Rococo study: a real-world evaluationof an over-the-counter medicine in acutecough (a multicentre, randomised,controlled study)

S S Birring,1 J Brew,2 A Kilbourn,2 V Edwards,2 R Wilson,3 A H Morice4

To cite: Birring SS, Brew J,Kilbourn A, et al. Rococostudy: a real-world evaluationof an over-the-countermedicine in acute cough (amulticentre, randomised,controlled study). BMJ Open2017;7:e014112.doi:10.1136/bmjopen-2016-014112

▸ Prepublication history andadditional material isavailable. To view please visitthe journal (http://dx.doi.org/10.1136/bmjopen-2016-014112).

Received 31 August 2016Revised 17 November 2016Accepted 24 November 2016

1Division of Asthma, Allergyand Lung Biology, King’sCollege London, London, UK2Infirst Healthcare Ltd,London, UK3Spica Consultants Ltd,Marlborough, UK4Hull York Medical School,Castle Hill Hospital,East Yorkshire, UK

Correspondence toDr SS Birring;surinder.birring@nhs.net

ABSTRACTObjectives: To investigate the efficacy and safety ofCS1002, an over-the-counter cough treatmentcontaining diphenhydramine, ammonium chloride andlevomenthol in a cocoa-based demulcent.Design: A multicentre, randomised, parallel group,controlled, single-blinded study in participants withacute upper respiratory tract infection-associated cough.Setting: 4 general practitioner (GP) surgeries and 14pharmacies in the UK.Participants: Participants aged ≥18 years who self-referred to a GP or pharmacist with acute cough of<7 days’ duration. Participant inclusion criterion wascough severity ≥60 mm on a 0–100 mm visualanalogue scale (VAS). Exclusion criteria includedcurrent smokers or history of smoking within the past12 months (including e-cigarettes). 163 participantswere randomised to the study (mean participant age38 years, 57% females).Interventions: Participants were randomised toCS1002 (Unicough) or simple linctus (SL), a widelyused cough treatment, and treatment duration was7 days or until resolution of cough.Main outcome measures: The primary analysis wasintention-to-treat (157 participants) and comprisedcough severity assessed using a VAS after 3 days’treatment (prespecified primary end point at day 4).Cough frequency, sleep disruption, health status(Leicester Cough Questionnaire (LCQ-acute)) and coughresolution were also assessed.Results: At day 4 (primary end point), the adjustedmean difference (95% CI) in cough severity VASbetween CS1002 and SL was −5.9 mm (−14.4 to 2.7),p=0.18. At the end of the study (day 7) the meandifference in cough severity VAS was −4.2 mm (−12.2to 3.9), p=0.31. CS1002 was associated with a greaterreduction in cough sleep disruption (mean difference−11.6 mm (−20.6 to 2.7), p=0.01) and coughfrequency (mean difference −8.1 mm (−16.2 to 0.1),p=0.05) compared with SL. There was greaterimprovement in LCQ-acute quality of life scores withCS1002 compared with SL: mean difference (95% CI)1.2 (0.05 to 2.36), p=0.04 after 5 days’ treatment. Moreparticipants prematurely stopped treatment due tocough improvement in the CS1002 group (24.4%)compared with SL (10.7%; p=0.02). Adverse events

(AEs) were comparable between CS1002 (20.5%) andSL (27.6%) and largely related to the study indication. 6participants (7%) in the CS1002 group reduced thedose of medication due to drowsiness/tiredness, whichsubsequently resolved. These events were not reportedby participants as AEs.Conclusions: Although the primary end point was notachieved, CS1002 was associated with greaterreductions in cough frequency, sleep disruption andimproved health status compared with SL.Trial registration number: EudraCT number2014-004255-31.

INTRODUCTIONApproximately one in five people in the UKsuffer an acute cough over the winter1 and it

Strengths and limitations of this study

▪ A recent Cochrane systematic review of coughmedicines found no good evidence for or againstthe effectiveness of over-the-counter medicationsin acute cough.

▪ This is one of the largest multiple dosing, multi-centre, randomised, controlled trials in partici-pants with cough to date, and the first to recruitparticipants seeking cough medicines at pharma-cies and is therefore more likely to represent thebroader population with acute cough due toupper respiratory tract infection.

▪ Participants were unselected for the category ofcough, and included a broad range of partici-pants with self-reported dry, chesty and ticklycough.

▪ The study was single-blinded because an activecontrol, simple linctus, was used as the com-parator but it is possible that there may havebeen greater differences in efficacy outcomemeasures if an inactive placebo had been used.

▪ Our findings highlight the challenges of evaluat-ing cough medicines in a rapidly improving con-dition and will facilitate the design of futurestudies of acute cough.

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is one of the most common reasons for consulting ageneral practitioner (GP), at a cost to the NationalHealth Service (NHS) of ∼£2 billion per year.2–4

Although most acute coughs improve spontaneously,many patients use over-the-counter (OTC) medicines. In2014, £98.7 million was spent in the UK on OTC coughtreatments.5 OTC cough medicines include antitussives,expectorants, mucolytics, antihistamines, decongestantsand numerous drug combinations.6 There is a lack ofdata supporting the efficacy of OTC medicines in thetreatment of acute cough associated with upper respira-tory tract infection (URTI). In 2012, a Cochrane system-atic review concluded there was no strong evidence foror against their effectiveness.6 Methodological flaws inclinical trial design, paucity of placebo-controlled trials,use of unvalidated outcome measures and inefficacy ofmedicines were some of the reasons for the poor evi-dence base.CS1002 is an OTC cough medicine that contains

three active ingredients: diphenhydramine, levomentholand ammonium chloride in a cocoa-based demulcentpreparation. Diphenhydramine is an antihistamine thathas been reported to reduce the heightened coughreflex sensitivity in participants with cough associatedwith an URTI.7 Menthol and eucalyptus have beenused for many centuries for treating coughs andcolds.8 Menthol is obtained from mint oils, mainlypeppermint, or made synthetically from coal tar. It hasa pungent odour that provides a cooling and soothingeffect in the mouth and throat and is often used torelieve congestion.8 Menthol has also been reported toinhibit cough reflex sensitivity compared with placebo.9

Ammonium chloride is an acid-forming salt that isthought to exert an expectorant effect by looseningsputum.10 The effectiveness and mode of action ofammonium chloride remains controversial.10 Thecocoa-based demulcent preparation used in CS1002 ismore viscous than most available OTC cough medi-cines. Demulcents are thought to reduce cough andcold symptoms because of a soothing effect on themucus membrane.11 The aim of this study was to inves-tigate the efficacy of CS1002, an OTC cough medicinefor cough associated with URTI, in a randomised con-trolled trial.

METHODSStudy designThis multicentre, randomised, parallel group, con-trolled, single-blinded study was conducted in 4 GP sur-geries and 14 pharmacies in the UK between 30December 2014 and 9 May 2015. The control was awidely used simple linctus (SL) medicine available foracute cough in the UK. The investigators were blindedto the nature of the investigational product by usingidentical sealed packaging for both medicines.Participants self-administered their assigned medicationoutside the pharmacy or GP surgery.

ParticipantsParticipants aged ≥18 years who self-referred themselvesto a GP or pharmacist with an acute cough of <7 days’duration were recruited. Participant inclusion criterionwas a severity of at least 60 mm on a 0–100 mm visualanalogue scale (VAS). Participant exclusion criteria were(1) participants with a chronic cough, (2) current orhistory of smoking within the past 12 months (includinge-cigarettes), (3) participants with any relevant hospitalstay of >2 days within a 6-month period, (4) use of anycough or cold treatment for the current cough episode,including antibiotics, (5) productive cough with exces-sive secretion, (6) use of ACE inhibitors medication.

Participant involvementParticipants were not involved in the design or conductof this study.

Ethics and trial registrationThe trial protocol was registered prior to starting thestudy in the publically available EudraCT database (ref-erence: 2014-004255-31) and no protocol amendmentswere made subsequently. All participants providedwritten informed consent.

RandomisationAll participants considered eligible for study participa-tion and who signed a consent form were given aunique randomisation number based on a predefinedcomputer-generated randomisation scheme correspond-ing to a sealed medication pack that contained eitherCS1002 (2×150 mL) or SL (2×150 mL). Participantswere allocated treatment using a block randomisationwith a block size of 4.

Study medicationParticipants were randomised to one of the followingtreatments:▸ CS1002 (Unicough): diphenhydramine 14 mg/5 mL,

levomenthol 1.1 mg/5 mL and ammonium chloride135 mg/5 mL in a cocoa-based demulcentpreparation.

▸ SL: citric acid monohydrate 125 mg/5 mL in a syrupbase.

InterventionsThe participants were approached, screened, consentedand randomised during their initial consultation withtheir GP or the pharmacist. Participants took their studymedication orally four times daily (5 mL in the morning,5 mL at lunchtime, 10 mL at teatime and 10 mL atbedtime) for up to 7 days. Participants were instructed totake the medication regularly until the cough resolved.

Methods of evaluationParticipants completed their assessments and compli-ance with medication in a daily diary. Each participantreceived a tamper-evident unidentifiable patient pack

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which was only opened on leaving the site. On comple-tion, the pack was returned in a resealed and unidentifi-able state. An independent data managementorganisation was used for data entry and to manageadverse event (AE) reporting. The investigators wereblinded to the assignment of treatment and to theoutcome assessments. The schedule of study visits is pre-sented in figure 1. The participants were asked to com-plete assessments at baseline (day 1) and then at thesame time of day from day 2–8. The study evaluated theefficacy of the study medications by assessing variousaspects of acute cough.12 Cough severity, frequency andimpact on sleep disruption in the previous 24 hourswere assessed using a VAS. Health-related quality of life(HRQoL) was assessed using the Leicester CoughQuestionnaire for acute cough (LCQ-acute).3 13 TheLCQ is a valid and reliable health status measure ofacute cough in adults and is responsive to change. Itcomprises 19 items divided into three domains (phys-ical, psychological and social) and uses a seven-pointLikert response scale. A higher score indicates a betterhealth status. The LCQ is designed for self-administration and takes <5 min to complete.3 14

Primary efficacy end pointThe primary efficacy end point was change from base-line to day 4 (ie, after 3 complete days of treatment) incough severity on a 100 mm VAS (ranging from 0=nocough to 100=worst cough ever).

Secondary efficacy end pointsThe following prespecified end points were evaluated:(1) change from baseline in cough severity VAS at days 6and 8; (2) change from baseline in cough frequencyand cough sleep disruption VAS at days 4, 6 and 8; (3)time to resolution of cough symptoms, defined as theday at which cough severity VAS<17 mm (the threshold

considered to be of minimal severity and the minimallyimportant difference (MID) in acute cough);12 (4)change from baseline in LCQ-acute score at days 4, 6and 8.

Safety monitoringParticipants were advised to reduce the dose of medica-tion if they experienced drowsiness, and to documentthis in their daily diary. If drowsiness persisted, they wereadvised to discontinue the medication. Participants wereadvised to contact their doctor or a 24-hour help line ifthey felt unwell. Safety was assessed in terms of the fre-quency and severity of AEs occurring during the studyand this was recorded by the investigator.

Statistical analysis and sample sizeThe sample size calculation was based on a difference inthe change in cough severity VAS of 17 mm between par-ticipants treated with CS1002 and SL. Evaluation of theVAS in acute cough has suggested that the MID is17 mm.12 It was estimated that ∼180 participants wouldbe required to achieve a power of 90% to detect a differ-ence between the treatment groups of 17 mm, with anSD of 35 mm.12

The primary analysis was conducted on theintention-to-treat (ITT) population, comprising all ran-domised participants who were treated with at least onedose of study medication and provided a baseline and atleast one on-treatment assessment of cough severity. Noimputation was used for missing data (ie, only observeddata were used). A mixed model for repeated measuresanalysis was used to compare the effect of study treat-ments on cough parameters from baseline. The modelincluded effects for treatment group, day, pooled centre,baseline cough severity, and treatment-by-day andbaseline-by-day cough severity interaction terms.Residual plots and a normality test were used to assess

Figure 1 Study design. GP, general practitioner; LCQ-acute, Leicester Cough Questionnaire; VAS, visual analogue scale.

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normality. The results were also repeated for the per-protocol set (PPS), defined as participants in the ITTpopulation who did not have an important protocol vio-lation. A sensitivity analysis was also conducted to assessthe robustness of the primary efficacy results to themethod of handling missing data, using a last observa-tion carried forward approach and a baseline observa-tion carried forward approach for participants with noon-treatment data. Parametric data were presented asmean and either SD, SEM or 95% CIs. Statistical signifi-cance was defined as p≤0.05. The proportions of partici-pants with cough resolution were compared using astratified (by centre) Cochran-Mantel-Haenszel test.Time-to-event analysis using a Cox proportional hazardsmodel stratified by centre was used to estimate a HR.

RESULTSParticipantsA total of 163 participants were randomised into thestudy at 4 GP sites and 14 pharmacy sites. The reasonsfor screening failures are shown in figure 2. The ITTpopulation comprised 157 participants (82 CS1002, 75SL), and the PPS comprised 142 participants (75CS1002, 67 SL; figure 2). The baseline characteristics ofboth treatment groups were well matched (table 1). Themean age of the participants was 38 years, 57% of parti-cipants were female and 62% of participants were white(34% Asian and 4% black). The groups were wellmatched for the proportion of participants describingthe characteristics of their cough as dry (CS1002 50%;SL 52%), chesty (CS1002 29%; SL 31%) or tickly(CS1002 21%; SL 17%).

Figure 2 Trial CONSORT flow diagram. VAS, visual analogue scale.

Table 1 Participant demographic and baseline

characteristics

CS1002n (%)N=82

Simple linctusn (%)N=75

Gender (N (%))

Male 34 (42) 34 (45)

Female 48 (59) 41 (55)

Age (years)

Mean (SD) 38.5 (17.3) 38.2 (16.6)

Median (range) 31.5 (18, 75) 34.0 (18, 86)

Type of referral (N (%))

GP 30 (37) 27 (36)

Pharmacist 52 (63) 48 (64)

Smoking status (N (%))

Never smoked 64 (78) 54 (72)

Ex-smoker 18 (22) 21 (28)

Cough characteristics, mean (SD)

Cough duration (days) 3.0 (1.5) 3.1 (1.6)

Cough severity

VAS (mm)

80.4 (10.1) 81.6 (9.9)

Cough frequency

VAS (mm)

79.5 (16.1) 76.7 (15.5)

Cough sleep disruption

VAS (mm)

75.5 (23.2) 64.6 (29.2)

LCQ-acute scores, mean (SD)

Total score 10.8 (3.5) 11.4 (3.2)

Physical score 3.7 (1.2) 4.1 (1.1)

Psychological score 3.7 (1.2) 3.9 (1.1)

Social score 3.4 (1.4) 3.5 (1.3)

Based on ITT population.GP, general practitioner; ITT, intention-to-treat; LCQ, LeicesterCough Questionnaire; VAS, visual analogue scale (using a scaleof 0–100 mm).

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ExposureParticipants took CS1002 medication for a mean (SD) of6.2 (2.1) days and SL medication for 6.6 (1.8) days. Themean number of doses of study medication were 22.2(8.7) for the CS1002 group and 23.7 (8.3) in the SLgroup. The maximum number of medication doses pos-sible during the study was 28. The weight of the bottlesof treatment returned at the end of study was plannedto be used to estimate compliance, excluding doses nottaken due to early termination from the study due torecovery. The weight of medicine broadly agreed withself-reported consumption stated by participants receiv-ing CS1002, with a mean (SD) of 94% (17%) vs 94%(18%) for participants receiving SL.

Primary efficacy end pointThere was a clinically meaningful improvement incough severity VAS at day 4 in both groups (table 2 andfigure 3). The magnitude of the reduction in coughseverity score was greater in the CS1002 group comparedwith the SL group but was not statistically significant;mean (95% CI) difference of −5.9 mm (−14.4 to 2.7),p=0.18. The PPS and ITT sensitivity analyses with impu-tations were also consistent with this finding (see onlinesupplementary file).

Secondary efficacy end pointsCough severity: There was a progressive decrease in coughseverity VAS over the study, with the CS1002 group report-ing a greater reduction compared with the SL groupbetween days 3 and 7 (figure 3). The between groupchanges in cough severity VAS did not achieve statistical

significance (mean (95% CI) difference of −4.2 mm(−12.2 to 3.9), p=0.31 at day 7; table 2 and figure 3).Cough frequency: There was a greater reduction in cough

frequency VAS with CS1002 compared with SL at all timepoints (figure 4). At Day 4, there was an −8.1 mm (95%CI −16.2 to 0.1) greater reduction in cough frequencyVAS for CS1002 compared with SL (p=0.05; table 2 andfigure 4).Cough resolution: By day 4, 29.3% of participants in the

CS1002 group had achieved cough resolution comparedwith 17.3% in the SL group (p=0.08; table 2). There wasno significant difference between the treatment groupsregarding median time taken to achieve cough reso-lution (CS1002 6.5 days, SL 7.0 days, HR 1.300, p=0.20,figure 5). In a post hoc analysis, 20 participants (24.4%)

Figure 3 Change in cough severity over time.

ITT, intention-to-treat.

Table 2 Analysis of key efficacy parameters at day 4

Key efficacy assessments CS1002 Simple linctus

Number of participants 82 75

Cough severity

Baseline value (mean±SD) 80.4 (10.1) 81.6 (9.9)

Change from baseline to day 4: mean ( 95% CI) −38.9 (−45.2 to −33.2) −32.8 (−39.6 to −27.0)Adjusted mean difference (95% CI) −5.9 (−14.4 to 2.7)

p Value (between groups) p=0.18Cough frequency

Baseline value (mean±SD) 79.5 (16.1) 76.7 (15.5)

Change from baseline to day 4: mean ( 95% CI) −40.7 (−46.0 to −34.6) −32.1 (−38.1 to −26.4)Adjusted mean difference (95% CI) −8.1 (−16.2 to 0.1)

p Value (between groups) p=0.05Cough resolution

Day 4 value (n, %) 24 (29.3%) 13 (17.3)

Difference (%) 12%

p Value (between groups) p=0.08Sleep disruption

Baseline value (mean±SD) 75.5 (23.2) 64.6 (29.2)

Change from baseline to day 4; mean ( 95% CI) −42.8 (−46.9 to −34.4) −26.3 (−35.5 to −22.6)Adjusted mean difference (95% CI) −11.6 (−20.6 to −2.7)p Value (between groups) p=0.01

Based on intention-to-treat (ITT) population.Negative values indicate a reduction in cough symptoms.Adjusted mean difference, difference in between group differences.Cough severity, frequency and sleep disruption measured on a visual analogue scale (0-100 mm) Bold signifies p values.

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in the CS1002 group and 10 (10.7%) in SL groupstopped treatment by day 4 due to improvement incough (p=0.02).Sleep disruption: There was a greater reduction in sleep

disruption with CS1002 compared with SL at all timepoints (figure 6). At day 4, the magnitude of reductionin cough sleep disruption score was greater for theCS1002 group than for the SL group, mean differenceof −11.6 mm (95% CI −20.6 to −2.7), p=0.01 (figure 6and table 2). A summary of all VAS results is provided inonline supplementary figure S1.Health-related quality of life: LCQ-acute total scores

increased over time for both treatment groups, indicat-ing an improvement in HRQoL. At day 6, the magnitudeof the improvement was significantly greater in theCS1002 group compared with the SL group (mean dif-ference 1.21 (95% CI 0.05 to 2.36), p=0.04; see onlinesupplementary figures S2 and S3).

Adverse eventsAEs were reported for 17 participants (20.5%) in theCS1002 group and 21 participants (27.6%) in the SLgroup during the study (table 3). The AEs were gener-ally indicative of the study indication or likely to be asso-ciated with URTI, with the majority being mild ormoderate severity. Events classified as severe were onlyseen in the SL treatment group, and comprised cough,sneezing and joint swelling (all occurring in one partici-pant each). No SAEs or deaths were reported. Therewere no AEs of drowsiness reported during the study. Sixparticipants (7%) in the CS1002 group and no partici-pants in the SL group reported in their diary that theyreduced the dose of medication due to drowsiness/tired-ness. These events were not reported by the participantsas AE. Following the reduction of the dose of medica-tion, there were no further reports of drowsiness ortiredness.

Figure 4 Change in cough frequency over time. ITT,

intention-to-treat; MMRM, mixed model for repeated

measures.

Figure 5 Resolution of cough: cumulative percentage of participants. ITT, intention-to-treat; VAS, visual analogue scale.

Figure 6 Change in cough sleep disruption over time. ITT,

intention-to-treat; MMRM, mixed model for repeated

measures.

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DISCUSSIONThis multicentre, randomised study compared the effi-cacy and safety of two OTC cough mixtures: CS1002 con-taining diphenhydramine, ammonium chloride andlevomenthol in a cocoa-based demulcent preparationversus SL containing citric acid monohydrate. This isone of the largest multiple dosing, randomised con-trolled trials in participants with URTI-associated coughto date, and the first to recruit participants seekingcough medicines at pharmacies. The study did notachieve a significant reduction in primary end pointcough severity after 3 days of treatment, but there weregreater reductions in cough frequency and sleep disrup-tion and resolution of cough in participants receivingCS1002 compared with SL.Our trial represents a significant advance in the study

of URTI-associated cough for a number of reasons. ACochrane systematic review of cough medicines con-cluded that there was no evidence for or against coughmedicines for URTI-associated cough.6 Previous trials ofcough medicines have been hampered by the recruit-ment of small numbers of participants, the recruitmentof participants not representative of URTI-associatedcough, uncontrolled study design and the use of unval-idated end points. We conducted a randomised clinicaltrial that included validated cough outcome measures.Our primary outcome measure, the VAS, is widely usedin studies of cough.15 We recruited participants with anURTI-associated cough who were otherwise healthy and

seeking an antitussive medicine. Our participants wereunselected for the category of cough, and included abroad range of participants with self-reported dry,chesty and tickly cough. We conducted a large study,recruiting participants from 18 sites. This is the firststudy to recruit participants presenting to pharmacies,and therefore the study population is more likely toresemble the broader population seeking cough medi-cines. There were few participants that dropped out ofthe trial, and therefore our data completeness wasgood. The efficacy of the interventions was evaluatedwith widely used and validated end points of coughseverity VAS and LCQ-acute HRQoL questionnaires.15 16

We conducted a controlled trial and the comparatorwas a widely used OTC treatment. SL, which costs lessthan many OTC medicines to purchase but like mostcough medicines, it lacks a strong evidence base. Itsefficacy has not been compared with natural recovery,placebo or to other cough medicines. The rate ofreduction of cough severity VAS associated with SL inour study does appear to be greater than that reportedfor natural recovery.12 The mechanism of action of SLis poorly understood, but is thought to be related to ademulcent effect and the hypersalivation resulting fromthe sugary taste.11

There was a clinically significant reduction in primaryend point cough severity VAS at day 4 in both groups.However, CS1002 did not achieve the primary end pointof a greater reduction in cough severity at day 4 com-pared with SL. There were, however, greater reductionsin secondary end points of sleep disruption and coughfrequency, and improvements in HRQoL associated withCS1002 compared with SL. There was also a trendfavouring greater resolution of cough at day 4 withCS1002 compared with SL, with a near doubling of theproportion of participants whose cough had resolved.This was supported by a post hoc analysis that found asignificantly greater number of participants had discon-tinued their medication due to resolution of cough byday 4 (CS1002, 24.4% vs SL, 10.7%: p=0.02). The MIDfor cough outcome measures of frequency VAS, sleepdisruption VAS and cough resolution have not beenreported in URTI-associated cough, and this should bestudied in future to facilitate the clinical interpretationof data. CS1002 was well tolerated, and there were fewsignificant AEs, including drowsiness. Drowsiness wasmanaged with dose reduction, and no participants dis-continued the medication because of this symptom.Participants were compliant with both medications, andthis was verified by counting the doses of medicationreturned at the end of the study. The mechanism ofaction of CS1002 is poorly understood. There are anumber of possibilities, which include a reduction incough reflex sensitivity,7 promotion of more restful sleepand a demulcent action. CS1002 contains a cocoa-flavoured demulcent that is more viscous than mostavailable OTC cough medicines, and this may potentiallypromote palatability.

Table 3 Adverse events (AEs)

CS1002N=83

Simple linctusN=79

AEs, n (%)TotalN (%)

TotalN (%)

Number of participants with

an AE

17 (20.5) 21 (27.6)

Nervous system disorders 7 (8.4) 10 (13.2)

Headache 5 (6.0) 9 (11.8)

Dizziness 1 (1.2) 2 (2.6)

Respiratory, thoracic and

mediastinal disorders

8 (9.6) 9 (11.8)

Oropharyngeal pain 2 (2.4) 4 (5.3)

Cough 2 (2.4) 3 (3.9)

Productive cough 3 (3.6) 1 (1.3)

Dyspnoea 0 (0.0) 2 (2.6)

Gastrointestinal disorders 5 (6.0) 2 (2.6)

Diarrhoea 3 (3.6) 0 (0.0)

Abdominal pain upper 2 (2.4) 0 (0.0)

General disorders and

administration site conditions

0 (0.0) 5 (6.6)

Pain 0 (0.0) 3 (3.9)

Fever 0 (0.0) 2 (2.6)

Infections and infestations 1 (1.2) 2 (2.6)

Lower respiratory tract

infection

0 (0.0) 2 (2.6)

Treated set population. AEs reported for >1 participant.

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There are a number of important limitations with ourstudy. We did not use a placebo comparator, and thestudy was not double-blinded. The limitations of a single-blinded study were reduced by informing the partici-pants that they were going to receive a cough medicine,but not the characteristics of the medicine. The investi-gators were blinded to the study because both medicineswere contained in identical packaging, and participantswere instructed to start their medication outside thepharmacy or GP clinic. We used SL as the comparatorsince this is a widely used cough treatment. It is possiblethat there may have been greater differences in efficacyoutcome measures if we had used an inactive placebo.Another option for comparator that should be consid-ered in future studies is the demulcent used in CS1002.It is likely that there was also significant natural recoveryin our study. Our data highlight the difficulty in evaluat-ing cough medicines in a rapidly resolving condition.We do not know whether the cough at study entry wasworsening or improving and this could have impactedon our findings. We were short of our recruitmenttarget of 180 participants; we recruited 163 participants.This was due to a delay in the start of the study, and con-sequently a reduced time window for recruitmentduring the cough and cold winter season. We think it isunlikely that the slight under-recruitment of participantswould have altered our study conclusions. The reasonsfor screen failures were not recorded for many patients,particularly at busy pharmacy sites. The reasons were,however, recorded for 2238 participants and suggest thata large number of participants approached had durationof cough >7 days. It is possible that the discontinuationof medication could have reflected lack of efficacy aswell as recovery. We did not investigate the cause of theacute cough, and future studies should possibly assessviruses, pertussis and bacterial causes. We did not assesscough with objective outcome measures, such as coughfrequency monitoring.16 Recently, there have been sig-nificant advances in cough monitoring technology, andthis should be possible in future studies.17

In conclusion, the OTC cough medicine CS1002 didnot achieve a significant reduction in the primary endpoint cough severity, but it was associated with a greaterreduction in cough frequency and sleep disruption, andincreased resolution of cough leading to early discon-tinuation of medication and improved HRQoL com-pared with comparator SL. Further studies shouldinvestigate the impact of natural recovery and placeboon cough outcome measures to facilitate the optimalstudy protocol in URTI-associated cough.

Acknowledgements The authors would like to acknowledge all the doctorsand pharmacists who recruited participants for this study: Dr Mark Blagden,Ashgate Medical Practice, Chesterfield; Dr Naseem Gill, CH Medical, Oldham;Dr Paula Evans, Acomb Surgery, York; Dr Mark Roman, Woodthorpe Surgery,York; Dr Astrid Henckel, Monkgate Surgery, York; Maimuna Sultana, PeakPharmacy, Manchester; Amanda Gilchrist, Peak Pharmacy, Cheadle; DeborahKelly, Tims and Parker, Manchester; Jonathan Hill, Peak Pharmacy,Manchester; Anthony Parker, Tims and Parker, Manchester; Rahbeia Najeeb,

Peak Pharmacy, Manchester; Johanne Nesbit, Davey’s Pharmacy, Liverpool;Manjeet Patter, Jhoots Pharmacy, Darlaston; Keval Jagatiya, Jhoots Pharmacy,Dudley; Rumeesha Damaree, Jhoots Pharmacy, Rowley Regis; RashimiSharma, Jhoots Pharmacy, Wolverhampton; David Meddings, JhootsPharmacy, Rowley Regis; David Bott, Jhoots Pharmacy, Cradley Heath; AasmaAhmed, Jhoots Pharmacy, Birmingham; Fezza Hassan, Jhoots Pharmacy,Birmingham; Kiranjit Sidhu, Jhoots Pharmacy, Birmingham; Indira Panchal,Meiklejohn Pharmacy, Bedford; Mohammed Fahim, Wexham Road Pharmacy,Slough; Zahoor Sharif, Oxford Road Pharmacy, Reading. Medical writingsupport was provided by Debbie Jordan, with funding provided by InfirstHealthcare. Medical safety monitoring was conducted by Dr Sunita Chauhan,Pharsafer.

Contributors SB, JB, AK, VE, RW and AM were involved in conception anddesign of work. RW, VE and JB were involved in data analysis. All authorswere involved in data interpretation. SB was involved in drafting themanuscript with input from JB, AK, VE, RW and AM. All authors wereinvolved in review and approval of the manuscript.

Funding The study was funded by Infirst Healthcare and Infirst Healthcare isthe manufacturer of CS1002 (Unicough).

Competing interests SSB has received personal fees from Infirst Healthcareduring the conduct of the study for advisory work. AHM has receivedpersonal fees from Infirst Healthcare during the conduct of the study foradvisory work. JB, VE and TK are employees of Infirst Healthcare. RW is astatistical consultant to Infirst Healthcare.

Ethics approval North West—Greater Manchester South Research EthicsCommittee (Reference: 14/NW/1424).

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement No additional data are available.

Open Access This is an Open Access article distributed in accordance withthe Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, providedthe original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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