Developing antitussives: The ideal clinical trial
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 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-labelling 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 numbers 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 laboratory based studies carried out in healthy human subjects and those with an upper respiratory tract infection. Furthermore, they were often limited by poor design, use of non-clinical endpoints and lack of objective assessment of cough severity. Many clinical trials of antitussives failed to establish whether the efficacy of the 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 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, leading to 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. The unique clinical characteristics of patients with chronic cough suggest a common underlying mechanism for cough. 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 a symptom. New antitussive drugs are desperately needed for patients with chronic cough/CHS for whom currently available drugs are ineffective.
The need for antitussive drug development has been recognised by all international respiratory societies [5], [6], [7]. It is likely that the recent concerns of the regulatory authorities may act as a catalyst for 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]. Furthermore, significant advances in the assessment of cough severity should facilitate further research [9]. This review focuses 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.
Section snippets
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 since the mechanism of cough may differ between conditions.
Acute cough (<3 weeks in
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 reflex sensitivity such as age and gender [4]. This can be achieved by stratification of subjects at randomisation. A cross-over trial has merits and should not be overlooked. It requires fewer patients, without the need for stratification. The suitability of a drug for study in a
Choice of placebo
Inert placebos are commonly used in clinical trials. The side-effects of antitussive drugs, particularly those acting on the central nervous system make blinding difficult so active placebos need consideration. Benzodiazepines might be useful 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 [12]. Alternatively, codeine could be used
The assessment of cough severity
The choice of outcome parameter for any clinical trial is of critical importance. Clinical trials of antitussive drugs should evaluate cough severity with objective and subjective tools. 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
Sample size
Recent validation studies have provided information on the variability of cough severity parameters [4], [13], [21] that can be used to determine ideal sample size (Table 2). This data should be considered preliminary since these studies involved small numbers of patients. It is likely that 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
The ideal trial
The ideal clinical trial should be a 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 Fig. 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
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Cited by (23)
Single- and multiple-dose pharmacokinetics of the peripheral non-narcotic antitussive moguisteine in healthy Chinese volunteers
2019, European Journal of Pharmaceutical SciencesCitation Excerpt :Antitussive drugs can relieve cough and reduce risk of complications or worsening of the underlying disease. However, the majority of antitussive drugs were developed more than 30 years ago, with little development since then (Birring, 2009). Most currently available antitussives show limited efficacy, intolerable side effects or both (Chung, 2008).
Advances in mechanisms and management of chronic cough: The Ninth London International Cough Symposium 2016
2017, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :An important role for specialist cough centres is in educating and training primary and secondary care in the management of chronic cough. There has been progress in the management of chronic cough with the establishment of non-pharmacologic and pharmacologic treatments made possible by use of validated tools to measure cough severity and counts and by establishing clinical trials in chronic cough using these tools [60–63]. One aspect of management that has received particular attention is the use of physiotherapy, speech and language therapy intervention.
How best to measure cough clinically
2015, Current Opinion in PharmacologyCitation Excerpt :The limitations of cough challenge tests are that they cannot be used as diagnostic tests because they do not discriminate healthy subjects from patients with cough. Additionally they cannot be used to measure the severity of cough as they do not reflect symptom burden [35]. Recently, a capsaicin challenge test that involves measuring the Emax, which is the maximum cough response evoked by any concentration of capsaicin, has been reported to discriminate healthy subjects from those with cough better than the standard methodology [36•].
Cough suppression therapy: Does it work?
2013, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :It causes significant psychological and physical morbidity: chest pain, vomiting, headaches, lethargy, social embarrassment, low mood and sleep disturbance are frequent adverse consequences of persistent cough [2-4]. Few effective pharmacological antittussive therapies are available to patients [5,6]. Voluntary suppression of cough may be used as part of a self-help management programme for patients with chronic cough to minimise the impact of excessive or intense coughing.
The difficult-to-treat, therapy-resistant cough: Why are current cough treatments not working and what can we do?
2013, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :This significant gap needs to be filled with new models that more accurately reflect human disease. The features of an ideal clinical trial have been detailed in the excellent review by Birring [43]. The key factors outlined in his article were patient selection, trial design, the use of appropriate study endpoints and the selection of an appropriate placebo.