Octreotide treatment of idiopathic pulmonary fibrosis: a proof-of-concept study
- B. Crestani*,#¶⇓,
- J. Chapron#,
- B. Wallaert+,
- E. Bergot§,
- P. Delavalf,
- D. Israel-Biet**,
- J. Lacronique##,
- I. Monnet¶¶,
- M. Reynaud-Gaubert++,
- A. Tazi§§,
- R. Lebtahiff,
- M-P. Debray***,
- M. Brauner###,
- M. Dehoux¶¶¶¶,
- Q. Dornic+++§§§,
- M. Aubier*,#¶,
- F. Mentré+++§§§ and
- X. Duval§§§,fff
- *Universite Paris Diderot, PRES Paris Cité, Inserm U700
- #Service de Pneumologie A
- ffService de Médecine Nucléaire
- ***Service de Radiologie
- ¶¶¶Laboratoire de Biochimie
- +++UF de Biostatistiques
- fffCentre d'Investigation Clinique, Assistance Publique Hôpitaux de Paris, Hôpital Bichat
- ¶Inserm, UMR 700
- **Service de Pneumologie, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou
- ##Service de Pneumologie, Assistance Publique Hôpitaux de Paris, Hôpital Cochin
- §§Service de Pneumologie, Assistance Publique Hôpitaux de Paris, Hôpital Saint Louis
- §§§Inserm, UMR738, Paris
- +CHRU, Hôpital Calmette, Service des Maladies Respiratoires, Lille
- §CHU Côte de Nacre, Service de Pneumologie, Caen
- fService de Pneumologie, Hôpital Pontchaillou, Rennes
- ¶¶Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil
- ++Service de Pneumologie, Assistance Publique Hôpitaux de Marseille, Hôpital de Sainte Marguerite, Marseille
- ###Service de Radiologie, Assistance Publique Hôpitaux de Paris, Hôpital Avicenne, Bobigny, France
- B. Crestani, Service de Pneumologie A, Centre de Compétence des Maladies Pulmonaires Rares, Hôpital Bichat, 46 rue Henri Huchard, 75877 Paris Cedex 18, France. E-mail: bruno.crestani{at}bch.aphp.fr
To the Editors:
Idiopathic pulmonary fibrosis (IPF) is the most frequent form of idiopathic interstitial pneumonia. It is a chronic, progressive and fatal disease of unknown aetiology, characterised by histological features of usual interstitial pneumonia (UIP). Disease progression is marked by worsening dyspnoea, progressive loss of lung volume, abnormal gas exchange and poor quality of life. Median survival after diagnosis is 3–5 yrs. Currently, pirfenidone is the only drug approved in Europe for the treatment in IPF, as it has been shown to slow the decline of lung function [1]. However, no effect on survival has been demonstrated until now.
Somatostatin is an endogenous cyclic peptide initially identified as a regulator of growth hormone secretion. In humans, it has been shown to bind with equal efficiency to five receptors: sst1, sst2A, sst3, sst4 and sst5. We have recently shown that the sst2A receptor is highly expressed in fibrotic lung tissue in IPF patients and that the uptake of octreotide, a somatostatin analogue that has a high affinity for sst2A, is elevated in the lungs of IPF patients and is correlated with the severity of lung fibrosis [2, 3]. Octreotide has been widely used for the treatment of neuroendocrine tumours for >20 yrs. In this study, we investigated the safety and efficacy of octreotide as a therapy for IPF.
This was an open-label, proof-of-concept, non-randomised, non-controlled, multicentre phase II study performed in France between October 2006 and April 2008 to evaluate the safety and efficacy of intramuscular long-acting octreotide in patients with IPF. The trial was registered with ClinicalTrials.gov (identifier number NCT00463983). Patients had to be aged ≥40 yrs and meet the diagnostic criteria for IPF described in the American Thoracic Society/European Respiratory Society consensus statement [4]. In patients aged <50 yrs, a lung biopsy showing a UIP pattern was required for inclusion. Inclusion criteria in patients aged >50 yrs required either a computed tomography (CT) scan showing “definite” IPF features or one showing “probable” features and a lung biopsy showing histological features of UIP. High-resolution CT was reviewed by two radiologists (M-P. Debray and M. Brauner) before confirming inclusion. Exclusion criteria included previous treatment with a somatostatin agonist, such as octreotide, and hypersensitivity to octreotide. Concomitant medication for IPF was not permitted during the study period and all prior IPF medication, except for prednisone (≤10 mg per day), was stopped ≥6 weeks before inclusion. Long-acting octreotide (30 mg) was administered intramuscularly every 4 weeks for 1 yr (12 injections, 48 weeks).
Recent clinical studies have shown that a decline in forced vital capacity (FVC) of ≥10% from baseline over a period of 6–12 months is a strong predictor of mortality in IPF patients [5]. Hence, the primary assessment in this study was treatment failure, defined by the percentage of patients who died or whose FVC decreased by ≥10% between two consecutive measurements (with a 12-week interval) compared with baseline. These patients were termed “decliners”. Secondary assessments consisted of various lung function tests, high-resolution CT, clinical evaluation, quality of life assessment (St George's Respiratory Questionnaire) and biochemical assays. These assays included measurement of serum octreotide (by a radioimmunoassay) and fibrosis biomarkers (by ELISA), namely CC chemokine ligand (CCL)2, which is a marker of progression in IPF patients, and CCL-18, surfactant protein-D and Krebs von den Lungden-6, which are associated with prognosis [6]. The safety profile was assessed based on reports of adverse events, routine physical examinations and laboratory determinations. Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, NC, USA). A linear regression method was applied to replace the missing data from patients who discontinued prematurely. This method was considered appropriate for a progressive disease such as IPF, where a continuous decrease of lung function is expected in most patients.
We enrolled and followed up 25 patients who received at least one octreotide injection. 17 patients completed the study (12 injections of 30 mg octreotide every 4 weeks). Interestingly, only eight (32%) patients had been diagnosed with IPF >3 yrs previously. Eight patients discontinued between 16 and 32 weeks because of adverse events either related or not related to octreotide treatment (one and three patients, respectively), or worsening of IPF symptoms (four patients) as indicated by a decrease in FVC or in diffusing capacity of the lung for carbon monoxide (DL,CO) of >10% from the baseline.
Among the 17 patients who completed the study (48 weeks), FVC decreased by ≥10% in five (29%) patients. Among the eight who discontinued, three were identified as decliners based on their performance in the period up to discontinuation. Thus, eight (32%) out of 25 patients (95% CI 15–54%) experienced a decline in lung function, while 17 (68%) out of 25 were non-decliners. For the whole population, median FVC was 2.23 L (95% CI 1.22–3.80 L) at study entry and 2.20 L (95% CI 0.99–4.71 L) after 48 weeks. The percentage of decliners seen in our study was lower than the 54% (p=0.044) observed in the study by Flaherty et al. [7], the 55% observed in the placebo group in the etanercept trial (48 weeks) [8] and the 52% reported in a Japanese pirfenidone trial (52 weeks) [9]. At least two measurements of FVC obtained before treatment were available in all patients. Application of a linear mixed model to assess the rate of decline of FVC before and after treatment over the entire cohort (n=25) estimated the slopes to be 5.1% and 2.2% predicted per year (p=0.76), respectively (data not shown). Similarly, a decrease in DL,CO of ≥10% was seen in 42% of patients (95% CI 22–63%), which is lower than the 69% observed in the study by Flaherty et al. [7]. Although our study is not strictly comparable with the other studies mentioned previously due to differences in sample size, characteristics of patient population, diagnostic criteria, therapeutic regimens, etc., these comparisons provide an overall perspective in which to evaluate our results.
A comparison of some of the primary and secondary end-points between decliners and non-decliners is given in table 1. The most significant difference observed was for high-resolution CT lung alveolar score which tended to be lower in non-decliners (p=0.053), i.e. patients who appeared to benefit from octreotide treatment. Clinical features, lung function tests, and levels of serum octreotide and fibrosis biomarkers were similar in the two groups. Among decliners, the percentage of nonsmokers was higher than among non-decliners (table 1). This may be attributed to the greater antifibrotic effects of octreotide in smokers, although there are no data to support this hypothesis. Alternatively, it may be due to smoking itself, which is a well-identified risk factor for IPF, although the links between tobacco smoking and decline in lung function remain a subject of debate [10]. A third possibility could be that emphysema, which is often associated with IPF in ex-smokers, compensates for the loss in FVC.
Interestingly, the lung uptake of 111In-octreotide measured at baseline before any octreotide administration tended to be higher in non-decliners (p=0.11), suggesting that non-decliners had more octreotide receptors than decliners or that their rate of uptake per receptor was higher. This observation indirectly supports the notion of an antifibrotic action attributed to octreotide.
Patients included in this study appeared to be fairly stable over the study period (48 weeks) for all the recorded end-points: lung function tests, quality of life and blood biomarkers. Such stability of the disease was surprising, as the population was older than in most of the retrospective and prospective studies published to date, and had a rather severe disease grade based on a low DL,CO (32% pred).
Overall, the tolerability of octreotide was good and there were no deaths during the study. 85 adverse effects were reported in 20 patients. Adverse events were mainly gastrointestinal (diarrhoea) or respiratory (cough, increased dyspnoea and acute bronchitis) and generally mild. Seven severe adverse effects were reported, of which only one was thought to be related to octreotide (diarrhoea complicated with dehydration). One acute exacerbation of IPF was observed in a patient who had received 11 injections of octreotide.
In summary, this was a non-randomised, non-controlled study on 25 patients treated over 48 weeks. While the sample size and study design do not provide any definite conclusions, the results indicate that long-acting octreotide is well tolerated and provide a proof of concept that octreotide treatment slows down the progression of lung fibrosis. These results need to be confirmed by a larger placebo-controlled study.
Acknowledgments
The authors acknowledge the support of S. Bisot-Locard (Novartis Pharma S.A.S, Rueil-Malmaison, France), H. Papayan and C. Vergne as clinical research assistants, J. Benessiano and the Centre for Biological Resources, and A. Certain (all Bichat Hospital, Paris, France) for help in the drug management of the trial.
Footnotes
Support Statement
Octreotide was kindly donated by Novartis Pharma S.A.S. (Rueil-Malmaison, France).
Clinical Trial
This study is registered at Clinicaltrials.gov with identifier number NCT00463983.
Statement of Interest
Astatement of interest for this study can be found at www.erj.ersjournals.com/site/misc/statements.xhtml
- ©ERS 2012