Excessive Crying in Children With Cerebral Palsy and Communication Deficits

Study Overview
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Brief Summary
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Management of excessive crying in children with cerebral palsy and communication deficits [ECCCPCD] was guided by the associated clinical findings and investigations.

Detailed Description
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Pain treatments are frequently hit or miss, trial & error, or because of the fear of litigations, not offered at all, particularly in cerebral palsy. Pain is an under-suspected and under-diagnosed cause of ECCCPCD. It was hypothesized that pain/discomfort was responsible for ECCCPCD, and a vicious cycle of pain-spasm-pain aggravated the pain/discomfort. So, the response of ECCCPCD to treatment guided by clinical findings & investigations was studied. There was an initial placebo run-in period. This study was a prospective, single-center, interventional, with initial placebo-control, double-blind for initial 110 days, open-label for the next 290 days, fixed-sequence, two treatment, two-period, crossover clinical trial. The placebo run-in period (15 days) was followed by the placebo period (15 days). After a washout period (10 days), drug treatment (360 days) was started depending on the clinical findings and investigations. The drugs used either singly or in various combinations were GABA-B agonists, muscarinic acetylcholine receptor antagonists, benzodiazepines, inhibitors of the vesicular monoamine transporter, antiepileptics, and tricyclic antidepressants. The outcome measure was total, and unexplained mean cry durations in hours per day. The cry duration was measured for one 10-day period while on placebo [days P6-P15], and four 10-day periods while on treatment [T61-70, T241-250, T311-320, and T351-360]. Total and unexplained mean cry durations in hours per day were calculated from 10-day measurements of cry durations. From the 251st day of therapy, the dose was reduced by 5% every week until [ECCCPCD] started to increase. This reduction of the dose was made to confirm the efficacy of drugs and to check if the dosage requirement has reduced after 250 days of treatment. This dose was maintained until the next measurement between T311 and T320. Then the dosages were adjusted as necessary. The caregivers were allowed to volunteer any additional observations of interest. Drug adverse effects were recorded. Epidemiological data, GMFCS levels, and MAS scores were noted at the time of enrollment. Summary statistics were tabulated and plotted. Paired t-tests and Wilcoxon tests were done to study the statistical significance.

Official Title
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Excessive Crying in Children With Cerebral Palsy and Communication Deficits -a Fixed-sequence, Crossover Clinical Trial

Conditions
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Cerebral Palsy, Excessive Crying, Pain

Intervention / Treatment
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* Other: Placebo
* Drug: Baclofen, Diazepam, Clonazepam, Trihexyphenidyl, Tetrabenazine, Gabapentin, Topiramate, Lamotrigine, Amitriptyline.


Participation Criteria
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Eligibility Criteria
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A child with cerebral palsy under the age of 15 years and could not communicate the reason for excessive crying because of young age or global developmental delay/profound intellectual retardation. Excessive crying of >7.5 hours daily for 30 consecutive days unresponsive to treatment by the pediatrician, orthopedic surgeon, gastroenterologist, and physiotherapist. Minimum cry intensity for recording: If the intensity of crying was so high that the caregiver could not hear radio, TV, or another person talking to her [sitting near her], the cry duration was recorded. History, clinical, and neuroimaging findings (structural MRI) were suggestive of chronic static encephalopathy. Motor impairment could be explained by an insult that occurred in the developing fetal or infant brain. Exclusion Criteria: Medicines used in the study were used in the previous 30 days, and it was impossible to taper off the drugs without worsening of symptoms. Excessive crying due to known causes. Progressive encephalopathies.

Ages Eligible for Study
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Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: There was an initial placebo run-in period. This clinical trial was a prospective, single-center, interventional, with initial placebo-control, double-blind for initial 110 days, open-label for the next 290 days, fixed-sequence, two-treatment, two-period, crossover clinical trial. The placebo run-in period (15 days) was followed by the placebo period (15 days). After a washout period (10 days), drug treatment (360 days) was started depending on the clinical findings and investigations.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo-Sequence 1<br>The placebo contained fructose powder in packets identical to the medicines. | Other: Placebo<br>* Fructose powder identical with the drugs was used<br>* Other names: Fruit sugar, levulose.;|
| Active Comparator: Drug-Sequence 2<br>GABA-B agonists, muscarinic acetylcholine receptor antagonists, inhibitors of the vesicular monoamine transporter, benzodiazepines, antiepileptics, and tricyclic antidepressants were used. | Drug: Baclofen, Diazepam, Clonazepam, Trihexyphenidyl, Tetrabenazine, Gabapentin, Topiramate, Lamotrigine, Amitriptyline.<br>* Drugs were used either singly or in combination guided by clinical findings and investigations.<br>* Other names: Baclofen(Liofen®),Diazepam,(Valium®),Clonazepam,(Klonopin®),Trihexyphenidyl(Artane®),Tetrabenazine(Xenazine®),Gabapentin(Neurontin®),Topiramate(Topamax®),Lamotrigine(Lamictal®),Amitriptyline(Elavil®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Epidemiologic data (Age and sex). | Epidemiologic data (age rounded up in years, sex-number of males, females, and transgender, if any). | 400 days. | 
| The Gross Motor Function Classification System (GMFCS) levels | The gross motor function of children with cerebral palsy was categorized into 5 different levels using the Gross Motor Function Classification System tool. A higher score means a worse condition. | 400 days | 
| The Modified Ashworth Scale (MAS) scores | The Modified Ashworth Scale (MAS) scores from 0 to 4 were used. A higher score means a worse condition. | 400 days | 
| Measurement of both Total and Unexplained cry durations | Caregivers measured both Total and Unexplained cry durations with a digital watch or a mobile phone in hours: minutes: seconds over five ten-day periods. MM1 while on placebo days 6-15 [P6-P15], and four measurements MM2 to MM5 while on treatment days 61-70 [T61-70], 241-250 [T241-250], 311-320 [T311-320], and 351-360 [T351-360]. Statistician calculated means of cry duration in hours per day. | 400 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any other changes in the clinical profile observed during the study period and reported by the caregivers. | Any other changes in the clinical profile (frequency changes) observed during the study period were reported by the caregivers. The number and percentages of children with the change were calculated. | 400 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allodynia, Neuropathic pain, Run-in period, childhood onset dystonia, drooling, dysphagia, hyperalgesia, muscle spasticity