Clinical Trial Results:
A single blind study comparing the efficacy of Glycopyrronium and Hyoscine on drooling in children with neurodisability - DRI Trial (Drooling Reduction Intervention)
Summary
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EudraCT number |
2013-000863-94 |
Trial protocol |
GB |
Global end of trial date |
31 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Jan 2019
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First version publication date |
05 Jan 2019
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
6474
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Additional study identifiers
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ISRCTN number |
ISRCTN75287237 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
REC : 13/NE/0078 | ||
Sponsors
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Sponsor organisation name |
The Newcastle upon Tyne Hospitals NHS Foundation Trust
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Sponsor organisation address |
Regent Point, Regent Farm Road, Newcastle upon Tyne, United Kingdom, NE3 3HD
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Public contact |
Dr Parr, Chief Investigator, Newcastle University, 44 0191 282 5966, jeremy.parr@ncl.ac.uk
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Scientific contact |
Dr Parr, Chief Investigator, Newcastle University, 44 0191 282 5966, jeremy.parr@ncl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Oct 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Jan 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jan 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To identify whether Glycopyrronium or Hyoscine is more effective in treating drooling in children with non-progressive disability
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Protection of trial subjects |
The trial involved an independent Data Monitoring Committee (DMC) and Trial Steering Commitee to provide overall supervision for the trial on behalf of the Trial Sponsor and Trial Funder and to safeguard the interests of trial participants, monitor the main outcome measures including safety and efficacy, and monitor the overall conduct of the trial.
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Background therapy |
Drooling is due to oromotor impairment, and is a common problem in children with neurodevelopmental disorders. The negative consequences of drooling for children and their relatives include skin breakdown to the child’s chin, dehydration, and damage to clothing and equipment such as electronic communication aids. Children, siblings and parents often suffer social embarrassment due to drooling. There is no evidence about the relative effectiveness of the two medications most commonly used to reduce drooling. There are only limited data about their side effects and how acceptable they are to children and parents; this lack of information makes it difficult for children, parents and doctors to make informed decisions about which drug to use, and at what dose. This study will determine whether there is a difference in the effectiveness of the medications, and which doses are associated with fewest side effects. This information will be used to develop evidence based guidance to help children, parents and doctors firstly to decide which medication to prescribe to reduce problematic drooling and at what dose; secondly to show how adverse effects can be monitored, and when dosage should be reduced or medication stopped. The study will benefit children with neurodisability who drool and their families. By identifying how best to choose medication, decide on dosage and monitor effect and side effects, this applied research study relates to day to day practice of health service staff – specifically paediatricians and speech and language therapists. Children’s drooling will be better controlled with the accompanying physical and psychosocial benefits for child and family. | ||
Evidence for comparator |
Medication is the first intervention used by most UK clinicians and helps many children; both Hyoscine and Glycopyrronium work by reducing cholinergic stimulation of salivary glands, and the volume of saliva produced. There is a lack of research evidence about which of the two most commonly used medications works best, and which is best tolerated. Glycopyrronium is an oral medication (liquid) and hyoscine a skin patch; a double blind trial was therefore not appropriate.. The most effective dose and regime to increase doses is not known. The study involved escalating doses up to a maximum suggested in the British National Formulary for Children. The medication regime: 1. Glycopyrronium study arm Week 1: 40mcg/kg/ per dose Week 2, 60mcg/kg/ per dose Week 3, 80mcg/kg/ per dose Week 4, 100mcg/kg/ per dose All doses three times a day. Adjusted according to response up to maximum 2 mg per dose per day 2. Hyoscine study arm Week one ¼ patch, week two ½ patch, week three ¾ patch, week four full patch The patch will be replaced every three days, alternating sites to minimise the risk of a local skin reaction. The patch will not be cut (this results in loss of absorption), but an occlusive dressing will be used as per usual clinical practice. | ||
Actual start date of recruitment |
01 Sep 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 90
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Worldwide total number of subjects |
90
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EEA total number of subjects |
90
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
85
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Adolescents (12-17 years) |
5
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
In the course of normal clinical practice, parents/guardians and the local paediatrician would determine if a child needed medication for drooling. If it was the case, the local paediatrician the trial approached the family regarding the child's potential participation in the study. | |||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Recruitment was conducted by the local paediatrician during standard clinical care visit, so that only children who were deemed by the clinician and the family to need treatment for drooling were invited to participate. Parent/Guardian were provided with an Information Sheet and an opportunity to ask any questions about the study. | |||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
Blinding implementation details |
Randomised trial of two medication regimes known to patient and clinician but not the Trial Outcome Assessor.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Glycopyrronium | |||||||||||||||||||||||||||||||||
Arm description |
Children randomised to glycopyrronium liquid received three doses per day: week-1: 40 μg/kg/per dose; week-2: 60 μg/kg/per dose; week-3: 80 μg/kg/ per dose; week-4: 100 μg/kg/per dose to a maximum 2 mg per dose. Medication was given orally or by feeding tube. Please note the number of participants started refers to the number of participants randomised to the trial. Five participants withdrew prior to receiving any treatment on the trial. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Glycopyrronium Bromide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
The medication regime for participants randomised to the Glycopyrronium study arm:
Week 1: 40mcg/kg/ per dose
Week 2, 60mcg/kg/ per dose
Week 3, 80mcg/kg/ per dose
Week 4, 100mcg/kg/ per dose
All doses three times a day. Adjusted according to response up to maximum 2 mg per dose per day.
Trial medication continued for 12 weeks after which all trial medication was then returned. At the end of week 12, the Trial Research Paediatrician contacted the parent again to remind
them of a pre-arranged appointment with their usual local paediatrician. Their local paediatrician will discussed with the parents whether their child should continue on the same
medication (locally prescribed) or use alternative management.
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Arm title
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Hyoscine | |||||||||||||||||||||||||||||||||
Arm description |
Children randomised to the hyoscine received the following regime: week-1: ¼ patch; week-2: ½ patch; week-3: ¾ patch; week-4: full patch. The patch was typically placed below an ear with an occlusive dressing applied over and replaced every 3 days, alternating sites to minimise local skin reaction risk. The plastic patch backing was cut to expose the prescribed portion of the patch; the patch itself was not cut to avoid leakage of product from the non-loculated reservoir. Please note the number of participants started refers to the number of participants randomised to the trial. Five participants withdrew prior to receiving any treatment on the trial. | |||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Hyoscine
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Investigational medicinal product code |
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Other name |
Scopoderm
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Pharmaceutical forms |
Transdermal patch
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Routes of administration |
Transdermal use
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Dosage and administration details |
Transdermal patch containing 1.5mg hyoscine.
Hyoscine patches 1mg/72 hours were provided as a 12 week supply of patches; the patch was replaced every three das, alternating sites to minimise the risk of a local skin reaction.
Treatment schedule:
Week one 1/4 patch, week two 1/2 patch, week three 3/4 patch, week four full patch.
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Baseline characteristics reporting groups
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Reporting group title |
Glycopyrronium
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Reporting group description |
Children randomised to glycopyrronium liquid received three doses per day: week-1: 40 μg/kg/per dose; week-2: 60 μg/kg/per dose; week-3: 80 μg/kg/ per dose; week-4: 100 μg/kg/per dose to a maximum 2 mg per dose. Medication was given orally or by feeding tube. Please note the number of participants started refers to the number of participants randomised to the trial. Five participants withdrew prior to receiving any treatment on the trial. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Hyoscine
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Reporting group description |
Children randomised to the hyoscine received the following regime: week-1: ¼ patch; week-2: ½ patch; week-3: ¾ patch; week-4: full patch. The patch was typically placed below an ear with an occlusive dressing applied over and replaced every 3 days, alternating sites to minimise local skin reaction risk. The plastic patch backing was cut to expose the prescribed portion of the patch; the patch itself was not cut to avoid leakage of product from the non-loculated reservoir. Please note the number of participants started refers to the number of participants randomised to the trial. Five participants withdrew prior to receiving any treatment on the trial. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Glycopyrronium
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Reporting group description |
Children randomised to glycopyrronium liquid received three doses per day: week-1: 40 μg/kg/per dose; week-2: 60 μg/kg/per dose; week-3: 80 μg/kg/ per dose; week-4: 100 μg/kg/per dose to a maximum 2 mg per dose. Medication was given orally or by feeding tube. Please note the number of participants started refers to the number of participants randomised to the trial. Five participants withdrew prior to receiving any treatment on the trial. | ||
Reporting group title |
Hyoscine
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Reporting group description |
Children randomised to the hyoscine received the following regime: week-1: ¼ patch; week-2: ½ patch; week-3: ¾ patch; week-4: full patch. The patch was typically placed below an ear with an occlusive dressing applied over and replaced every 3 days, alternating sites to minimise local skin reaction risk. The plastic patch backing was cut to expose the prescribed portion of the patch; the patch itself was not cut to avoid leakage of product from the non-loculated reservoir. Please note the number of participants started refers to the number of participants randomised to the trial. Five participants withdrew prior to receiving any treatment on the trial. |
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End point title |
Drooling Impact Scale (DIS) score at 4 weeks | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Drooling Impact Scale (DIS) score at 4 weeks
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Statistical analysis title |
Difference in mean scores week 4 DIS Scores | ||||||||||||
Comparison groups |
Hyoscine v Glycopyrronium
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Number of subjects included in analysis |
70
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
6.8
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1.6 | ||||||||||||
upper limit |
15.3 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
4.2
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End point title |
Sensitivity analysis of the primary outcome measure: Week 4 DIS Score | ||||||||||||
End point description |
The analysis set is the treatment tolerated set.
This analysis repeats the analysis of the primary outcome measure, however, rather than an ITT analysis, only those patients who tolerated their treatment and were still on the treatment to which randomised at week 4 are included.
Of the 70 patients included in the ITT analysis of the primary outcome, 58 were still on the treatment to which randomised at week 4.
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End point type |
Primary
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End point timeframe |
Week 4 DIS Score
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Statistical analysis title |
Difference in mean scores week 4 DIS Scores | ||||||||||||
Comparison groups |
Glycopyrronium v Hyoscine
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Number of subjects included in analysis |
58
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
4.3
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.2 | ||||||||||||
upper limit |
11.8 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
3.7
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End point title |
Week-12 DIS Scores | ||||||||||||
End point description |
The analysis set is the Intention to treat (ITT) set.
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End point type |
Secondary
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End point timeframe |
Week-12 DIS Scores
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No statistical analyses for this end point |
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End point title |
Change in Drooling Severity-Frequency Scale (DSFS) score at baseline | ||||||||||||
End point description |
The analysis set is the Treatment Tolerated Set.
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End point type |
Secondary
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End point timeframe |
Baseline
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No statistical analyses for this end point |
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End point title |
Change in Drooling Severity-Frequency Scale (DSFS) score at week 4 | ||||||||||||
End point description |
The analysis set is the Treatment Tolerated Set.
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End point type |
Secondary
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End point timeframe |
week 4
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No statistical analyses for this end point |
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End point title |
Change in Drooling Severity-Frequency Scale (DSFS) score at week 12 | ||||||||||||
End point description |
The analysis set is the Treatment Tolerated Set.
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End point type |
Secondary
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End point timeframe |
week 12
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No statistical analyses for this end point |
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End point title |
Change in Treatment Satisfaction Questionnaire for Medication (TSQM) score at 4 weeks | ||||||||||||||||||||||||
End point description |
TSQM is a series of 11 questions coded and scored into 4 scales: effectiveness, side effects, convenience, global satisfaction. Each scale score is generated from selected questions and scaled to range from 0 to 100.
Effectiveness: 0 extremely dissatisfied, 100 extremely satisfied
Side effects: 0 extremely dissatisfied, 100 not at all dissatisfied
Convenience: 0 extremely dissatisfied, 100 extremely satisfied
Global satisfaction: 0 extremely dissatisfied, 100 extremely satisfied
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End point type |
Secondary
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End point timeframe |
4 week
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No statistical analyses for this end point |
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End point title |
Week 12 DIS score- treatment tolerated set (TT) | ||||||||||||
End point description |
The analysis set is the treatment tolerated set.
Only those patients who tolerated their treatment and were still on the treatment to which randomised at week 12 are included in this analysis.
57 patients were still on the treatment to which randomised at week 12.
1 was still on treatment at week 12 but no DIS score was available.
4 had DIS assessments outside the required window (80 to 91 days inclusive).
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End point type |
Secondary
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End point timeframe |
Week 12
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Statistical analysis title |
Difference in mean scores week 12 DIS Scores | ||||||||||||
Statistical analysis description |
The analysis set is the treatment tolerated set.
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Comparison groups |
Glycopyrronium v Hyoscine
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Number of subjects included in analysis |
52
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
2.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-4.3 | ||||||||||||
upper limit |
9 | ||||||||||||
Variability estimate |
Standard error of the mean
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End point title |
Comparison of week 4 vs week 12 DIS Scores | ||||||||||||
End point description |
Paired t-test. Results shown for each group separately.
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End point type |
Secondary
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End point timeframe |
Comparison of week 4 vs week 12 DIS Scores
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Statistical analysis title |
Comparison of week 4 vs week 12 Glycopyrronium | ||||||||||||
Comparison groups |
Hyoscine v Glycopyrronium
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Number of subjects included in analysis |
63
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-1.1
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-7.3 | ||||||||||||
upper limit |
5.2 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
3
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Statistical analysis title |
Comparison of week 4 vs week 12 Hyoscine | ||||||||||||
Comparison groups |
Hyoscine v Glycopyrronium
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Number of subjects included in analysis |
63
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
Method |
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Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-7.2 | ||||||||||||
upper limit |
10 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
4.3
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Adverse events information
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Timeframe for reporting adverse events |
Adverse Events will be recorded from randomisation to 52 week follow up.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
verbatim | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1
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Reporting groups
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Reporting group title |
Hyoscine
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Glycopyrronium
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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23 Jul 2013 |
Substantial amendment 1 involved:
The removal of the SMPC for Hyoscine and Glycopyrronium from the protocol appendices.
Revision of the fax number for notifying SAEs and pregnancy.
Addition and removal of the sites who will take part in the trial.
Change of PI at Newcastle upon Tyne Hospitals NHS Foundation Trust.
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17 Sep 2013 |
Administrative changes to protocol and CTA.
Participant Information Sheet modified to include instructions to parents regarding the application of the occlusive dressing.
Updates to monitoring of the study.
Revised sIMPD confirming Glycopyrronium shelf life (6 months).
Introduction of diary cards to record dose adjustments.
Introduction of a nurses letter. |
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12 Mar 2014 |
Addition of trial sites. |
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20 Jun 2014 |
Addition of a trial site. |
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31 Jul 2014 |
Addition of sites. |
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14 Nov 2014 |
Update to sIMPD.
Update to protocol. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |