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

• ClinicalTrials.gov Identifier: NCT00607542
• Recruitment Status: Completed
• First Posted: February 5, 2008
• Last Update Posted: December 6, 2011
• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

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 (Clinical Trial)
• 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: November 2008
• Actual Primary Completion Date: January 2011
• Actual Study Completion Date: January 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 Name: Lioresal

Outcome Measures

Primary Outcome Measures :

1. Determine pharmacokinetic parameters of oral baclofen in children with spasticity associated with cerebral palsy (CP). [ Time Frame: 1 year ]
2. Describe the relationship between plasma concentrations of oral baclofen and clinical measures of spasticity. [ Time Frame: 1 year ]
3. 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 ]

Secondary Outcome Measures :

1. 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 ]
2. Describe the safety and tolerability of oral baclofen in children with spasticity associated with CP. [ Time Frame: 1 year ]
3. Investigate preliminarily whether oral baclofen improves dystonia [ Time Frame: 1 year ]

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 16 Years (Child)
• Sexes Eligible for Study: All
• 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

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

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

Investigators

• Principal Investigator: Janice Brunstrom, MD; Washington University of St. Louis
• Principal Investigator: Richard Stevenson, MD; University of Virginia

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

McLaughlin MJ, He Y, Brunstrom-Hernandez J, Thio LL, Carleton BC, Ross CJD, Gaedigk A, Lewandowski A, Dai H, Jusko WJ, Leeder JS. Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy. PM R. 2018 Mar;10(3):235-243. doi: 10.1016/j.pmrj.2017.08.441. Epub 2017 Sep 1.

He Y, Brunstrom-Hernandez JE, Thio LL, Lackey S, Gaebler-Spira D, Kuroda MM, Stashinko E, Hoon AH Jr, Vargus-Adams J, Stevenson RD, Lowenhaupt S, McLaughlin JF, Christensen A, Dosa NP, Butler M, Schwabe A, Lopez C, Roge D, Kennedy D, Tilton A, Krach LE, Lewandowski A, Dai H, Gaedigk A, Leeder JS, Jusko WJ. Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy. J Pediatr. 2014 May;164(5):1181-1188.e8. doi: 10.1016/j.jpeds.2014.01.029. Epub 2014 Mar 5.

• Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• ClinicalTrials.gov Identifier: NCT00607542
• Other Study ID Numbers: NICHD-2005-13-2; 267200603421
• First Posted: February 5, 2008
• Last Update Posted: December 6, 2011
• Last Verified: February 2011

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:

Muscle Spasticity; Cerebral Palsy; Neurologic Manifestations; Nervous System Diseases; Brain Damage, Chronic; Brain Diseases; Central Nervous System Diseases; Muscular Diseases; Musculoskeletal Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Baclofen; Muscle Relaxants, Central; Physiological Effects of Drugs; Neuromuscular Agents; Peripheral Nervous System Agents; GABA-B Receptor Agonists; GABA Agonists; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action