Comparison of Efficacy and Tolerability of Two Cough Syrups in Cough Due to Cold in Children. (URTI)

• ClinicalTrials.gov Identifier: NCT01968434
• Recruitment Status: Completed
• First Posted: October 24, 2013
• Results First Posted: November 1, 2015
• Last Update Posted: February 23, 2018
• Sponsor: Clalit Health Services
• Collaborator: Aboca Spa Societa' Agricola
• Information provided by (Responsible Party): Avner Herman Cohen, Clalit Health Services

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Cough; Upper Respiratory Tract Infection
• Interventions: Device: protective cough syrup; Drug: carbocisteine cough syrup
• Enrollment: 150

Participant Flow

Recruitment Details	Recruiting took place within the Clalit health service community day hospitals. Community day hospitals are places where parents go for usual illnesses and treat most community ailments.
Pre-assignment Details	Access for eligibility= 195 Excluded =45 (refused to participate n= 24, not meeting inclusion criteria n=21)

Arm/Group Title	Protective Cough Syrup	Carbocisteine Cough Syrup
Arm/Group Description	syrup containing honey, plantago lanceolata, grindelia robusta, helichrysum italicum ina syrup form. The cough syrup is a CE marked medical device acting in a non pharmacological way to reduce cough. Dosage: 6,5 ml three times a day for the duration of the study (4 nights, 3 days) protective cough syrup: The mucoadhesive and radical scavenging properties of the components create a protective film on the pharynx which protects irritated mucosa from cough generating stimuli such as post nasal drip, irritating elements, dehydration. Access for eligibility= 195 Excluded =45 (refused to participate n= 24, not meeting inclusion criteria n=21) Enrolled: 150 completed pre-treatment questionnaire and randomized into groups Allocated protective syrup n = 78 received intervention n= 78 Lost to follow up n=3 Discontinued intervention n=0 Analyzed n=75 Excluded from analysis n=0	Dosage 20-25 mg/kg/day three times a day (3 days/4 nights) carbocisteine cough syrup: Mucolytic Access for eligibility= 195 Excluded =45 (refused to participate n= 24, not meeting inclusion criteria n=21) Enrolled: 150 completed pre-treatment questionnaire and randomized into groups Allocated carbocisteine syrup n = 72 received intervention n= 72 Lost to follow up n=6 Discontinued intervention n=0 Analyzed n=66 Excluded from analysis n=0
Period Title: Overall Study
Started	78	72
Completed	75	66
Not Completed	3	6
Reason Not Completed
Lost to Follow-up	3	6

Baseline Characteristics

Arm/Group Title		Protective Cough Syrup	Carbocisteine Cough Syrup	Total
Arm/Group Description		syrup containing honey, plantago lanceolata, grindelia robusta, helichrysum italicum in a syrup form. The cough syrup is a CE marked medical device acting in a non pharmacological way to reduce cough. Dosage: 6.5 ml three times a day for the duration of the study (4 nights, 3 days) protective cough syrup: The mucoadhesive and radical scavenging properties of the components create a protective film on the pharynx which protects irritated mucosa from cough generating stimuli such as post nasal drip, irritating elements, dehydration. Enrolled: 150 completed pre-treatment questionnaire and randomized into groups Allocated protective syrup n = 78 received intervention n= 78 Lost to follow up n=3 Discontinued intervention n=0 Analyzed n=75 Excluded from analysis n=0	Dosage 20-25 mg/kg/day three times a day (3 days/4 nights) carbocisteine cough syrup: Mucolytic Enrolled: 150 completed pre-treatment questionnaire and randomized into groups Allocated carbocisteine syrup n = 72 received intervention n= 72 Lost to follow up n=6 Discontinued intervention n=0 Analyzed n=66 Excluded from analysis n=0	Total of all reporting groups
Overall Number of Baseline Participants		78	72	150
Baseline Analysis Population Description		Enrolled patients had a minimum cough intensity both day and night, according to questionnaire, had not received any cough medicine the day before enrollment and fulfilled all inclusion criteria.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Months
	Number Analyzed	78 participants	72 participants	150 participants
		42.49 (12.96)	43.17 (14.57)	42.8 (13.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	78 participants	72 participants	150 participants
	Female	41 52.6%	38 52.8%	79 52.7%
	Male	37 47.4%	34 47.2%	71 47.3%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Israel	Number Analyzed	78 participants	72 participants	150 participants
		78	72	150
Participants coughing since ≥ 3 days at time of enrollment; Measure Type: Number; Unit of measure: Participants
	Number Analyzed	78 participants	72 participants	150 participants
		47	46	93

Outcome Measures

1. Primary Outcome

Title	Change in Night Cough Score on First Night of Treatment (From N0 to N1)
Description	Night cough is most bothersome to the child and family. Cough was measured with a validated questionnaire which asks parents to rate 5 aspects of night cough: frequency, severity, bothersomeness, child sleep and parent sleep according to a 7 point Likert scale, from 0 (not at all) to 6 (extremely). Lower scores indicate a better condition. The morning after the first night of treatment (N1) the parents rated the passed night by scoring from 0-6 each of the 5 aspects of night cough. The sum of scores for all 5 aspects gives the combined night cough score. This score, ranging between 0-30, was subtracted from the sum of all aspects, also ranging between 0-30, form the basal night cough score of the night before enrollment (N0). This change is recorded as "change in combined night cough score" and it refers to the change from N0 to N1. Negative values of the change indicate an improvement in the condition of the patient.
Time Frame	1 night from before enrollment (N0) to first night after treatment (N1)

Outcome Measure Data

Analysis Population Description

the population analyzed are the children who completed the protocol and submitted the complete questionnaire for night and day cough. 78 patients were enrolled in the protective syrup Group and 72 in the carbocysteine Group. 3 patients in the protective syrup group and 6 in the carbocysteine group never began the study.

Arm/Group Title	Protective Cough Syrup	Carbocisteine Cough Syrup
Arm/Group Description:	syrup containing honey, plantago lanceolata, grindelia robusta, helichrysum italicum ina syrup form. The cough syrup is a CE marked medical device acting in a non pharmacological way to reduce cough. Dosage: 20 ml divided in three doses per day for the duration of the study (4 nights, 3 days) protective cough syrup: The mucoadhesive and radical scavenging properties of the components create a protective film on the pharynx which protects irritated mucosa from cough generating stimuli such as post nasal drip, irritating elements, dehydration.	Dosage 20-25 mg/kg/day three times a day (3 days/4 nights) carbocisteine cough syrup: Mucolytic
Overall Number of Participants Analyzed	75	66
Mean (Standard Error); Unit of Measure: change in combined night cough score
	-5.16 (0.85)	-1.77 (0.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Protective Cough Syrup, Carbocisteine Cough Syrup
	Comments	The sample size was calculated to detect a 0.75 point difference between any two treatment groups with a 90% power and p<0.05. Such sample size was 60 subject which was elevated ot 75 subjects per group to account for drop outs. For comparison of cough evaluation before and after treatment a paired Student t test was used.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.01
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

2. Secondary Outcome

Title	Change in Night Cough Score at End of Study (From N0 to N4)
Description	A validated cough questionnaire measuring 5 aspects of night cough (frequency, severity, bothersomeness, child sleep and parents' sleep) on a 7 point Likert scale was used each morning to rate the passed night. The scale rates each parameter from 0 (not at all) to 6 (extremely). Every night of the trial is rated. The morning after the last night of the study (N4) the parents rated the passed night by scoring from 0-6 each of the 5 aspects of night cough. The summed score for all aspects gives the combined night cough score. This score, ranging between 0-30, was subtracted from the sum of all aspects, also ranging between 0-30, form the basal night cough score of the night before enrollment (N0). This change is recorded as "change in combined night cough score" and it refers to the change from N0 to N4. Negative values of the change indicate an improvement in the condition of the patient.
Time Frame	4 nights (onset of trial Night 1 to Night 4) and 3 days

Outcome Measure Data

Analysis Population Description

78 patients were enrolled in the protective syrup Group and 72 in the carbocysteine Group. 3 patients in the protective syrup group and 6 in the carbocysteine group never began the study. 7 patients from the protective syrup group and twelve 12 patients from the carbocysteine group did not answer the questions for the last night.

Arm/Group Title	Protective Cough Syrup	Carbocisteine Cough Syrup
Arm/Group Description:	syrup containing honey, plantago lanceolata, grindelia robusta, helichrysum italicum ina syrup form. The cough syrup is a CE marked medical device acting in a non pharmacological way to reduce cough. Dosage: 20 ml divided in three doses per day for the duration of the study (4 nights, 3 days) protective cough syrup: The mucoadhesive and radical scavenging properties of the components create a protective film on the pharynx which protects irritated mucosa from cough generating stimuli such as post nasal drip, irritating elements, dehydration.	Dosage 20-25 mg/kg/day three times a day (3 days/4 nights) carbocisteine cough syrup: Mucolytic
Overall Number of Participants Analyzed	71	60
Mean (Standard Error); Unit of Measure: change in combined night cough score
	-13.92 (0.92)	-9.48 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Protective Cough Syrup, Carbocisteine Cough Syrup
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.01
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

3. Secondary Outcome

Title	Change in Day Cough Score at End of Study (From D0 to D4)
Description	A validated cough questionnaire measuring 3 aspects of daytime cough (frequency, severity, bothersomeness) on a 7 point Likert scale was used each evening to rate the passed day, as regards these aspects. The scale rates each parameter from 0 (not at all) to 6 (extremely). Every day of the trial is rated. The last evening of the study (D4) the parents rated the passed day by scoring from 0-6 each of the 3 aspects of day cough. The summed score for all aspects gives the combined day cough score. This score, ranging between 0-18, was subtracted from the sum of all aspects, also ranging between 0-18, form the basal day cough score of the day before enrollment (D0). This change is recorded as "change in combined day cough score" and it refers to the change from D0 to D4. Negative values of the change indicate an improvement in the condition of the patient.
Time Frame	4 nights (onset of trial Night 1 to Night 4) and 3 days

Outcome Measure Data

Analysis Population Description

78 patients were enrolled in the protective syrup Group and 72 in the carbocysteine Group. 3 patients in the protective syrup group and 6 in the carbocysteine group never began the study. 6 patients from the protective syrup group and twelve 11 patients from the carbocysteine group did not answer the questions for the last day.

Arm/Group Title	Protective Cough Syrup	Carbocisteine Cough Syrup
Arm/Group Description:	syrup containing honey, plantago lanceolata, grindelia robusta, helichrysum italicum ina syrup form. The cough syrup is a CE marked medical device acting in a non pharmacological way to reduce cough. Dosage: 20 ml divided in three doses per day for the duration of the study (4 nights, 3 days) protective cough syrup: The mucoadhesive and radical scavenging properties of the components create a protective film on the pharynx which protects irritated mucosa from cough generating stimuli such as post nasal drip, irritating elements, dehydration.	Dosage 20-25 mg/kg/day three times a day (3 days/4 nights) carbocisteine cough syrup: Mucolytic
Overall Number of Participants Analyzed	72	61
Mean (Standard Error); Unit of Measure: change in combined day cough score
	-6.17 (0.43)	-4.54 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Protective Cough Syrup, Carbocisteine Cough Syrup
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.05
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

Adverse Events

Time Frame	Adverse events were recorded during study period, from first enrollment to last collected data, which was a period of 5 months. Due to the nature of ailment and of treatment it was envisaged that any adverse event would be evident within study period.
Adverse Event Reporting Description	Adverse events were systematically collected by the CRF questionnaire.
Arm/Group Title	Protective Cough Syrup		Carbocisteine Cough Syrup
Arm/Group Description	syrup containing honey, plantago lanceolata, grindelia robusta, helichrysum italicum ina syrup form. The cough syrup is a CE marked medical device acting in a non pharmacological way to reduce cough. Dosage: 6,5 ml three times a day for the duration of the study (4 nights, 3 days) protective cough syrup: The mucoadhesive and radical scavenging properties of the components create a protective film on the pharynx which protects irritated mucosa from cough generating stimuli such as post nasal drip, irritating elements, dehydration.		Dosage 20-25 mg/kg/day three times a day (3 days/4 nights) carbocisteine cough syrup: Mucolytic
All-Cause Mortality
	Protective Cough Syrup		Carbocisteine Cough Syrup
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Protective Cough Syrup		Carbocisteine Cough Syrup
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0.00%)		0/66 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Protective Cough Syrup		Carbocisteine Cough Syrup
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/75 (8.00%)		9/66 (13.64%)
Gastrointestinal disorders
nausea † 1	5/75 (6.67%)	5	6/66 (9.09%)	6
Nervous system disorders
drowsiness † 1	0/75 (0.00%)	0	2/66 (3.03%)	2
Skin and subcutaneous tissue disorders
rash † 1	1/75 (1.33%)	1	1/66 (1.52%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA (10.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Prof. Herman Avner Cohen
• Organization: Clalit HS
• Phone: 00972 3-939-8203
• EMail: hermanc@clalit.org.il

Publications:

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Paul IM, Yoder KE, Crowell KR, Shaffer ML, McMillan HS, Carlson LC, Dilworth DA, Berlin CM Jr. Effect of dextromethorphan, diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents. Pediatrics. 2004 Jul;114(1):e85-90. doi: 10.1542/peds.114.1.e85.

Paul IM, Beiler J, McMonagle A, Shaffer ML, Duda L, Berlin CM Jr. Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents. Arch Pediatr Adolesc Med. 2007 Dec;161(12):1140-6. doi: 10.1001/archpedi.161.12.1140.

Department of child and adolescent health. Cough and cold remedies for the treatment of acute respiratory infections in young children. Geneva, Switzerland: World Health Organization: 2001.

Allen KL, Molan PC, Reid GM. A survey of the antibacterial activity of some New Zealand honeys. J Pharm Pharmacol. 1991 Dec;43(12):817-22. doi: 10.1111/j.2042-7158.1991.tb03186.x.

Schramm DD, Karim M, Schrader HR, Holt RR, Cardetti M, Keen CL. Honey with high levels of antioxidants can provide protection to healthy human subjects. J Agric Food Chem. 2003 Mar 12;51(6):1732-5. doi: 10.1021/jf025928k.

Cohen HA, Rozen J, Kristal H, Laks Y, Berkovitch M, Uziel Y, Kozer E, Pomeranz A, Efrat H. Effect of honey on nocturnal cough and sleep quality: a double-blind, randomized, placebo-controlled study. Pediatrics. 2012 Sep;130(3):465-71. doi: 10.1542/peds.2011-3075. Epub 2012 Aug 6.

Bogdanov S, Jurendic T, Sieber R, Gallmann P. Honey for nutrition and health: a review. J Am Coll Nutr. 2008 Dec;27(6):677-89. doi: 10.1080/07315724.2008.10719745.

Rimsza ME, Newberry S. Unexpected infant deaths associated with use of cough and cold medications. Pediatrics. 2008 Aug;122(2):e318-22. doi: 10.1542/peds.2007-3813.

Kraft K. Efficacy of fluid in Plantago lanceolata extract (PLFE) in acute respiratory disease. Phytomedicine, Supplement 1, 1996

Wegener T, Kraft K. [Plantain (Plantago lanceolata L.): anti-inflammatory action in upper respiratory tract infections]. Wien Med Wochenschr. 1999;149(8-10):211-6. German.

• Responsible Party: Avner Herman Cohen, Clalit Health Services
• ClinicalTrials.gov Identifier: NCT01968434
• Other Study ID Numbers: COM-13-00
• First Submitted: October 17, 2013
• First Posted: October 24, 2013
• Results First Submitted: May 14, 2015
• Results First Posted: November 1, 2015
• Last Update Posted: February 23, 2018