Best PK/PD: Oral Baclofen Pharmacokinetics and Pharmacodynamics in Children With Spasticity

Sponsor

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)

Overall Status

Completed

CT.gov ID

NCT00607542

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

5.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Oral baclofen is used commonly to treat spasticity in children with cerebral palsy. Although for adults there is dosing,safety and efficacy information in the package insert, this is not the case for children. The purpose of this study is to determine how fast the drug is cleared from the body, the correct dose, and long-term safety and efficacy for children with spasticity.

Condition or Disease	Intervention/Treatment	Phase
Spasticity Cerebral Palsy	Drug: baclofen	Phase 1/Phase 2

Detailed Description

Although oral baclofen has been used for several decades for the treatment of spasticity in adults and in children, there is very little data regarding the pharmacokinetic (PK) or pharmacodynamic (PD) properties of baclofen in children. Therefore, pediatric guidelines, including dose ranges, dosing schedules, dose escalation strategies and anticipated side effects are extrapolated from adult data and require an assumption that safety and efficacy in children is comparable to that in adults. Furthermore, there is wide variability in dosing strategies among practitioners who treat children with cerebral palsy (CP) with respect to starting doses, maximum doses and rates of dose escalation.Establishment of safe and effective dosing strategies for children with CP requires an understanding of the PK and PD properties of baclofen in children and recognition of individual differences that may contribute to divergent clinical responses to baclofen among children with CP.

Study Design

Study Type:

Interventional

Actual Enrollment :

61 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Pediatric Pharmacokinetic and Pharmacodynamic Study of Oral Baclofen for the Treatment of Spasticity Associated With Cerebral Palsy

Study Start Date :

Nov 1, 2008

Actual Primary Completion Date :

Jan 1, 2011

Actual Study Completion Date :

Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 starting dose of baclofen 2.5 mg PO TID with dose escalation as tolerated	Drug: baclofen 2.5 mg oral baclofen tablets given three times a day; dose gradually escalated as specified in the protocol Other Names: Lioresal

Arm

Intervention/Treatment

Active Comparator: 1

starting dose of baclofen 2.5 mg PO TID with dose escalation as tolerated

Drug: baclofen

2.5 mg oral baclofen tablets given three times a day; dose gradually escalated as specified in the protocol

Other Names:

Lioresal

Outcome Measures

Primary Outcome Measures

Determine pharmacokinetic parameters of oral baclofen in children with spasticity associated with cerebral palsy (CP). [1 year]
Describe the relationship between plasma concentrations of oral baclofen and clinical measures of spasticity. [1 year]
Determine optimal dosing range and interval for administration of oral baclofen for use in a randomized clinical trial of safety and efficacy. [1 year]

Secondary Outcome Measures

Describe the relationship between plasma concentrations of oral baclofen and measures of strength, function, ease of care, pain/comfort and health related quality of life. [1 year]
Describe the safety and tolerability of oral baclofen in children with spasticity associated with CP. [1 year]
Investigate preliminarily whether oral baclofen improves dystonia [1 year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 16 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Males and females aged 2-16 years, inclusive.
Triceps skinfold thickness between the 5th and 95th percentiles for age (Refer to Appendix 3).
Gross Motor Function Classification Scale (GMFCS) Level II - V (GMFCS classifies children by functional mobility with Level I indicating minimal motor disability and V indicating total body involvement and dependence on others for mobility (Palisano et al, 1997).
Ashworth score of 2 or higher in at least one arm and one leg (knee + elbow flexors and/or extensors).
Cerebral Palsy: Motor disability due to a static, non-progressive brain injury/ malformation occurring prenatally or any time prior to the age of 2 years.
No history of baclofen use within the past 4 months.
Female subject, is premenarchal, or is incapable of pregnancy because of a hysterectomy or tubal ligation; or female subject who is sexually active and capable of pregnancy, has been using an acceptable method of contraception (hormonal contraceptives, intrauterine device, spermicide and barrier) for at least one month prior to study entry and agrees to continue to use one of these for the duration of the study; or female subject who is sexually abstinent and capable of pregnancy, agrees to continued abstinence or to use an acceptable method of birth control (either intrauterine device or spermicide and barrier) should sexual activity commence.
Subject ≥10 years of age has negative urine tests at screening and baseline for alcohol, non-medically prescribed drugs of abuse, and no history of tobacco use.

Exclusion Criteria:

Hypersensitivity to baclofen.
Selective dorsal rhizotomy.
Active intrathecal baclofen pump within the past 6 months.
Use of botulinum toxin in past 4 months or use any time during the study.
Use of tone altering medications (e.g. baclofen, benzodiazepines, levodopa, trihexyphenidyl) for >3 consecutive days duration within the past 4 months.
Start of any drug or product known to be a significant cytochrome P450 enzyme inducer or inhibitor within the past 30 days.
Orthopaedic surgery within the past year or any time during the study.
Abdominal surgery within the past six months or any time during the study.
Uncontrolled seizures (baseline seizure frequency >1 per month or history of more than 2 prolonged seizures lasting longer than 5 minutes duration within the past year.
Severe behavior difficulties or psychiatric disturbance
Proven gastric dysmotility: known history of abnormal gastric emptying study and/or history of vomiting 3 or more times per week.
Severe Gastroesophageal Reflux Disease: known history of esophagitis (documented on abnormal endoscopy or biopsy).
Malnutrition: defined as triceps skin fold thickness less than 5th or greater than 95th percentile for age.
Renal or Liver disease: Elevated bilirubin, LFTs greater than twice the upper limit of normal, reduced BUN/Cr ratio (<5), or abnormal creatinine clearance that is clinically significant as determined by the investigator.
Abnormal CBC: Anemia, polycythemia, neutropenia, leukocytosis, thrombocytopenia, or thrombocytosis clinically significant as determined by the investigator.
Pregnancy or lactation.
Severe respiratory or cardiac disease: Requirement for prolonged supplemental oxygen (>7 days), history of clinically significant congenital heart disease, congestive heart failure or cardiomegaly, and/or hospital admission within past 6 months for cardiac symptoms or respiratory distress.
Previous baclofen failure: Lack of response to baclofen or presence of unacceptable side effects. If previous baclofen therapy was tried >4 months prior to study and discontinued, the decision to enroll subject will be at the discretion of the site investigator and reason for discontinuation of oral baclofen will be recorded.
Use of medications that interfere with measurements of serum creatinine levels within the past 14 days (e.g., trimethoprim-sulfa, fibric acid derivatives other than gemfibrizol, keto acids, salicylates, some cephalosporins, cimetidine, phenacemide) .
Subject tests positive at screening for the hepatitis B surface antigen or hepatitis C antibody, or has a history of a positive result for one of these tests.
Subject is known to have tested seropositive for the human immunodeficiency virus (HIV) or subject is concomitantly receiving anti-retroviral therapy.
Any serious, unstable medical illness or clinically significant abnormal laboratory assessment that would adversely impact the scientific interpretability or unduly increase the risks of the protocol.
Subject has a disorder or history of a condition, other than that related to CP that could interfere with drug absorption, distribution, metabolism, or excretion.
Any condition which would make the patient

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rehabilitation Institute of Chicago	Chicago	Illinois	United States	60611
2	Children's Hospital of Lousiana	New Orleans	Louisiana	United States	70118
3	Kennedy Krieger Institute	Baltimore	Maryland	United States	21205
4	Gillette Children's Speciality Healthcare	St. Paul	Minnesota	United States	55101
5	Children's Mercy Hospital and Clinics	Kansas City	Missouri	United States	64108
6	Washington Univeristy - St. Louis Children's hospital	St. Louis	Missouri	United States	63110-1093
7	SUNY Upstate Medical University	Syracuse	New York	United States	13210
8	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
9	Texas Children's Hospital	Houston	Texas	United States	77030
10	Kluge Children's Rehabilitation Center - University of Virginia	Charlottesville	Virginia	United States	22903
11	Seattle Children's Hospital	Seattle	Washington	United States	98105