.e. a forced vital capacity of < 75% predicted). Patients could be taking licensed medication for idiopathic pulmonary fibrosis, but were excluded if they had significant comorbidities, including airflow obstruction. Intervention: Oral co-trimoxazole, 960 mg twice per day (two 480-mg tablets twice per day), compared with placebo tablets (two tablets twice per day) for a median of 27 months (range 12–42 months). Otherwise, both trial groups had standard care. Main outcome measures: The primary outcome was the time to death (all causes), transplant or first non-elective hospital admission. Secondary outcomes were the individual components of the primary end point and the number of respiratory-related events. Questionnaires (the King’s Brief Interstitial Lung Disease questionnaire; the Medical Research Council Dyspnoea Scale; EuroQol-5 Dimensions, five-level version; the Leicester Cough Questionnaire; and the Cough Symptom Score) and lung function tests (forced vital capacity and diffusing capacity for carbon monoxide) were undertaken at baseline and at 12 months. Results: The trial randomised a total of 342 (295 male) patients (active treatment group, n = 170; placebo group, n = 172), using minimisation for hospital and receipt of licensed antifibrotic medication, from 39 UK hospitals. The patients had a mean (standard deviation) age of 71.3 years (7.47 years) and a mean forced vital capacity of 2.25 l (0.56 l). A total of 137 (40%) patients were taking pirfenidone (Esbriet, Roche Holding AG, Basel, Switzerland) and 116 (34%) were taking nintedanib (Ofev®, Boehringer Ingelheim, Brackness, UK). There was one post-randomisation exclusion from the co-trimoxazole group, but no withdrawals. There was no difference in the time to event for the composite primary end point (co-trimoxazole: hazard ratio 1.2, 95% confidence interval 0.9 to 1.6; p = 0.319). Likewise, there was no difference in other event outcomes, lung function measurements or patient-reported outcomes, other than a beneficial effect on the total Leicester Cough Questionnaire score, the social domain of the Leicester Cough Questionnaire score and the chest domain of the King’s Brief Interstitial Lung Disease questionnaire in the adjusted analysis. The repeated-measures analysis showed a significant overall difference in Cough Symptom Score. There were significantly more reports of nausea, but fewer reports of diarrhoea, with co-trimoxazole; however, differences in frequency of hyperkalaemia, rash and headache were not significant. The limitations of the trial were that it was not possible to evaluate the lung microbiota, there were missing data for secondary end points and there was no health economic analysis. Conclusion: These results suggest that co-trimoxazole does not reduce the likelihood of death or number of hospitalisations among people with idiopathic pulmonary fibrosis with moderate to severe idiopathic pulmonary fibrosis. Further work is required to evaluate the effect in subgroups of individuals with idiopathic pulmonary fibrosis or the effect of antibiotics with different antibacterial properties. Trial registration: Current Controlled Trials ISRCTN17464641. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 9. See the NIHR Journals Library for further project information.https://doi.org/10.3310/eme08090idiopathic pulmonary fibrosisco-trimoxazolemortalityhospitalisationcoughrandomised controlled trial |
| spellingShingle | Andrew M Wilson Allan B Clark Anthony Cahn Edwin R Chilvers William Fraser Matthew Hammond David M Livermore Toby M Maher Helen Parfrey Ann Marie Swart Susan Stirling David Thickett Moira Whyte Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT Efficacy and Mechanism Evaluation idiopathic pulmonary fibrosis co-trimoxazole mortality hospitalisation cough randomised controlled trial |
| title | Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT |
| title_full | Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT |
| title_fullStr | Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT |
| title_full_unstemmed | Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT |
| title_short | Co-trimoxazole to reduce mortality, transplant, or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis: the EME-TIPAC RCT |
| title_sort | co trimoxazole to reduce mortality transplant or unplanned hospitalisation in people with moderate to very severe idiopathic pulmonary fibrosis the eme tipac rct |
| topic | idiopathic pulmonary fibrosis co-trimoxazole mortality hospitalisation cough randomised controlled trial |
| url | https://doi.org/10.3310/eme08090 |
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