Cerebral Palsy, Mental Retardation, Neurological Conditions, Sialorrhea
Conditions
Keywords
Mental Retardation, Neurological Impairment, Cerebral Palsy, Drooling, Neurological Conditions
Brief summary
This is an open-label clinical research study of an oral glycopyrrolate liquid for the treatment of chronic moderate to severe drooling in patients with cerebral palsy or other neurological conditions. Patients participating in the study will receive oral glycopyrrolate liquid (1 mg/5 ml) three times a day (TID) for study duration of 24 weeks. After a washout, screening, and 2-day baseline period, patients will be enrolled in a 4-week dose titration period. Glycopyrrolate liquid doses will be titrated using dose levels in the Dose Titration Schedule. Titration will begin at 0.02 mg/kg per dose TID and sequentially increased in 0.02 mg/kg per dose increments TID every 5-7 days during the first four weeks until optimal individualized response is obtained for each patient or a maximum dose of 0.1 mg/kg TID is reached, not exceeding 3 mg TID or Dose-level 5 in the Dose Titration Schedule, whichever is lesser. Optimal dose for each patient is the dose at which he/she is receiving the maximum benefit from the study drug (greatest improvement in drooling) while experiencing minimum side effects. All patients will receive close attention by study staff throughout the study.
Interventions
DRUGOral Glycopyrrolate Liquid
Study medication is administered three times a day at 7-8 AM, 1-2 PM, and 7-8 PM by the parent/caregiver
Sponsors
Shionogi
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
To be included in this study, patients must meet the following criteria: * Male or female, weighing at least 13 kilograms (27 pounds), aged 3 through 18 years * Diagnosis of cerebral palsy and/or mental retardation or any other neurologic impairment or condition (cognitively capable and cognitively impaired patients may be enrolled) * Chronic drooling in the absence of treatment to the extent that the chin or clothing becomes wet on most days by confirming the Modified Teacher's Drooling Scale score ≥ 5 * Must be living in a situation where reliable parents/caregivers are willing and capable of administering medications, as determined by the investigator * Written informed consent signed by the parent or legally acceptable representative * Written assent signed by the age-appropriate patient if mentally capable, as determined by the investigator, and required by the site's Institutional Review Board * If female of childbearing potential, the patient must have a negative pregnancy test at screening and Visit 2 * If female of childbearing potential and sexually active, she must use a medically acceptable form of contraception
Exclusion criteria
Patients are excluded from this study if they meet any of the following criteria: * Patients who used glycopyrrolate within approximately 24 hours prior to the start of the baseline period, which began on Day -2 * Patients who used prohibited medications within 5 plasma half-lives of the medication prior to the start of the baseline period * Patients injected with intrasalivary gland botulinum toxin within 10 months prior to the start of the baseline period * Patients using intraoral devices or prosthetics for the treatment of drooling within 1 week prior to the start of the baseline period * Patients receiving acupuncture for the treatment of drooling or who have received acupuncture for the treatment of drooling within 3 months prior to the start of the baseline period * Patients who have medical conditions contraindicating anticholinergic therapy including gastrointestinal reflux, narrow-angle glaucoma, obstructive uropathy, obstructive disease of the gastrointestinal tract (i.e., delayed gastric emptying, pyloroduodenal stenosis, etc.), paralytic ileus, intestinal atony, vesicoureteral reflux, reactive airway disease, myasthenia gravis, hyperthyroidism, cardiac arrhythmias and/or tachycardia, and/or clinically significant electrocardiogram abnormalities, as determined by the investigator * Patients who have a known contraindication to the study medication, including allergy to the study medication or any of its components * Patients who have poorly controlled seizures defined as daily seizures * Patients who have a history of obstructive disease of the gastrointestinal tract (i.e., intestinal obstruction) * Patients who have clinically significant hepatic or renal impairment, at the discretion of the investigator * Patients who are pregnant or breastfeeding * Patients who have received any investigational drugs within 30 days of study entry * Patient, families, or parents/caregivers who are expected to be non-compliant with the study procedures, as judged by the investigator * Patients who are unable to meet the requirements of the study for any reason, as determined by the investigator * Patients who have unstable mental disease, as determined by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Responders According to the Modified Teacher's Drooling Scale (mTDS) | 6 months | The primary efficacy variable was patient's response status using the change from baseline to Week 24 evaluations of the mTDS assessment. Each patient was classified as a responder or non-responder according to the change in their mean mTDS rating from baseline to Week 24. Responders were patients who had at least a 3-point decrease in mTDS rating from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parent/Caregiver's Assessment of the Extent of Drooling Using Visual Analog Scale (VAS) | Baseline | Parents/caregivers were to complete a 10 cm Parent/Caregiver's Assessment of Extent of Drooling for the Day VAS assessment (0 = normal; 10 = extremely wet) to provide an overall assessment of the extent of drooling for that day. |
| Parent/Caregiver's Assessment of the Extent of Drooling Using VAS | Week 24 | Parents/caregivers were to complete a 10 cm Parent/Caregiver's Assessment of Extent of Drooling for the Day VAS assessment (0 = normal; 10 = extremely wet) to provide an overall assessment of the extent of drooling for that day. |
| Parent/Caregiver's Global Assessment of Treatment | Week 24 | The parent/caregiver performed an overall evaluation of glycopyrrolate liquid for the treatment of drooling, benefits, and side effects over the duration of the study. The parent/caregiver selected one of the following choices to assess if 'This is a worthwhile treatment': 1 = strongly agree, 2 = agree, 3 = neutral, 4 = disagree, 5 = strongly disagree. A dichotomous global assessment was also performed and summarized with the categories 'responder' (strongly agree and agree responses aggregated) and 'non-responder'(neutral, disagree, and strongly disagree responses aggregated) |
| Investigator's Global Assessment of Treatment | Week 24 | The investigator performed an overall evaluation of glycopyrrolate liquid for the treatment of drooling, benefits, and side effects over the duration of the study. The investigator selected one of the following choices to assess if 'This is a worthwhile treatment': 1 = strongly agree, 2 = agree, 3 = neutral, 4 = disagree, 5 = strongly disagree. A dichotomous global assessment was also performed and summarized with the categories 'responder' (strongly agree and agree responses aggregated) and 'non-responder' (neutral, disagree, and strongly disagree responses aggregated) |
Countries
United States
Participant flow
Recruitment details
First patient was enrolled on April 03, 2007 and last patient completed on May 30, 2008
Pre-assignment details
After a washout and screening period, and 2-day baseline period, patients were enrolled in a 4-week dose titration period which commenced with the goal of identifying an optimal 3 times daily maintenance dose for each patient. The resulting individualized optimal maintenance dose was to be administered for the remainder of the 24-week study
Participants by arm
| Arm | Count |
|---|---|
| Patients With Chronic Drooling A 4-week dose titration period until an optimal individualized response was obtained for each patient or a maximum dose of 0.1 mg/kg/dose was reached. Doses were not to exceed 3.0 mg/kg TID | 137 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 14 |
| Overall Study | Death | 3 |
| Overall Study | Lack of Efficacy | 2 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Other-Failed to meet any criteria | 2 |
| Overall Study | Other-Intake of prohibited medication | 1 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Patients With Chronic Drooling |
|---|---|
| Age, Categorical <=18 years | 137 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age Continuous | 11.0 years STANDARD_DEVIATION 4.35 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 121 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 98 Participants |
| Sex: Female, Male Female | 60 Participants |
| Sex: Female, Male Male | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 122 / 137 |
| serious Total, serious adverse events | 14 / 137 |
Outcome results
Primary
Proportion of Responders According to the Modified Teacher's Drooling Scale (mTDS)
The primary efficacy variable was patient's response status using the change from baseline to Week 24 evaluations of the mTDS assessment. Each patient was classified as a responder or non-responder according to the change in their mean mTDS rating from baseline to Week 24. Responders were patients who had at least a 3-point decrease in mTDS rating from baseline
Time frame: 6 months
Population: The analysis was done by intention to treat method. For purposes of statistical estimation, patients who dropped out due to lack of efficacy had their worst observation carried forward. Patients who dropped out for reasons other than lack of efficacy had their last observation carried forward
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients With Chronic Drooling | Proportion of Responders According to the Modified Teacher's Drooling Scale (mTDS) | Responders | 68 Participants |
| Patients With Chronic Drooling | Proportion of Responders According to the Modified Teacher's Drooling Scale (mTDS) | Non-Responders | 62 Participants |
| Patients With Chronic Drooling | Proportion of Responders According to the Modified Teacher's Drooling Scale (mTDS) | Missing | 7 Participants |
Secondary
Investigator's Global Assessment of Treatment
The investigator performed an overall evaluation of glycopyrrolate liquid for the treatment of drooling, benefits, and side effects over the duration of the study. The investigator selected one of the following choices to assess if 'This is a worthwhile treatment': 1 = strongly agree, 2 = agree, 3 = neutral, 4 = disagree, 5 = strongly disagree. A dichotomous global assessment was also performed and summarized with the categories 'responder' (strongly agree and agree responses aggregated) and 'non-responder' (neutral, disagree, and strongly disagree responses aggregated)
Time frame: Week 24
Population: The analysis for investigator's Global Assessment was done by intention to treat method
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients With Chronic Drooling | Investigator's Global Assessment of Treatment | Responders | 109 Participants |
| Patients With Chronic Drooling | Investigator's Global Assessment of Treatment | Non-Responders | 18 Participants |
| Patients With Chronic Drooling | Investigator's Global Assessment of Treatment | Missing | 10 Participants |
Secondary
Parent/Caregiver's Assessment of the Extent of Drooling Using VAS
Parents/caregivers were to complete a 10 cm Parent/Caregiver's Assessment of Extent of Drooling for the Day VAS assessment (0 = normal; 10 = extremely wet) to provide an overall assessment of the extent of drooling for that day.
Time frame: Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients With Chronic Drooling | Parent/Caregiver's Assessment of the Extent of Drooling Using VAS | 3.21 VAS score | Standard Deviation 2.2 |
Secondary
Parent/Caregiver's Assessment of the Extent of Drooling Using Visual Analog Scale (VAS)
Parents/caregivers were to complete a 10 cm Parent/Caregiver's Assessment of Extent of Drooling for the Day VAS assessment (0 = normal; 10 = extremely wet) to provide an overall assessment of the extent of drooling for that day.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Patients With Chronic Drooling | Parent/Caregiver's Assessment of the Extent of Drooling Using Visual Analog Scale (VAS) | 6.56 VAS score | Standard Deviation 2.34 |
Secondary
Parent/Caregiver's Global Assessment of Treatment
The parent/caregiver performed an overall evaluation of glycopyrrolate liquid for the treatment of drooling, benefits, and side effects over the duration of the study. The parent/caregiver selected one of the following choices to assess if 'This is a worthwhile treatment': 1 = strongly agree, 2 = agree, 3 = neutral, 4 = disagree, 5 = strongly disagree. A dichotomous global assessment was also performed and summarized with the categories 'responder' (strongly agree and agree responses aggregated) and 'non-responder'(neutral, disagree, and strongly disagree responses aggregated)
Time frame: Week 24
Population: The analysis for parent/caregiver's Global Assessment was done by intention to treat method
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Patients With Chronic Drooling | Parent/Caregiver's Global Assessment of Treatment | Responders | 101 Participants |
| Patients With Chronic Drooling | Parent/Caregiver's Global Assessment of Treatment | Non-Responders | 20 Participants |
| Patients With Chronic Drooling | Parent/Caregiver's Global Assessment of Treatment | Missing | 16 Participants |