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Randomized, Placebo-Controlled Study of Tolcapone in Patients with Fluctuating Parkinson Disease Treated with Levodopa-Carbidopa

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Randomized, Placebo-Controlled Study of Tolcapone in Patients with Fluctuating Parkinson Disease Treated with Levodopa-Carbidopa ORIGINAL CONTRIBUTION Randomized, Placebo-Controlled Study of Tolcapone in Patients With Fluctuating Parkinson Disease Treated With Levodopa-Carbidopa Charles H. Adler, MD, PhD; Carlos Singer, MD; Christopher O’Brien, MD; Robert A. Hauser, MD; Mark F. Lew, MD; Kenneth L. Marek, MD; Ernest Dorflinger, MD; Simon Pedder, PhD; Dennis Deptula, PhD; Kisook Yoo, PhD; for the Tolcapone Fluctuator Study Group III Objective: To assess the efficacy and tolerability of the tively, and increased on time by 2.1 and 2.3 hours per catechol-O-methyltransferase inhibitor tolcapone in re- day, respectively (P,.001 vs placebo). Investigators’ ducing “off/on” fluctuations in levodopa-treated parkin- global measures of disease severity indicated that signifi- sonian patients. cantly more tolcapone-treated patients had reduced wear- ing off and symptom severity (P,.001 vs placebo). No Design: A randomized, double-blind, placebo- significant change in quality-of-life measures occurred. controlled, parallel-group study. Clinical improvements occurred despite a reduction in total daily levodopa dose of 185.5 mg (23%) in the tol- Setting: Fifteen Parkinson disease clinics. capone, 100 mg 3 times daily, group and 251.5 mg (29%) in the 200 mg 3 times daily group. Principal adverse events Patients: Two hundred fifteen referred outpatients with (mainly dyskinesia and nausea) were levodopa related, Parkinson disease who showed predictable end-of-dose mo- were not treatment limiting, and were seldom reported torfluctuationsthatwerenotcontrolledbyastablelevodopa- as reasons for withdrawal. The frequency of withdraw- carbidopa (Sinemet) regimen of at least 4 weeks’ duration. als because of adverse events was similar in all groups (3% to 7%). Interventions: In addition to their usual levodopa- carbidopa regimen, patients received placebo or tolca- Conclusions: Tolcapone was well tolerated and sub- pone, 100 or 200 mg, 3 times daily orally for 6 weeks. stantially increased on time and reduced off time in patients with fluctuating Parkinson disease. Addi- Primary Outcome Measure: Change in daily off/on time. tionally, levodopa requirements were significantly decreased. Results: Tolcapone, 100 and 200 mg 3 times daily, re- duced off time by 2.0 and 2.5 hours per day, respec- Arch Neurol. 1998;55:1089-1095 OLCAPONE (3,4-dihydrox- tive of levodopa was reduced.2 These 49-methyl-5-nitrobenzo- results suggest that tolcapone should sta- phenone) is a selective and bilize plasma levodopa concentrations in reversible catechol-O- parkinsonian patients who are experienc- methyltransferase inhibi- ing “wearing off.”3 Ttor1 that is being developed as adjunctive Preliminary clinical trials showed therapy to levodopa plus a peripheral dopa that tolcapone reduced “off” time and decarboxylase inhibitor (benserazide or increased “on” time in parkinsonian carbidopa) in the treatment of Parkinson patients with the wearing-off phe- disease. nomenon.4-8 These results were subse- In pharmacokinetic studies in healthy quently confirmed in a larger trial, in volunteers receiving combination treat- which tolcapone was shown to be well ment with levodopa plus carbidopa or tolerated in patients with Parkinson dis- benserazide, the area under the plasma ease.9 The present study provides fur- The affiliations of the authors concentration–time curve and the elimi- ther confirmation of the efficacy and appear in the Acknowledgment section at the end of the article. nation half-life of levodopa were in- tolerability of tolcapone (100 and 200 A list of the participants in the creased when tolcapone was added to the mg given 3 times daily [tid]) in increas- Tolcapone Fluctuator Study regimen. There was no effect on peak con- ing on time and reducing off time in Group III appears on page centrations. At the same time, the area un- levodopa-treated parkinsonian patients 1094. der the curve for the methylated deriva- with wearing off. ARCH NEUROL / VOL 55, AUG 1998 1089 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 PATIENTS AND METHODS complete at least 3 diaries each week during the 3- to 4- week screening period (only the last 3 diaries completed each week were assessed). The diaries had to reveal at least 2 sepa- This double-blind, placebo-controlled, randomized, parallel- rate off periods after the first on period of the day, or at least group trial was conducted at 15 centers in the United States 3 hours of off time after the first on period of the day. Pa- and Canada. All patients provided signed informed con- tients who qualified were then assessed by means of the Uni- sent that was approved by each site’s institutional review fied Parkinson’s Disease Rating Scale (UPDRS)10 in the on board. state only, and completed the Sickness Impact Profile (SIP)11 on the day before randomization. PATIENTS RANDOMIZATION AND BLINDING Patients were eligible for the study if they were at least 30 years old, had at least 2 of the cardinal signs of idiopathic Patients who completed the screening period and satisfied Parkinson disease (rigidity, resting tremor, or bradykine- the criteria for both inclusion and exclusion were allo- sia), and had been treated with levodopa-carbidopa for at cated randomly to treatment groups. Patient randomiza- least 1 year, with clear clinical improvement. They were re- tion numbers were generated in blocks of 6 for each cen- quired to be taking at least 4 daily doses of levodopa- ter by the sponsor’s drug-packaging department and carbidopa (Sinemet), or 3 doses if at least 2 were controlled incorporated into double-blind labeling. These random- release, and to show predictable end-of-dose wearing off that ization numbers were then assigned sequentially in each could not be eliminated by adjusting their existing antipar- center in the order in which the patients were enrolled. kinsonian medications. They had to be able to keep reliable During the study, both the patients and the investi- diaries of off time and on time, alone or with the help of a gators were blind to the treatment. Blinding was effected family member. The minimum acceptable dose of car- by the use of matching placebo tablets. No open key to the bidopa was 20 mg with each dose of levodopa or a total daily blinding code was available to investigators, study moni- dose of 70 mg. Women had to be sterile or using effective tors, or the sponsor’s employees. The investigators re- contraception. Patients were required to have been taking a ceived medications bearing sealed coded labels (contain- stable regimen of levodopa (either immediate-release or con- ing the identity of the treatment dispensed) for each patient. trolled-release formulations), dopamine agonists, selegi- At the final monitoring visit, all labels were counted and line hydrochloride, or other antiparkinsonian drugs for at checked by the study monitor for evidence of tampering least 4 weeks before randomization. before being returned to the sponsor. No labels were opened The principal exclusion criteria were nonidiopathic during the study. Parkinson disease or parkinsonian variants, sudden and un- predictable off/on fluctuations, or a diphasic pattern of dys- TREATMENT kinesias. Other exclusion criteria included treatment with centrally acting dopamine antagonists or monoamine oxi- In addition to their usual levodopa-carbidopa regimen, pa- dase inhibitors (other than selegiline) within the previous tients randomly received placebo or tolcapone, 100 or 200 2 months, drug or alcohol abuse within the previous 2 years, mg tid. The first daily dose of tolcapone or placebo was given psychotic illness or major depression within the previous with the first dose of levodopa-carbidopa; the second and 6 months, and any other clinically significant medical or third doses of tolcapone or placebo were taken at 6-hour in- neurological abnormalities. tervals thereafter, regardless of meals or subsequent levodopa- carbidopa intakes. Treatment was continued for 6 weeks. SCREENING After the first day of study medication, the dosage of levodopa could be modified either by increasing the dosage Eligible patients underwent an evaluation with medical his- interval or by reducing the dose at each time point, if the pa- tory and examination, laboratory tests, and an electrocar- tient had dopaminergic-related side effects. If this occurred, diogram. Patients received instructions from the investiga- the dosage could be increased at a later date, but the total le- tor on completing the diary forms (see below) and had to vodopa dose or dosage frequency was not to exceed that at RESULTS EFFICACY The effects of tolcapone treatment on levodopa dosage, In total, 215 patients correctly completed their off/on off/on time, UPDRS scores, IGAs, and SIP scores are sum- self-rating charts according to the protocol during the marized in Table 2. screening period and were randomized to treatment Analysis of the patients’ diaries showed that off time (Figure 1). The 3 groups were well matched, on was significantly reduced and on time significantly increased average, in terms of patient characteristics and disease in both tolcapone groups, compared with the placebo group history (Table 1). Patients entered into the study had (P,.001; Table 2). The onset of response was rapid and suffered from Parkinson disease for approximately marked: improvement was observed after 2 weeks of treat- 10.5 years and had been taking levodopa for approxi- ment (first assessment performed after baseline; Figure 2). mately 8.5 years. Most patients (194 of the 215) had a By week 6, on time had increased by more than 2 hours, Hoehn and Yahr score of 2 to 3 during on time, and and off time had decreased to a similar extent in both tol- 163 of the 215 (76%) experienced “on” dyskinesias capone groups. This represents a reduction in off time of before randomization. up to 38%. ARCH NEUROL / VOL 55, AUG 1998 1090 ©1998 American Medical Association. All rights reserved.
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