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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT00607542
First received: January 22, 2008
Last updated: December 2, 2011
Last verified: February 2011
  Purpose

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 Intervention Phase
Spasticity
Cerebral Palsy
Drug: baclofen
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pediatric Pharmacokinetic and Pharmacodynamic Study of Oral Baclofen for the Treatment of Spasticity Associated With Cerebral Palsy

Resource links provided by NLM:


Further study details as provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

Primary Outcome Measures:
  • Determine pharmacokinetic parameters of oral baclofen in children with spasticity associated with cerebral palsy (CP). [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Describe the relationship between plasma concentrations of oral baclofen and clinical measures of spasticity. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Determine optimal dosing range and interval for administration of oral baclofen for use in a randomized clinical trial of safety and efficacy. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]

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. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Describe the safety and tolerability of oral baclofen in children with spasticity associated with CP. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
  • Investigate preliminarily whether oral baclofen improves dystonia [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Enrollment: 61
Study Start Date: November 2008
Study Completion Date: January 2011
Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Lioresal

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.

  Eligibility

Ages Eligible for Study:   2 Years to 16 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males and females aged 2-16 years, inclusive.
  2. Triceps skinfold thickness between the 5th and 95th percentiles for age (Refer to Appendix 3).
  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).
  4. Ashworth score of 2 or higher in at least one arm and one leg (knee + elbow flexors and/or extensors).
  5. 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.
  6. No history of baclofen use within the past 4 months.
  7. 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.
  8. 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:

  1. Hypersensitivity to baclofen.
  2. Selective dorsal rhizotomy.
  3. Active intrathecal baclofen pump within the past 6 months.
  4. Use of botulinum toxin in past 4 months or use any time during the study.
  5. Use of tone altering medications (e.g. baclofen, benzodiazepines, levodopa, trihexyphenidyl) for >3 consecutive days duration within the past 4 months.
  6. Start of any drug or product known to be a significant cytochrome P450 enzyme inducer or inhibitor within the past 30 days.
  7. Orthopaedic surgery within the past year or any time during the study.
  8. Abdominal surgery within the past six months or any time during the study.
  9. 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.
  10. Severe behavior difficulties or psychiatric disturbance
  11. Proven gastric dysmotility: known history of abnormal gastric emptying study and/or history of vomiting 3 or more times per week.
  12. Severe Gastroesophageal Reflux Disease: known history of esophagitis (documented on abnormal endoscopy or biopsy).
  13. Malnutrition: defined as triceps skin fold thickness less than 5th or greater than 95th percentile for age.
  14. 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.
  15. Abnormal CBC: Anemia, polycythemia, neutropenia, leukocytosis, thrombocytopenia, or thrombocytosis clinically significant as determined by the investigator.
  16. Pregnancy or lactation.
  17. 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.
  18. 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.
  19. 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) .
  20. 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.
  21. Subject is known to have tested seropositive for the human immunodeficiency virus (HIV) or subject is concomitantly receiving anti-retroviral therapy.
  22. 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.
  23. 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.
  24. Any condition which would make the patient
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00607542

Locations
United States, Illinois
Rehabilitation Institute of Chicago
Chicago, Illinois, United States, 60611
United States, Louisiana
Children's Hospital of Lousiana
New Orleans, Louisiana, United States, 70118
United States, Maryland
Kennedy Krieger Institute
Baltimore, Maryland, United States, 21205
United States, Minnesota
Gillette Children's Speciality Healthcare
St. Paul, Minnesota, United States, 55101
United States, Missouri
Children's Mercy Hospital and Clinics
Kansas City, Missouri, United States, 64108
Washington Univeristy - St. Louis Children's hospital
St. Louis, Missouri, United States, 63110-1093
United States, New York
SUNY Upstate Medical University
Syracuse, New York, United States, 13210
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229-3039
United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
United States, Virginia
Kluge Children's Rehabilitation Center - University of Virginia
Charlottesville, Virginia, United States, 22903
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Investigators
Principal Investigator: Janice Brunstrom, MD Washington University of St. Louis
Principal Investigator: Richard Stevenson, MD University of Virginia
  More Information

No publications provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT00607542     History of Changes
Other Study ID Numbers: NICHD-2005-13-2, 267200603421
Study First Received: January 22, 2008
Last Updated: December 2, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):
spasticity
cerebral palsy
baclofen
pharmacokinetics
pharmacodynamics
dosing
safety
efficacy

Additional relevant MeSH terms:
Cerebral Palsy
Muscle Spasticity
Paralysis
Brain Damage, Chronic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Muscular Diseases
Musculoskeletal Diseases
Muscle Hypertonia
Neuromuscular Manifestations
Neurologic Manifestations
Signs and Symptoms
Baclofen
Muscle Relaxants, Central
Physiological Effects of Drugs
Pharmacologic Actions
Neuromuscular Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
GABA-B Receptor Agonists
GABA Agonists
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 01, 2014