Trial 1: Wigal S, Swanson JM, Feifel D, et al. A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2004;43:1,406-1,414.
Drug Criteria & Outcomes: Drug evaluation: Dexmethylphenidate hydrochloride tablets (Focalin)
Drug Criteria & Outcomes
Drug evaluation: Dexmethylphenidate hydrochloride tablets (Focalin)
Part 2 of 2: Clinical Studies, Cost, Application, Formulary Recommendation
By Emily K. Pauli, BS, BMS, PharmD Candidate
Harrison School of Pharmacy
Auburn (AL) University
Clinical studies
Trial 1: Wigal S, Swanson JM, Feifel D, et al. A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2004;43:1,406-1,414.
Study goal: Evaluate d-MPH relative to placebo and d,l-MPH in the treatment of ADHD, including a comparison of the duration of action.
Methods
- Randomized, prospective, multicenter (12 U.S. centers), placebo-controlled clinical trial.
- Children (ages 6-17 years) diagnosed with ADHD according to DSM-IV criteria.
- Primary outcome: Determine efficacy and safety of d-MPH relative to d,l-MPH.
- Secondary outcome: Evaluate the duration of action in clinically titrated doses of d-MPH and d,l-MPH.
- Experimental design
One-week, single-blind placebo lead-in period.
Four-week, double-blind treatment period with randomization into three groups:
- Placebo (n = 42).
- d-MPH (n = 44); initiated at 2.5 mg/day and titrated to 20 mg/day as-needed based on response; average dose = 18.25 mg/day.
- d,l-MPH (n = 46); initiated at 5 mg/day and titrated to 40 mg/day as needed based on response; average dose = 32.14 mg/day.
Treatment definition
- Oral, twice-daily dosing (separated by four hours).
Response measurement
- Primarily by Teacher SNAP rating and secondarily by Parent SNAP rating, CGI-S, and math tests.
- Inclusion criteria
- Ages 6-17 years, diagnosed with ADHD according to DSM-IV criteria, and within 30% of normal body weight.
- Enrolled in school.
- Available for the entire study duration.
- Exclusion criteria
- History or evidence of: cardiovascular, respiratory (other than asthma or allergies), renal, endocrine, central nervous system (other than ADHD), or immune system disease and disorders; or substance abuse.
- Hypersensitivity to stimulants or any MPH product component.
- Treatment with any investigational agent 30 days prior to screening.
- Treatment with antidepressants, sedative/hypnotics, mood stabilizers, anticonvulsants, beta-blockers, alpha-2 agonists, thyroid medications, or oral steroids.
- Strengths
- RCT, multicenter, intention-to-treat.
- Multiple evaluation techniques.
- Statistical power.
- Weaknesses
- Multicenter.
- Four-week treatment period; no counseling included in treatment.
- Treatment response measured primarily by nonclinical evaluator.
- Protocol violation not accounted for in analysis.
- Data reporting incomplete and questionable.
- Failed to meet all study goals.
Analysis of data
- Baseline comparison: Cochran-Mantel-Haenszel (categorical variables) and ANOVA (continuous variables).
- Outcomes →
Efficacy: Cochran-Mantel-Haenszel (categorical variables) and ANCOVA (continuous variables).
Safety (Adverse Events; AE): Fisher’s exact
Duration: ANCOVA
Results
- Primary outcome
- Efficacy: Improvement from baseline compared to placebo for d-MPH and d,l-MPH.
Teacher SNAP rating
d-MPH and d,l-MPH show significant improvement (P < 0.05).
Parent SNAP ratings
3 p.m.: d-MPH and d,l-MPH significant improvement (P < 0.05).
6 p.m.: d-MPH significant improvement (P < 0.05)
d,l-MPH not significant (P > 0.05).
CGI-S scores
Significant improvement (P < 0.05) for d-MPH; not significant for d,l-MPH (P> 0.05).
Math test
Significant (P < 0.05) for d-MPH and d,l-MPH at office exam.
Significant (P < 0.05) for d-MPH at evening/home exam; d,l-MPH not reported.
- Safety
No serious adverse events; mild to moderate only.
Similar relative frequency among all treatment groups.
- Secondary outcome
Duration of action: Change from baseline compared to placebo for d-MPH only
- 6 p.m. data: Parent SNAP and math test.
- Possible six-hour duration for d-MPH.
Conclusion
- Authors’ conclusion
No difference in efficacy and safety between d-MPH and d,l-MPH.
Results suggest slightly longer duration of efficacy for d-MPH over d,l-MPH.
- Emily Pauli’s conclusion
Since d-MPH is the active enantiomer of d,l-MPH, it is not surprising that equivalence in efficacy is established between the active treatment groups. However, a four-week trial is insufficient to draw conclusions regarding safety of a medication.
Data reporting is equivocal and incomplete. It is scientifically indecorous to suggest that d-MPH may have a longer duration of action than d,l-MPH based on reported data in this trial.
Additionally, clinical significance of a six-hour duration of action is questionable with the availability of longer-acting formulations of d,l-MPH.
Trial 2: Arnold LE, Lindsay RL, Conners CK, et al. A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2004;14:542-554.
- Arnold et al have studied 89 adolescents (ages 6-17 years) in a six-week open-label titration of d-MPH followed by a two-week randomized, placebo-controlled withdrawal period designed to determine the efficacy and safety of d-MPH after 7-8 weeks of treatment, and secondarily, to retest the hypothesis that d-MPH has a six-hour duration of action.
- Only 75 adolescents completed the study — evaluation techniques were identical to those used by Wigal et al; the sole determinant for duration of action was the 6 p.m. math test administered on Saturday and Sundays of the last two weeks of the study.
- The authors’ results and conclusions are similar to Wigal et al in that d-MPH is efficacious and safe in treatment of ADHD and that based on the 6 p.m. math score, it shows a duration of six hours compared to placebo (P < 0.05).
Cost
Cost comparisons are presented in Table 2.
Application
- d-MPH is an additional option for the treatment of ADHD in children 6-17 years of age. The efficacy and safety of d-MPH is equal that of the racemic mixture products (d,l-MPH).
- Adverse events are no more common or less frequent with d-MPH.
- All of the studies available regarding clinical use of d-MPH are pre-marketing, Phase III trials. Novartis Pharmaceuticals (which also markets Ritalin) has recently purchased the rights to Focalin from Celgene.
- A head-to-head trial of d-MPH and d,l-MPH that controls for severity of disease and reports all data is needed. Additionally, further investigation into the pharmacology of d-MPH is needed in determining it distinct from methylphenidate.
Formulary recommendation
An automatic formulary interchange is recommended for any child 6-17 years of age that is admitted and requires ADHD treatment with methylphenidate; he or she should be given eqimolar doses of the current methylphenidate formulary agent in lieu of d-MPH or Focalin XR, unless otherwise stated by the prescribing physician.
Recommended reading
- Arnold LE, Lindsay RL, Conners CK, et al. A double-blind, placebo-controlled withdrawal trial of dexmethyl-phenidate hydrochloride in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2004;14:542-554.
- Ding YS, Fowler JS, Volkow ND, et al. Chiral drugs: Comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain. Psychopharmacology 1997;131:71-78.
- Methylphenidate HCl. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc., pp. 773-775.
- MICROMEDEX Healthcare Series. Greenwood Village, CO: MICROMEDEX; (edition expired July 2005).
- National Institute of Mental Health. Attention Deficit Hyperactivity Disorder: An Update. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services; 2003 [cited July 12, 2005]. NIMH Pub No. 3572. Available at: www.nimh.nih.gov/publicat/adhd.cfm#ref.
- Novartis Pharmaceuticals Corp. Focalin package insert. East Hanover, NJ; May 2005.
- Novartis Pharmaceuticals Corp. Focalin XR package insert. East Hanover, NJ; May 2005.
- Red Book Pharmacy’s Fundamental Reference, Thomson Physicians’ Desk Reference. Montvale, NJ; 2005.
- Wigal S, Swanson JM, Feifel D, et al. A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2004;43:1,406-1,414.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.