ORIGINAL CONTRIBUTION Evaluation of Dyskinesias in a Pilot, Randomized, Placebo-Controlled Trial of Remacemide in Advanced Parkinson Disease Parkinson Study Group Context: Long-term levodopa therapy for Parkinson dis- (MGDRS), a newly created Lang-Fahn Activities of Daily ease commonly results in motor complications includ- Living Dyskinesia scale (LFADLDS), and diary dyskine- ing “on-off” fluctuations and dyskinesias, but it is still sia ratings. unclear how best to assess treatment effects on dyskine- sias in clinical trials. Results: Patient and investigator diaries showed excel- lent agreement in dyskinesia ratings. The MGDRS score Objective: To compare several methods of rating le- correlated with clinic diary ratings of the percentage of vodopa-induced dyskinesias to evaluate the effect of rema- “on” time with dyskinesias, and the LFADLDS score cor- cemide hydrochloride treatment in patients with ad- related with home and clinic diary assessments of per- vanced Parkinson disease. centage of on time with severe dyskinesias. The MGDRS score did not correlate highly with the LFADLDS score. Design: Two-week multicenter randomized, double- This pilot study also validated previous results demon- blind, placebo-controlled, parallel-group study. strating the safety and tolerability of remacemide treat- ment for advanced Parkinson disease but did not result Setting: Five academic sites of the Parkinson Study Group. in any demonstrable improvement or worsening in dys- kinesia measures. Patients: Thirty-nine subjects at least 30 years old with idiopathic Parkinson disease and disabling dyskinesias. Conclusions: Diaries may provide a valid means of evalu- ating dyskinesias in clinical trials for Parkinson disease, Interventions: Randomly received daily doses of 150 but there remain other aspects of dyskinesias, as as- mg, 300 mg, or 600 mg of remacemide hydrochloride or sessed by the MGDRS and LFADLDS, that are not re- matching placebo for 2 weeks. flected in diary ratings. Main Outcome Measures: The dyskinesia rating scales used were the Modified Goetz Dyskinesia Rating scale Arch Neurol. 2001;58:1660-1668 ITHIN 5 years of di- sonian response in both primates and ro- agnosis approxi- dents.6,9,10 Oh and colleagues11 have mately half of the reported that intermittent stimulation of patients with Par- normally functioning dopaminergic re- kinson disease (PD) ceptors activates intraneuronal signaling Wtreated with levodopa develop motor com- pathways in striatal spiny neurons that al- plications, including “on-off” fluctuations ters the phosphorylation state of coex- and dyskinesias.1 Dyskinesias often ex- pressed NMDA glutamate receptors. This hibit a dose-dependent relationship with causes an increased sensitivity of these glu- dopaminergic therapy, diminishing with tamatergic receptors to cortical input to the dosage decreases and worsening with in- striatum and consequent motor fluctua- creases.2 The pathophysiological origins of tions and dyskinesias.11,12 Thus, NMDA an- these phenomena have not been defini- tagonists may reduce or prevent the de- tively established; however, the mecha- velopment of these motor complications. nism underlying the development of dys- Remacemide hydrochloride is a non- kinesias may be distinct from that of competitive NMDA channel antagonist levodopa’s antiparkinsonian properties.3-8 with antiparkinsonian efficacy in rodent Systemic administration of N- and primate models of PD when used in methyl D-aspartate (NMDA) antagonists combination with levodopa, but not when A complete list of the authors can ameliorate levodopa-induced dyski- administered alone.13 It is safe and well tol- appears on page 1668. nesias without a reduction in antiparkin- erated in patients with PD, and prelimi- ARCH NEUROL / VOL 58, OCT 2001 WWW.ARCHNEUROL.COM 1660 ©2001 American Medical Association. All rights reserved. (REPRINTED WITH CORRECTIONS) Downloaded From: https://jamanetwork.com/ on 09/23/2021 PATIENTS AND METHODS these diaries by each patient, extensive instructions were given, an instructional videotape classifying dyskinesia severity was shown, and a training and practice scoring session was done PATIENTS with the investigator. During this session, the patient had to beseeninboth “fulloff”and“onwithseveredyskinesias”states Thirty-nine patients with idiopathic PD were enrolled from (adjusting the dosage and timing of antiparkinsonian medi- 5 sites of the Parkinson Study Group (Figure 2). Sub- cations, if necessary, to do so), and complete agreement be- jects were aged 30 years or older and had disabling dyski- tween the patient and the investigator on the classification of nesias that were defined by their presence historically greater all observed clinical states had to be achieved. Patients were than 25% of the average waking day (ie, score Ն2onthe then given home dyskinesia diaries to fill out on each of 3 con- Unified Parkinson’s Disease Rating Scale [UPDRS], part IV secutive days immediately prior to the baseline visit. [complications of therapy], item 32 [What proportion of Within 14 days, qualified patients returned for base- the waking day are dyskinesias present?]) and interfer- line evaluation and the 3-day home diaries were reviewed. ence with activities of daily living to at least a moderate ex- At this time, pretreatment clinical assessments were also tent (ie, score Ն2 on the UPDRS, part IV, item 33 [How performed during an observation period of 6 hours. Pa- disabling are the dyskinesias?], and a score of 2 or more tients were instructed to take their usual doses of antipar- on at least 2 of the 5 items in the LFADLDS [Table 1]). Sub- kinsonian medications with a low-protein breakfast prior jects were treated with stable optimized dosages of le- to arrival at the clinic and to report to the research center vodopa for at least 2 to 4 weeks prior to enrollment, and for the study visit at a fixed time (9 AM). All antiparkinso- could be taking stable dosages of selegiline hydrochlo- nian medications were given on a predefined schedule iden- ride, dopamine agonists, or catechol O-methyltransferase tical to the patient’s schedule at home, and a standardized inhibitors. Patients were excluded if they were taking medi- lunch was provided at a set hour. cations that could potentially alter parkinsonism, affect dys- At the end of the baseline visit, subjects were ran- kinesias, or interfere with the metabolism or mechanism domly assigned to receive remacemide hydrochloride, 150 of action of the study medication, or if there was evidence mg/d, 300 mg/d, or 600 mg/d, or matching placebo, in 2 of significant depression, dementia, psychosis, or other se- divided doses 12 hours (±2 hours) apart. The computer- rious medical conditions. generated randomization plan included stratification by cen- ter and blocking to ensure approximate balance among the PROCEDURES treatment groups within each center. Sites telephoned the Parkinson Study Group Coordination Center, Rochester, After informed consent was obtained, screening medical NY, to enroll patients, and patient identification numbers and laboratory evaluations were performed with the were assigned through an interactive computer module. Pa- patient in the “on” state (ie, with good function). Clinical tients were then instructed to fill out another set of 3 home assessments included the modified Hoehn and Yahr scale, diaries immediately prior to the next visit. UPDRS parts I to IV (ie, mentation, activities of daily liv- Administration of medication was initiated on the ing [ADL], motor function, and complications of therapy, evening of the baseline visit and titrated up to the as- respectively), Clinical Global Impressions scale, Schwab signed dosage over 5 days. This intervention continued for and England ADL scale, Mini-Mental State Examination, a total of 2 weeks. If a patient developed intolerance to the and the Beck Depression Inventory. Measures of dyskine- medication, a change from the twice daily regimen to a 4 sia severity were also obtained (described in the “Dyski- times daily regimen, without changing the total daily dos- nesia Outcome Measures” subsection of the “Patients and age, was recommended. Methods” section), and the home dyskinesia diaries were introduced. To ensure reliable and accurate completion of Continued on next page nary studies indicate that it may improve motor fluctua- (LFADLDS) (Table 1), and dyskinesia diary rating cards tions in levodopa-treated patients.14,15 Whether it has a (Figure 1). significant effect on dyskinesias has not yet been estab- lished, but it has been suggested that an NMDA antago- RESULTS nist effect accounts for the efficacy of amantadine hy- drochloride treatment in improving levodopa-induced SUBJECT CHARACTERISTICS dyskinesias.16 We planned this preliminary multicenter random- Baseline characteristics of the 4 treatment groups are given ized, double-blind, placebo-controlled, parallel-group in Table 2. Overall, patients’ ages averaged (±SD) study to evaluate the effects of 3 different dosages of rema- 64.3±8.4 years and they had a diagnosis of PD for cemide in patients with PD who have disabling dyski- 13.3±5.8 years (mean±SD). Patients spent 75.4%±16.1% nesias. Since no standard criterion for the evaluation of (mean±SD) of the waking day in the on state on aver- dyskinesia severity within a clinical trial exists and the age, including 59.5%±19.9% (mean±SD) of the waking problem is multifaceted, we used several methods of as- day with dyskinesias and 28.5%±25.7% (mean±SD) with sessment to determine