Developing antitussives: The ideal clinical trial

Transcription

1 Developing antitussives: The ideal clinical trial Surinder S Birring To cite this version: Surinder S Birring. Developing antitussives: The ideal clinical trial. Pulmonary Pharmacology Therapeutics, 2009, 22 (2), pp.155. < /j.pupt >. <hal > HAL Id: hal Submitted on 11 Sep 2010 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

2 Accepted Manuscript Title: Developing antitussives: The ideal clinical trial Authors: Surinder S Birring PII: S (08) DOI: /j.pupt Reference: YPUPT 874 To appear in: Pulmonary Pharmacology & Therapeutics Received Date: 27 October 2008 Revised Date: Accepted Date: 28 October 2008 Please cite this article as: Birring S.S. Developing antitussives: The ideal clinical trial, Pulmonary Pharmacology & Therapeutics (2008), doi: /j.pupt This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

3 1 DEVELOPING ANTITUSSIVES: THE IDEAL CLINICAL TRIAL Author: Surinder S Birring MD, MRCP Address: Department of Respiratory Medicine, King s College Hospital, London, SE5 9RS United Kingdom Telephone: (0044) surinder.birring@kch.nhs.uk Correspondence to: Dr Surinder S Birring WORD COUNT: 2425 words

4 2 CONTENTS Abstract 1.1 Introduction 1.2 Patient selection 1.3 Trial design 1.4 Choice of placebo 1.5 The assessment of cough severity 1.6 Sample size 1.7 The ideal trial 1.8 References

5 3 Abstract Antitussive drugs are amongst the most widely used medications worldwide; however no new drugs have been introduced into the market for many years. Trials showing patient benefit are scarce and have been hampered by the lack of objective and validated outcome measures. Recent improvements in the assessment of cough will facilitate better trials and aid the development of antitussive drugs. When conducting a trial, patient selection is of paramount importance. Patients with unexplained chronic cough and subacute cough due to viral upper respiratory tract infection are ideal because they represent an unmet clinical need and an untapped market for pharmaceutical companies. Patients with asthma and chronic obstructive pulmonary disease are less suitable since cough suppression is not always desirable and the findings of trials may not be generalisable to all patients with cough. Randomized, placebo controlled, double blind clinical trials are obviously the gold standard. The choice of placebo, whether inert or active, depends on the incidence and severity of drug side-effects. The primary outcome measure should be objective, and cough monitors are the ideal tool. Subjective outcome measures should be used to assess symptoms and health related quality of life. Properly conducted clinical trials are an opportunity to evaluate the benefits of currently available therapies and aid advances in the antitussive market.

6 4 1.1 Introduction Antitussive drugs are amongst the most widely used medications worldwide and generate estimated sales of $4 billion per year. They are used to relieve cough associated with the common cold and also to treat persistent cough arising from a wide range of respiratory conditions such as chronic obstructive pulmonary disease, lung cancer and pulmonary fibrosis. There have been a number of recent concerns over the use of antitussives. Reports of cardiac arrhythmias, depressed consciousness and encephalopathy, hallucinations and deaths have led to the withdrawal, re-labeling and restriction of many preparations targeting young children.(1) Inadvertent misuse, accidental overdose and abuse have been important factors leading to these changes. Although the widespread use of these drugs suggests that they are efficacious, there is little clinical evidence to support this. A recent Cochrane meta-analysis review concluded that there was no good evidence for or against over the counter (OTC) medicines in acute cough. (2) The criteria for inclusion in a Cochrane meta-analysis are stringent. Only six adult and one paediatric study of antitussive drug use in acute cough met the clinical trial methodology criteria. These studies involved small number of subjects and reported conflicting results. Positive results did not always relate to clear clinical benefit. The majority of antitussive drugs were developed over 30 years ago and there has been little development since. Support for use of these drugs is largely based on studies carried out in animals or healthy human subjects. Furthermore, they were often limited by their poor design, use of non-clinical endpoints and lack of objective tools to assess cough severity. Many clinical trials of antitussives failed to establish whether the efficacy of the

7 5 preparation was due to the active drug. Improvements in symptoms may have been due to the natural recovery from an acute upper respiratory tract infection, placebo-effect or the demulcents. So why has there been little progress in the field of antitussive drug development? Until now, there has been little incentive. There has been a high uptake of the existing antitussive medications and relative commercial success. There has been little investment, compared with other respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). Cough is considered a symptom of respiratory disease rather than a condition in its own right. Cough is however very common and can be debilitating for its sufferers, having both physical and psychological effects.(3) Approximately 20% of respiratory out-patient referrals are for patients with chronic cough. Failure of the cough to resolve completely is common in patients. It is likely that cough reflex hypersensitivity is the key abnormality in most patients with an unexplained chronic cough.(4) The term cough hypersensitivity syndrome (CHS) may be appropriate to focus attention on chronic cough as a condition rather than as a symptom. New antitussive drugs are desperately needed for patients with chronic cough for whom the currently available drugs are ineffective. The need for antitussive drug development has been recognised by all international respiratory societies.(5-7) It is likely that the recent concerns of the regulatory authorities may act as a catalyst to further investment into drug development. The identification of the sensory receptors that mediate cough such as the Transient Receptor Protein Vanilloid-1 (TRPV1) and their antagonists is a welcome step forward.(8) There have been significant advances in the assessment of cough severity which should facilitate

8 6 further research.(9) This review will focus on the characteristics of a high quality clinical trial that includes patient selection, trial design, assessment of cough severity and the determination of sample size. 1.2 Patient selection Patient selection is of paramount importance when designing a clinical trial. Cough should be the main clinical problem. In the past, antitussive drugs have often been tested in patients with COPD and asthma or healthy subjects. Cough suppression is not always desirable in these patients due to the risk of infection. In addition, the findings of these studies may not be generalisable to all patients with cough as the mechanism of cough may differ between conditions. Acute cough (< 3 weeks in duration), due to upper respiratory tract infection is perhaps the most challenging cough to study. The changing nature of an acute cough illness, seasonal variation, multitude of viruses and the significant placebo effect all need to be considered when designing a clinical trial. Most clinical trials are carried out in patient with acute cough as this represents the largest market for antitussives. Patients with subacute cough (3-8 weeks in duration, due to a post-viral upper respiratory tract infection) and chronic cough (>8 weeks in duration) are ideal for clinical trials since their cough is more stable. Both these conditions are prevalent and represent a huge unmet clinical need.

9 7 Most patients referred to respiratory physicians for investigation of unexplained chronic cough will be suitable for antitussive therapies.(10) Typically, patients are non-smokers and have a dry or minimally productive cough.(11) They should have a clinically significant and stable cough on entry into clinical trials. This can be assessed with symptom scales. Patients with symptoms of gastro-oesophageal reflux (GOR) and rhinitis are sometimes excluded from clinical trials on the basis that specific therapies are preferable. It is increasingly being recognised that cough often persists despite optimal therapy for GOR and rhinitis. Such patients probably comprise a significant proportion of patients referred with chronic cough for whom there are no effective pharmacological therapies. They are therefore ideal for inclusion in trials. 1.3 Trial design The gold standard clinical trial is obviously a randomized, double-blind, parallel group, placebo-controlled trial. It is important that control subjects are well matched for clinical characteristics that affect cough sensitivity such as age and gender.(12) This can be achieved by stratification of subjects at randomisation. A cross-over trial has its merits and should not be overlooked. It requires fewer patients and without the need for stratification. However, the suitability of a drug for study in a cross-over trial is dependent on its potential for carry-over effects into the cross-over phase. 1.4 Choice of placebo It is most common to use inert placebos in clinical trials. The side-effects of antitussive drugs, particularly those acting on the central nervous system make blinding difficult so

10 8 active placebos need consideration. Benzodiazepines might be useful as active placebos although their effect on cough symptoms and cough reflex has not been studied. Active placebos are commonly used in clinical trials of analgesics but have never been applied to antitussive trials.(13) Alternatively, codeine could be used as a comparator since new antitussive drugs should aim to be more efficacious and have fewer side effects. 1.5 The assessment of cough severity The choice of outcome parameter for any clinical trial is of critical importance. Clinical trial of antitussive drugs should evaluate cough severity both objectively and subjectively. The primary outcome parameter should preferably be objective. Cough monitoring devices that measure cough frequency are ideal. Secondary outcome parameters should determine subjective symptom severity and the impact on health related quality of life. Significant progress in the development and validation of cough assessment tools have been made in the past 5 years and a range of options are discussed below. Symptom scales Symptom scales such as the 100mm visual analogue scale, cough scores and diaries, record the patients assessment of the severity of their cough symptoms. These are easy to administer, widely used and established in cough research. The visual analogue scale is the most validated of the symptom scales and has very good repeatability and responsiveness. It can also be used to assess the sensation of urge-to-cough. The main

11 9 drawback to symptom scales is their subjective nature and therefore they are best used in conjunction with objective tools. Quality of life Cough can have a profound effect on quality of life (QOL). Physical symptoms such as vomiting, chest pains, hoarse voice, incontinence and syncope are commonly associated with cough. Psychosocial impacts of cough are also important and include frustration, social embarrassment, depression, fear, sleep deprivation and interference with work and relationships. Health related QOL questionnaires can be used to evaluate the overall impact of cough, assessing aspects not captured by other tools. Three questionnaires have been designed and validated for use in patients with cough; LCQ: Leicester Cough Questionnaire,(14) CQLQ: Cough specific quality of life questionnaire(15) and CCIQ: Chronic cough impact questionnaire.(16) All have good repeatability and responsiveness. The minimal important difference QOL score can be used to aid clinical interpretation of QOL data and has been reported for the LCQ.(17) Recent clinical trials support the use of QOL questionnaires as an outcome measure.(18) Cough reflex sensitivity A variety of inhaled tussive stimuli such as capsaicin, citric acid and distilled water can be used to assess the sensitivity of the cough reflex. This technique is well established, validated and has a good safety profile.(19) Capsaicin is the most widely used tussive agent. Cough reflex sensitivity measurement is a favoured tool for early phase clinical trials and animal studies because it provides an objective assessment of cough and gives

12 10 useful insights into the mechanism of antitussive therapy. Cough sensitivity measurement has been used effectively in clinical trials to determine the efficacy of antitussive therapies.(20) The disadvantage of measuring cough sensitivity in clinical trials is that it can be time-consuming and requires access to laboratory facilities. Furthermore it correlates poorly with cough symptoms as there may be important mechanistic differences between reflex cough and spontaneous coughing.(21) Despite these drawbacks, this has been a commonly-used objective method as there have been few alternatives. Cough monitoring The development of automated cough counting devices has been the goal of cough assessment for sometime. The challenges of developing cough monitors have been the automation and poor sensitivity of cough detection systems. Recent technological advances in recording devices, digital sound processing and battery life have allowed significant progress in this field. Modern cough monitors now provide a simpler, automated, objective tool for assessment. They are likely to provide useful data for the development and regulatory approval of antitussive drugs in future. Several cough monitors are in various stages of development and four devices are summarised in table 1. The Leicester Cough Monitor (LCM) has the most information available of all systems.(22) It comprises of a recording device, microphone and automated cough detection software.(23;24) This software is based on technology used in speech recognition systems. The LCM is a discrete, 24-hour, ambulatory device that

13 11 subjects wear in their own environment causing minimal disruption to their daily routine. The LCM detects single coughs, whether they occur in bouts or as isolated events. It has a sensitivity and specificity of 91% and 99% respectively for detecting coughs.(22) The LCM has been independently evaluated and has been shown to have a very good correlation with cough recordings from another centre (figure 1).(25) Preliminary data from the LCM indicates that cough frequency measurement is repeatable, responsive and can be used to evaluate treatments for cough.(22;26) Clinical trials utilizing the LCM are underway. The Hull automated cough counter (HACC) is currently in development. It comprises of a recording device and microphone. It is not yet fully automated but preliminary validation studies are promising. The reported sensitivity of the HACM to detect cough is 80%.(27) The Lifeshirt cough monitor is an automated system that compromises of a recording device and a vest containing sensors that detect chest wall movements. The Lifeshirt cough monitor has very limited published validation data, indicating sensitivity for cough detection of 78%.(28) The VitaloJak cough monitor comprises of a recording device and a microphone.(29) This system is currently being validated. Full cough detection sensitivity data is not yet available. 1.6 Sample size Recent validation studies have provided information on the variability of a range of cough severity parameters.(4;14;22) This information can be used to determine ideal sample size. (Table 2) This data should be considered preliminary since these studies

14 12 involved small numbers of patients. It is likely that the data from future larger clinical trials will refine the estimates of variability. The minimal important clinical difference for cough severity parameters is another important consideration. At present, this is based on physicians opinions. Further studies are clearly needed to take account of the patients perspective. 1.7 The ideal trial The ideal clinical trial should be of randomized controlled design, utilizing both subjective and objective cough severity outcome parameters and paying attention to patient selection, sample size and choice of placebo. An example of an antitussive clinical trial for patients with chronic cough is given in figure 1. Many clinical trials involve a run-in period to allow for baseline measurements. The choice of an observational or placebo run-in period will largely depend on the setting of the trial. It may be reasonable to consider a single blind placebo run-in period in a proof of concept study to ensure clinical stability of patients, identify non-compliers and placebo responders. An observational run-in phase is more appropriate for a definitive clinical trial conducted to guide clinical practice. This approach also ensures generalisation of findings to all patients being considered for therapy. There are obviously many different ways to approach clinical trials and studies. Different centres will have different objectives and priorities. However there is much to be done in developing antitussive drugs and this will provide an opportunity for physicians,

15 13 pharmaceutical industry and health care providers to collaborate and improve the care of patients with cough. 1.8 Reference List (1) Sharfstein JM, North M, Serwint JR. Over the counter but no longer under the radar--pediatric cough and cold medications. N Engl J Med 2007 December 6;357(23): (2) Smith SM, Schroeder K, Fahey T. Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev 2008;(1):CD (3) Brignall K, Jayaraman B, Birring SS. Quality of life and psychosocial aspects of cough. Lung 2008;186 Suppl 1:S55-S58. (4) Prudon B, Birring SS, Vara DD, Hall AP, Thompson JP, Pavord ID. Cough and glottic-stop reflex sensitivity in health and disease. Chest 2005 February;127(2): (5) Morice AH, Fontana GA, Belvisi MG, Birring SS, Chung KF, Dicpinigaitis PV et al. ERS guidelines on the assessment of cough. Eur Respir J 2007 June;29(6): (6) Morice AH, McGarvey L, Pavord I. Recommendations for the management of cough in adults. Thorax 2006 September;61 Suppl 1:i1-24. (7) Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest 2006 January;129(1 Suppl):1S-23S. (8) Morice AH, Geppetti P. Cough. 5: The type 1 vanilloid receptor: a sensory receptor for cough. Thorax 2004 March;59(3): (9) Raj AA, Birring SS. Clinical assessment of chronic cough severity. Pulm Pharmacol Ther 2007;20(4): (10) Birring SS, Brightling CE, Symon FA, Barlow SG, Wardlaw AJ, Pavord ID. Idiopathic chronic cough: association with organ specific autoimmune disease and bronchoalveolar lymphocytosis. Thorax 2003 December;58(12):

16 14 (11) Birring S.S., Murphy AC, Scullion JE, Brightling CE, Browning M, Pavord ID. Idiopathic chronic cough and organ specific autoimmune diseases: a case-control study. Respir Med. In press (12) Prudon B, Birring SS, Vara DD, Hall AP, Thompson JP, Pavord ID. Cough and glottic-stop reflex sensitivity in health and disease. Chest 2005 February;127(2): (13) Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005 March 31;352(13): (14) Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003 April;58(4): (15) French CT, Irwin RS, Fletcher KE, Adams TM. Evaluation of a cough-specific quality-of-life questionnaire. Chest 2002 April;121(4): (16) Baiardini I, Braido F, Fassio O, Tarantini F, Pasquali M, Tarchino F et al. A new tool to assess and monitor the burden of chronic cough on quality of life: Chronic Cough Impact Questionnaire. Allergy 2005 April;60(4): (17) Raj AA, Pavord ID, Birring SS. What is the minimal important difference of the Leicester Cough Questionnaire? In: Chung KF, Widdicombe J, editors. Pharmacology and Therapeutics of Cough.Berlin: Springer; p (18) Morice AH, Menon MS, Mulrennan SA, Everett CF, Wright C, Jackson J et al. Opiate therapy in chronic cough. Am J Respir Crit Care Med 2007 February 15;175(4): (19) Dicpinigaitis PV, Alva RV. Safety of capsaicin cough challenge testing. Chest 2005 July;128(1): (20) Birring SS, Passant C, Patel RB, Prudon B, Murty GE, Pavord ID. Chronic tonsillar enlargement and cough: preliminary evidence of a novel and treatable cause of chronic cough. Eur Respir J 2004 February;23(2): (21) Birring SS, Matos S, Patel RB, Prudon B, Evans DH, Pavord ID. Cough frequency, cough sensitivity and health status in patients with chronic cough. Respir Med 2006 June;100(6): (22) Birring SS, Fleming T, Matos S, Raj AA, Evans DH, Pavord ID. The Leicester Cough Monitor: preliminary validation of an automated cough detection system in chronic cough. Eur Respir J 2008 May;31(5):

17 15 (23) Matos S, Birring SS, Pavord ID, Evans DH. An automated system for 24-h monitoring of cough frequency: the leicester cough monitor. IEEE Trans Biomed Eng 2007 August;54(8): (24) Matos S, Birring SS, Pavord ID, Evans DH. Detection of cough signals in continuous audio recordings using hidden Markov models. IEEE Trans Biomed Eng 2006 June;53(6): (25) Birring SS, Mann VM, Matos S, Yousaf N, Wood C, Fleming T et al. The Leiceseter Cough Monitor. Eur Respir J 2008;32: (26) Savani A, Wood C, Cox D, Fleming T, Matos S, Pavord ID et al. The assessment of cough severity with a novel cough monitor. Thorax. In press (27) Barry SJ, Dane AD, Morice AH, Walmsley AD. The automatic recognition and counting of cough. Cough 2006;2:8. (28) Coyle MA, Keenan DB, Henderson LS, Watkins ML, Haumann BK, Mayleben DW et al. Evaluation of an ambulatory system for the quantification of cough frequency in patients with chronic obstructive pulmonary disease. Cough 2005 August 4;1:3. (29) Smith JA, Earis JE, Woodcock AA. Establishing a gold standard for manual cough counting: video versus digital audio recordings. Cough 2006;2:6.

18 16 Figure 1. The ideal antitussive trial for patients with chronic cough. VAS: Visual Analogue Score (VAS) QOL: Quality of Life CM: Cough Monitor

19 17 Table 1. Cough Monitor Characteristics LCM: Leicester Cough Monitor HACS: Hull automated cough counter See text for references. Table 2. With-in subject standard deviations for cough assessment tools. VAS: Visual Analogue Score (VAS) LCQ: Leicester Cough Questionnaire. QOL: Quality of Life C2: Concentration of capsaicin that causes 2 coughs DD: Doubling dose units LCM: Leicester Cough Monitor

20 Table 1. Cough Monitor Characteristics LCM HACC LifeShirt VitaloJak Input Sound Sound Chest wall Sound movement and sound Device Recorder/Microphone Recorder/Microphone Vest and microphone Recorder/Micropho ne Duration 24 Hours 24 Hours 24 Hours 24 Hours Setting Ambulatory Ambulatory Ambulatory Ambulatory Automation Yes under development Yes under development Sensitivity (cough detection) 91% 80% 78% - LCM: Leicester Cough Monitor HACS: Hull automated cough counter See text for references.

21 Table 2. With-in subject standard deviations for cough assessment tools. Cough Symptoms (VAS) Standard deviation (within subject) 7.8 mm Minimal Important Difference QOL (LCQ) Cough sensitivity (C2) Cough Frequency (LCM) 0.8 dd 11.4 C/Hour VAS: Visual Analogue Score (VAS) LCQ: Leicester Cough Questionnaire. QOL: Quality of Life C2: Concentration of capsaicin that causes 2 coughs DD: Doubling dose units LCM: Leicester Cough Monitor

22 Figure 1. Run-in Placebo Drug Observation or open phase DAY VAS QOL Randomisation VAS QOL CM VAS QOL CM VAS QOL CM VAS QOL CM VAS QOL