Clinical trial NCT00607542: Oral Baclofen Pharmacokinetics and Pharmacodynamics in Children With Spasticity
Official title: Pediatric Pharmacokinetic and Pharmacodynamic Study of Oral Baclofen for the Treatment of Spasticity Associated With Cerebral Palsy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Spasticity
Cerebral Palsy
Keywords: spasticity
cerebral palsy
baclofen
pharmacokinetics
pharmacodynamics
dosing
safety
efficacy
Lead sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Sponsor class: NIH
First posted: 2008-02-05
Enrollment: 61
Sex: ALL
Minimum age (years): 2
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Determine pharmacokinetic parameters of oral baclofen in children with spasticity associated with cerebral palsy (CP).
timeFrame: 1 year
measure: Describe the relationship between plasma concentrations of oral baclofen and clinical measures of spasticity.
timeFrame: 1 year
measure: Determine optimal dosing range and interval for administration of oral baclofen for use in a randomized clinical trial of safety and efficacy.
timeFrame: 1 year
Secondary outcomes:
measure: 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.
timeFrame: 1 year
measure: Describe the safety and tolerability of oral baclofen in children with spasticity associated with CP.
timeFrame: 1 year
measure: Investigate preliminarily whether oral baclofen improves dystonia
timeFrame: 1 year
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Rehabilitation Institute of Chicago
state: Illinois
city: New Orleans
country: United States
facility: Children's Hospital of Lousiana
state: Louisiana
city: Baltimore
country: United States
facility: Kennedy Krieger Institute
state: Maryland
city: St. Paul
country: United States
facility: Gillette Children's Speciality Healthcare
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital and Clinics
state: Missouri
city: St. Louis
country: United States
facility: Washington Univeristy - St. Louis Children's hospital
state: Missouri
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Charlottesville
country: United States
facility: Kluge Children's Rehabilitation Center - University of Virginia
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Washington University of St. Louis
name: Janice Brunstrom, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Virginia
name: Richard Stevenson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.