Evidence tables

Advice

Table 4 Mier et al. (2000)

Study reference	Mier RJ, Bachrach SJ, Lakin RC et al. (2000) Treatment of sialorrhea with glycopyrrolate: a double-blind, dose-ranging study. Archives of Pediatrics and Adolescent Medicine 154: 1214–8
Unique identifier	Not known
Study type	RCT
Aim of the study	To evaluate the efficacy and safety of glycopyrronium bromide in the treatment of children with developmental disabilities with sialorrhoea
Study dates	Not stated in the published study. The EPAR reports that the study was conducted from 1998 to 1999
Setting	US (2 centres)
Number of participants	n=39 randomised (27 included in efficacy analysis)
Population	Children and young people aged 4 years and older (mean age 10 years 9 months) with neurodevelopmental conditions and severe sialorrhoea^a
Inclusion criteria	Children aged 4 years and older, with neurodevelopmental conditions and severe sialorrhoea
Exclusion criteria	Not reported
Intervention(s)	2 dosing regimens of glycopyrronium bromide capsules^b, based on the weight of the child: <30 kg: 0.6 mg three times daily, increased weekly by 0.6 mg up to 2.4 mg at week 4 >30 kg: 1.2 mg three times daily, increased weekly by 0.6 mg to 3.0 mg at week 4 The maximum tolerated doses were then continued for a further 4 weeks. Doses were increased according to this schedule unless adverse effects occurred or desired 'dryness' (defined by the parent or carer) occurred^c,d
Comparator(s)	Placebo^b
Length of follow-up	8 week treatment phase. A cross-over design was used: the initial 8 week treatment phase was followed by a 1 week washout period, a 1 week observation period and then 8 weeks of the alternative intervention
Outcomes	Primary outcome^e,f: Change in mean mTDS score from baseline to mean maximum (best) score, over 8 weeks
	Secondary outcomes^e: Mean mTDS score after 4 weeks at highest dose by dose level Proportion of patients with ≥4-point improvement in mean mTDS score by dose level Parent or carer assessment of drooling odour Parent or carer assessment of dryness of clothing
	Safety outcomes: Any adverse events Adverse events requiring treatment withdrawal
Source of funding	Not reported
Overall risk of bias/quality assessment – CASP RCT checklist	Did the trial address a clearly focused issue?	Yes
	Was the assignment of patients to treatments randomised?	Unclear^g
	Were patients, health workers and study personnel blinded?	Yes^h
	Were the groups similar at the start of the trial?	Unclearⁱ
	Aside from the experimental intervention, were the groups treated equally?	Yes
	Were all of the patients who entered the trial properly accounted for at its conclusion?	Yes
	How large was the treatment effect?	See table 6
	How precise was the estimate of the treatment effect?	See table 6
	Can the results be applied in your context? (or to the local population)	Yes^j
	Were all clinically important outcomes considered?	Yes
	Are the benefits worth the harms and costs?	See key points
Study limitations	Short‑term study (8 weeks) Only participants who completed the study were included in the analysis. A high proportion of the participants did not complete the study (12/39, 31%) The study did not include an active comparator The study did not report on randomisation and blinding methods It is unclear whether allocation was concealed
Comments	^a 34/39 participants had cerebral palsy and 2/39 had tracheostomies (1 of whom dropped out of the study because of excessively thick secretions). 5/39 participants had previously received treatment for sialorrhoea, 3 of whom had taken glycopyrronium bromide and had stopped treatment because of adverse effects. ^b Capsules were specially compounded from oral glycopyrronium bromide. Placebo capsules were compounded using identical gelatin capsules. ^c The mean highest dose of glycopyrronium bromide for children who completed the study was 2.49 mg (range 1.2–3.0 mg) per dose. ^d 4 participants were given these doses twice rather than three times a day, at the parent's request. ^eThe authors do not specify which outcomes are primary and which are secondary, although mean change in mTDS is reported first in the paper. ^f Drooling was assessed weekly in the afternoon (2 hours after a dose) by parents or carers using mTDS. ^g Randomisation method and allocation concealment not described. ^h Although the study stated that it was double-blind, it was not clear if both investigators and clinicians providing care were blinded. ⁱ Baseline characteristics not reported. ^j The study population that completed the trial is not described in detail, and no account is given for the subjects who dropped out.
Abbreviations: EPAR, European Public Assessment Report; mTDS, Modified Teacher's Drooling Scale; RCT, randomised controlled trial.

Table 5 Zeller et al. 2012a

Study reference	Zeller RS, Lee HM, Cavanaugh PF et al. (2012a) Randomized phase III evaluation of the efficacy and safety of a novel glycopyrrolate oral solution for the management of chronic severe drooling in children with cerebral palsy or other neurologic conditions. Therapeutics and Clinical Risk Management 8: 15–23
Unique identifier	NCT00425087
Study type	RCT
Aim of the study	To assess the efficacy and safety of glycopyrronium bromide oral solution in managing problem drooling associated with cerebral palsy and other neurologic conditions in children
Study dates	November 2002 to April 2007
Setting	US (10 centres)
Number of participants	n=38 randomised
Population	People aged 3 to 23 years^a with cerebral palsy or another neurological condition, and problem drooling^b. The mean age was approximately 9.5 years; 22/36 (61%) were male
Inclusion criteria	Male and female patients weighing at least 27 lb (12.2 kg) and previously diagnosed with cerebral palsy, mental retardation, or another neurologic condition associated with problem drooling were eligible. People with oral feeding problems or who used a tube for feeding were included
Exclusion criteria	Patients were excluded if their extent of drooling was wetness of the lips and chin but their clothes did not become damp on most days; if they had used glycopyrronium bromide liquid within approximately 24 hours of baseline; if they had used any anticholinergic or cholinergic medications prohibited by the protocol within 3 plasma half-lives of that medication prior to baseline; or if they had medical conditions contraindicating anticholinergic therapy or treatment with the study medication
Intervention(s)	Glycopyrronium bromide (glycopyrrolate) oral solution^c, three times daily,with the dose titrated up weekly to the optimal tolerated dose^b. There were 5 dose levels: 0.02 mg/kg three times a day 0.04 mg/kg three times a day 0.06 mg/kg three times a da 0.08 mg/kg three times a day 0.10 mg/kg three times a day The maximum dose was 1.5–3.0 mg three times a day (based on weight). After the optimal dose level was reached, patients continued to receive the same medication and dose for a total of 8 weeks
Comparator(s)	Placebo
Length of follow-up	8 weeks (including 4‑week dose titration phase)
Outcomes	Primary outcome: Responder rate, defined as percentage of patients with an improvement of 3 points or more in mTDS score
	Secondary outcomes: Mean improvement in mTDS score at 8 weeks Daily mean parent/carer mTDS scores at weeks 2, 4, and 6 AUC analysis of all mTDS evaluations from screening to week 8 Proportion of patients who discontinued treatment due to lack of efficacy Proportion of investigators who considered treatment worthwhile^d Proportion of parents/carers who considered treatment worthwhile^d
	Safety outcomes: Any adverse events All assessed at baseline and at week 8 or study discontinuation
Source of funding	Shionogi Inc.
Overall risk of bias/quality assessment – CASP RCT checklist	Did the trial address a clearly focused issue?	Yes
	Was the assignment of patients to treatments randomised?	Unclear^e
	Were patients, health workers and study personnel blinded?	Unclear^f
	Were the groups similar at the start of the trial?	Yes
	Aside from the experimental intervention, were the groups treated equally?	Yes
	Were all of the patients who entered the trial properly accounted for at its conclusion?	Yes
	How large was the treatment effect?	See table 7
	How precise was the estimate of the treatment effect?	See table 7
	Can the results be applied in your context? (or to the local population)	Yes
	Were all clinically important outcomes considered?	Yes
	Are the benefits worth the harms and costs?	See key points
Study limitations	Short‑term study (8 weeks) The study did not include an active comparator The study did not report on randomisation and blinding methods It is unclear whether allocation was concealed
Comments	^a After randomisation the study protocol was amended and an upper age limit of 16 years was set. Two participants were excluded from the efficacy analysis, but were included in the safety analysis. ^b Problem drooling was defined as drooling in the absence of treatment such that clothing became damp approximately 5–7 days per week. Of the 36 participants analysed for efficacy, 30 had cerebral palsy, 18 had oral feeding problems and 15 used a tube for feeding. ^c This formulation of glycopyrronium bromide is available in the US as Cuvposa. This is a different product to the licensed product available in the UK (Sialanar), and there are differences in bioavailability. ^d Assessed at week 8 or at the last visit, using a 5-point scale, ranging from 1 (strongly agree) to 5 (strongly disagree) in response to the statement "This is a worthwhile treatment". ^e Unclear if allocation was concealed. ^f Although the study stated that it was double-blind, it was not clear if both investigators and clinicians providing care were blinded.
Abbreviations: AUC, Area under curve; mTDS, Modified Teacher's Drooling Scale; RCT, randomised controlled trial.