ESTD 1947
Original Article
Efficacy, Safety and Tolerability ofPholcodeine and Promethazine Cough Formulation in Children suffering from Dry Cough: An Open, Prospective, Comparative, Multi-centre, Randomized, Controlled, Parallel group, Three-arm study Tripathi R K, • Langade D G, •• On behalf of the Tixylix Study Group for the trial
ABSTRACT
Objective: Compare and confirm the non-inferiotity of pholcodeine plus promethazine (CS1) versus dextromethorphan plus chlorpheniramine (CS-2). and codeine plus chlorpheniramine (CS-3) in terms of efficacy, safety and tolerability for treatment of dry cough in paediatric population. Design: Open, prospective. comparative, multi-centre, randomized, controlled, parallel group, three-arm post-marketing study. Setting: The study was conducted at the paediatric and respiratory clinics and institutions at 26 centres across India. Patients: 418 children between 2 - 12 years of age, attending the outpatient departments and suffeting from dry cough associated with viral upper respiratory infections (URI) were included, of which 44 patients dropped out due to loss to follow-up. 2 patients excluded due to protocol violation, and 372 patients completed the study. Interventions: Patients were randomized to receive cough formulations CS-1 (132). CS-2 (131). or CS-3 (109) administered orally for a maximum petiod of 7 days. Dose of the cough formulation was as per the requirements of age. Main Outcome Measures: Reduction of cough frequency, proportion of patients with persistent cough at the end of 7 days. and time to symptom relief for cough. The safety and tolerability of formulations was also assessed. Results: An intention-to-treat analysis showed that CS-1 was comparable to both CS-2 (mean difference 0.50) and CS-3 (mean difference 0.41) for reduction in cough frequency on day7 (p >0.05). Also, CS-1 was comparable to CS-2 (HR 1.02, 95% C.!. 0.78-1.32) and CS-3 (HR 1.03, 95% C. I. 0.79- 1:35) for. number of patients having cough upto day 7. Three formulations were comparable for global well-being and safety. · Conclusion: Cough formulation. containing promethazine and pholcodeine (CS-1) was nonInferior to CS-2 and CS•3 and also demonstrated a favourable tolerability profile. (I'he Ind. Pract. 2009;62(5):281-289) Departilwnt ofPharma.colngy, • Seth G.S. Medica! College, Pare!, MWl1baL ••Grant Medical College, MumbaL Correspondence to: Dr. Rakhi 1lipathi, Asso. Professor in Phamiacolngy, Seth G.S.Medical College, Pare!, MumbaL E-mail:
[email protected] · May 2009 0 Vol. 62 No. 5
The Indian llracttttoner 0
281
INTRODUCTION
The commonest cause of upper respiratory tract symptoms in children is probably viral infection. On average, children have four to eight attacks of viral upper respiratory infection (URI) each year.' Cough suppressants are used for effective symptomatic relief of dry cough. First generation anti-histaminics, centrally acting opioid derivatives and anticholinergic drugs are often used alone or in combination. 2 Anti-histaminics (diphenhydramine, chlorpheniramine, promethazine) reduce .the cholinergic transmission of nerve impulses in the cough reflex, and hence reduce the frequency of cough, dry up the secretions, and making them ideal. for treating cough concomitant with rhinorrhoea. 3 Sedation caused by these is valuable, particularly if the . cough is disturbing the sleep.• Centrally acting cough suppressants (codeine, pholcodiene and dextromethorphan) act directly on the cough centre in the brain and reduce the discharge of nerve impulses to the muscles that cause coughing. 5 Opioids cause sedation and constipation, although pholcodeine and dextromethorphan are reported to produce fewer side-effects than codeine and are also known to have a lower abuse potential. A plethora of cough mixtures are available in India containing an anti-histaminic and opioid derivative with claims of increased efficacy. Although there is extensive experiential data on these cough mixtures, classical clinical trial reports are lacking to back their widespread use, particularly in the pediatric population. A clinical trial was therefore conducted to compare the efficacy, safety and tolerability of a marketed cough formulation containing pholcodeine and promethazine (CS-1), · with formulations containing dextromethorphan plus chlorpheniramine (CS-2), and codeine plus chlorpheniramine (CS-3) in treatment of dry cough in pediatric population. METHODS
Design an open, This was comparative, multi-center, 282
0 The Indian Practitioner
prospective, randomtzed,
controlled, parallel group, three"arm, postmarketing study with a non-inferiority design comparing the effects of CS-1 versus CS-2 and CS-3 in paediatric patients suffering from dry cough. The study was conducted in keeping with the principles descrtbed in .the Declaration of Helsinki and the Indian GCP guidelines at 26 paediatric and respiratory clinics and institutions across India. The study protocol and the sites were approved by the Independent Ethics Committee. 6
Patients Children of either sex between 2 and 12 years age with dry cough associated with viral URI attending paediatric outpatients departments of participating centres were screened for Inclusion in the study, and prtor to screening, a written informed consent/assent was taken from the parents/children. Children complaining of any one of the features: moderate/ high fever, throat congestion, coryza. or viral bronchitis; with no requirement of bronchodilators, expectorants or antibiotics were included in the study. Those with suspicion of any kind of allergic problems, multi-organ requiring hospitalization, involvement, septicaemia, severe cardiac, hepatic and renal diseases were excluded. Also, · children with Grade Ill and IV malnutrition, congenital disorders and immunodeficiency syndromes were also excluded. Children already receiving antitusslves, opioids, anti-histaminics, steroids, bronchodilators, tricyclic antidepressants and any nasal drops during prtor one week and with known hypersensitivity to any of the constituents of the study formulations were excluded. Children were withdrawn from the trial if there was no clinical improvement by the third day. Routine medical care. was made available to all these children.
Procedures The baseline clinical evaluation included demographics and vital parameters. Cough frequency was recorded as number of bouts per day. The nutnber of times the child woke up during the night due to cough was also May .2009 D Vol. 62 No. 5
noted. Playing activities were recorded on a 0-10 Visual Analogue Scale (VAS) where '0' was normal playing activities and '1 o· corresponded to no playing activilles; behaviour recorded on 0-10 VAS where ·o· was normal behaviour and 'l 0' corresponded to severely imitable child; appetite was recorded on 0-10 VAS where '0' was equivalent to normal appetite and '10' corresponded to complete loss of appeiite; and. the global assessment of wellbeing of the child evaluated on a 0-10 VAS where ·o· corresponded to the child feeling well and '1 0' corresponded to feeling most unwell. All VAS evaluations were recorded daily from day 0 to day 7 by the parent In a patient diary and the use of diary was explained to the parent at recruitment. Parents also recorded times the ch!ld woke up In the night due to cough cough frequency and the number of In the diary.
pholcodeine (1.5 mg/5 ml) plus promethazine (1.5 mg/5 ml). 2) CS-2 dextromethorphan (10 mg/5 mil plus chlorpheniramine (4 mg/5 ml), or 3) CS-3 codeine phosphate (I 0 mg/5 ml) plus chlorpheniram!ne maleate (4 mg/5 ml).
The child was called for re-evaluation on days 3 (± 1 day) and day 7 (± 1 day). The time taken for complete" cough relief and the number of times the parent of the patient contacted the Investigator due to deterioration th respiratory symptoms was noted.
Clinical Endpoints The efficacy endpoint was the time to relief (reduction In the frequency of cough episodes and nocturnal awakenings by > 75% from baseline, and > 75% Improvement In playing activities, behavior, appetite, and global well being Withh'l a period of 7 days as compared With the baseline). The total doses required for complete relief was calculated. Global wellbeing assessed on a 0 to 10 scale where ·o· = well and '10' = most unwell. Tolerability was assessed on a 0-5 scale where '0' = very good tolerability and '5' = very poor tolerability. The clinical endpoint for safety was defined as a worsening of the safety parameters by > 25 %.
The safety variables assessed included vomiting (rtumber. of episodes/day). stool frequency per ·day and total sleeJJ time (hours) in 24 hours. In addition, the parent recorded occurrence of vomiting, passage of hard stools, feeling of excessive thirst, drowsiness, and concentration Impairment daily from baseline to day 7 in the diary. The formulations were also evaluated for tolerability I . acceptability In terms of flavour. taste, hesitancy to take the drug, and appearance. All the parameters were scored on a 5-potnt scale and were recorded from the patient (for children of 8-12 years) as well as from the parent on day 7. Interventions Patients were randomized based on a predetermined randomization ·schedule · prepared on a PC based programme Randoa version 1998. Randomized patients received one of the three cough formulations: 1) CS-1 May 2009 0 Vol. 62 No. 5
A child of age 6-12 yrs was administered 10 ml of CS-1. 3 times daily; while 5 ml, 3' times daily was given to a child aged 2-6 yrs. CS-2 was administered at a dose of 2.5 ml to 5.0 ml, .4 times dally (for 6-12 yrs of age) or 1.25 ml to 2.5 ml, 4 times daily (If age was 26 yrs). CS-3 was administered at a dose of 5 ml, 3 times dally (for 6-12 yrs of age) or 2.5 ml, 3.times daily (if age was 2-6 yrs). Blinding was maintained upto randomization by providing separate sealed envelopes for each recruited patients. Home or herbal therapies were strictly not allowed during the trial period.
Statistical Methods Non-Inferiority of CS-1 was defined as CS1 being non-inferior With respect to all the efficacy and safety parameters With a difference of less than 10% compared With CS-2 and CS-3.
Data .was analyzed using the SPSS statistical package. All the safety parameters for completed, non-violated protocol patients was subjected to 'per protocol' (PP) analysis, whereas llie efficacy parameters were subjected to 'intention-toe treat' (!TI') analysis. The Indian Practitioner 0
283
The three treatments were compared for VAS scores (for safety and efficacy vartables) us!ng Kruskall Wallis test followed by posthoc Tukey's multiple comparisons. The subjects achieving the efficacy endpoints (cough and night awakening) were subjected to Kaplan-Meier Analysis ' using Cox Propo-rtional Hazards Model.
scheduled follow-up visits and were lost to follow-up. There were only 2 patients from CS-3 group who violated the protocol and were excluded from efficacy analysis. Thus. there were 46 patients with data that was not evaluable, and the data of 372 completed patients (132 CS-1, 131 CS-2 and 109 CS-3) was analyzed for efficacy.
RESULTS Of the 418 enrolled patients· (141 CS-1. 141 CS-2 and 136 CS-3). 44 patients (9 CS-1. 10 CS-2· and 25 CS-3) did not visit durtng
All the 3 groups were comparable in terms of demography (Table 1). Table 2 summarizes the efficacy parameters. All three formulations reduced the frequency of cough
Table 1 Baseline demographic data and presenting signs and symptoms
Parameter'
CSI (N=l32)
CS2 (N=l31)
Age (years)'
5.76 ± 0.23
6.11± 0.25 .
Gender (Male:Female)
77 (58.33): 55 (41.67)
72 (54.96) : 59 (45.04)
CS3 (N=l04) 6.14 ± 0.27 69 (63.3) : 40 (36. 7)
Weight (kg)'
18.47 ± 0.59
18.67 ±
0.65
18.69 ± 0.66
Height (em)'
108.88 ± 1.50
108.76 ± I. 70
110.01 ± L79
'Mean± SD 'Figures in parenthesis indicate percentages Table 2 Cough frequency, night awakenings, time to relief and total doses for complete relief CSI (N=I32)
CS2 (N=l31)
CS3 (N=l04) .
Baseline
14.6 ± 1.2
14.6 ± 1.5
12.4 ± 1.3
Day3
7.4 ± 0.8'
7.2 ± 0.9'
6.4 ±0.8'
Day7
1.9 ± 0.4'
2.4 ± 0.54'
1.5 ± 0.3'
3.2 ±0.3
2.8 ± 0.3
2.7 ±0.3
Day3
1.2 ± 0.2'
1.3 ± 0.2'.
1.4 ± 0.3'
Day7
0.6± 0.2'
0.1±0.1'
0.4 ± 0.2'
107.0 ± 6.5°
132.0±5.8
123.8 ±6.5
Parameter
Cough Frequency
Frequency of Night Awakenings Baseline
.
Time for complete relief (hrs)
15.8 ± 0.8 .· . 'p < 0.0001, comparison versusbaseline: 0 p < 0.01, comparison versus CS2 a11d CS3: . "p < 0.05, comparison versus CS3 ('Mean ± SD]
Total doses for complete relief .
284
0 The Indian Practitioner
.
14.1 ± 0.7" . .
21.8± 1.0
.
.
.
May 2009 0 Vol. 62 No. 5
Ii I ;-i
Table 3 Patients who achieved the CLINICAL JI!:NDPOINT (improvement of> 75%) for various parameters during the study period CS1 (N=132)
Parameter•
CS2 (N=131)
CS3 (N=104)
Day3
Day 7
Day3
Day7
Day3
Day7
44 (33.33)
111(84.09)'
36 (27.48)
102 (77.86)
37 (33.94)
109(100)
85 (64.39)
117 (88.64)'
85 (64.89)
124 (94.6)
69 (63.3)
105 (96.3)
score
64 (48.48)
101 (76.52.)
68 (47.71)
96 (75.23)
52 (46.85)
82 (73.87)
Appetite Score
59 (44.71)
97 (73.48)
56 (40.37)
96 (71.56)
44 (39.64)
78 ( 70.27)
Behaviour Score
69 (52.27)
105 (79.5)
73 (55.73)
100 (76.34)
59 (53.15)
91 (81.98)
.Global Assessment of Wellbeing
56 (42.42)
70 (53.03)
46 (35.11)
57 (43.51)
38 (34.86)
63 (57.8)
Cough Frequency Frequency at Night Awakenings Playing activity
• Figures in parentheses indicate the percentages ' p < 0,05, comparison versus CS-3 for day 7: 'p < 0.05, comparison versus CS-2 and CS-.3 for day 7: p > 0.05, for all other individual comparisons of CS-1 with CS-2/CS-3 for respective days Table 4 Patients who presented with adverse events during the study period CSl (N=132)
Adverse Event•
CS2 (N=131)
CS3 (N=104)
Day 1
Day7
Day 1
Day7
Day 1
Day7
Vomiting
16 (12.12)
1(0.76)
9 (6.87)
0(0.00)
14 (12.84)
1 (0.92)
Presence of hard stools
14 (10.61)
4 (3.03)
12 (9.16)
4 (3.05)
9 (8.26)
7 (6.42)
Excessive thirst
22 (16.67)
3 (2.27)
20 (15.27)
5 (3.82)
8 (7.34)
5 (4.59)
Drowsiness
29 (21.97)
6 (4.55)
27 (20.61)
7 (5.34)
19 (17.43)
1 ( 0.92)
Concentration impairment
16 (12.12)
4 (3.03)
15 (11.45)
5 (3.82)
13 (11.93)
2 (1.83)
'Figures in parentheses indicate the percentages
episodes by day 3 and day 7 (p < 0.000 1). however, they were similar In efficacy (p > 0.05). The change In the mean cough frequencywas 12.7withCS-I.12.2withCS' 2 and 10.9 with CS-3. Similarly, Improvement In frequency of night awakenings due to cough was also to the same extent (p > 0.05). The change In the mean frequency of night awakenings was 2.6 with CS-1, 2.7 May 2009 0 Vol. 62 No. 5
with CS-2 and 2:3 with CS3. There was Improvement In the playing activity with all three formulations. The appetite of the child and day time behaviour of . the child Improved comparably, by day 7 with all three form1.1lations. The global assessment of wellbeing of the .child was similar in the three treatment gro1.1ps at the end of therapy. ·
The Indian Practitioner 0
285
I
I
Fig. 1: Tolerability Assessment on a rating scale of 0 • 5 (lower the score, better the tolerability)
2.0
',•
1.83
e 1.5 ~ 1.0
1.27
1.42
1.25 1.33
1:
:
::0 0.5 0
Flavour ~ CS-1 (n=132)
Taste
Hesitancy
ftl CS-2 (n=131)
Appearance
0
CS-3 (n=109)
CS I appeared to afford symptomatic relief the fastest (p < 0.01), the mean time tall:en. for complete relief of symptoltls. being 107.0 , hrs compared to 132.0 and l23.il)wsJor C:s2 and CS3 respectively. Also;: . the total number of doses required. for complete relief of symptoms was less with CS•l. compared to CS-3 (p < 0.05).
CS-3 for these two parameters (table-3). For cough, CS-1 was comparable to CS-2 (HR 1.02, 95o/o C.L .0.78- 1.32) a.i>d CS-3 (HR 1.03, 95o/o C.!. 0.79 -1.35) upto day 7. Similarly, for night aw;~kenlngs, CS-1 was comparable to CS~2 (HR 1.10. 95o/o C.!. 0.82- 1.48) and CS-3 (HR 1.03, 95o/o C.I. 0. 76- 1.40) up to day 7. .
Table 3 summarizes the details of the number and percentage · of patients achieving clinical end-points for the symptoms. The percentage of patients achieving clinical endpoint by day 7 was greater with CS-3 as compa.red to CS-1 for Cough episodes; hence CS-1 app~•ts to be Inferior to CS-3 In Improvement of cough episodes; however, for all other symptoms, the difference between the CS-1 and CS-2/ CS-3 for the Improvement of symptoms scores was less than !Oo/o, hence It could be stated that CS-1 was not Inferior to CS-2.and CS-3 for the efficacy In the treatment of URI with cough.
The most common concomitant medication prescribed was paracetemol (acetaminophen), which was administered to 34o/o, 25% and 29o/o patients from CS-1. CS-2, and CS-3 groups respectively.
CS-1 was comparable to other. two treatments for night awakenings trable-3). Time to cough relief (table-2) was shorter (p
