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 (PϽ.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 wearing off and symptom severity (PϽ.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, reduced 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 4Ј-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 torT1 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.

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©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 (PϽ.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%.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 baseline. If dopaminergic-related adverse events did not re- ment group and placebo. On the basis of the results of pre- solve after reduction of the levodopa dose, adjustments in vious tolcapone studies,4-9 the standardized effect size (mean concomitant antiparkinsonian medication were allowed. divided by SD) of treatment difference in reduction of av- These medications could be decreased or discontinued if erage percentage on or off time from baseline to week 6 an adverse event was believed to be specific to that agent. was assumed to be approximately 0.6. Information on adverse events was collected at each ASSESSMENTS visit. Checklists were used to elicit information on dopaminergic symptoms associated with levodopa treatment. An Efficacy and safety of the study drug were assessed be- adverse event was defined as the worsening of a previous tween baseline (the day before study medication was first symptom or the emergence of a new symptom. Vital signs administered) and week 2 of treatment and at weeks 3 ( ± 3 (heart rate and standing and supine blood pressures) were days) and 6 ( ± 3 days). Patients were examined by the same recorded at each visit. Laboratory tests were performed at investigator at all visits and at the same time of day as the baseline and after 3 and 6 weeks. A 12-lead electrocardio- baseline evaluation. The primary efficacy measure was the gram was recorded at baseline and after 6 weeks. change from baseline in off/on time recorded on the patients’ diaries. For each 30-minute period during the day, STATISTICS the patients were asked to rate their mobility as off (poor mobility or complete immobility), on (good to excellent Efficacy was assessed in part by means of an intention-to- mobility), intermediate (neither off nor on), or asleep. In treat analysis. Patients were included in this analysis if they addition to the diaries completed during the screening pe- had been randomized to treatment, had taken at least 1 dose riod, patients had to complete diaries on at least 3 days dur- of study medication, and had at least 1 follow-up visit. Any ing the week before each visit; again, only the last 3 dia- missing data were replaced by the last available observation ries of each week were used to assess the patient’s off/on after baseline. The safety analysis included all patients who status to avoid bias. were randomized to treatment, received at least 1 dose of study Secondary efficacy measures were used to assess the medication, and had at least 1 safety evaluation. patients’ clinical status. The change in UPDRS subscales I Off/on time, UPDRS and SIP scores, and levodopa dos- (mentation, behavior, and mood), II (activities of daily liv- age were regarded as continuous variables and analyzed by ing) (on and off states), III (motor function) (on state only), analysis of covariance, with Bonferroni-Holm adjustment IVa (dyskinesia), and IVb (clinical fluctuations) scores were to correct for multiple comparisons. The 2-way analysis of evaluated. Investigator’s Global Assessments (IGAs) of covariance model included main effect terms of center and change were made for symptom severity, the wearing-off treatment, center-by-treatment interaction term, and the phenomenon, and overall efficacy and tolerability; a 9- baseline value as covariate. The IGAs of change in symp- point scale, ranging from 4 (very marked improvement) tom severity, the wearing-off phenomenon, and overall ef- to − 4 (very marked deterioration), was used in these as- ficacy were regarded as categorical variables and analyzed sessments. A 7-point scale, ranging from 3 (marked reduc- by the Cochran-Mantel-Haenszel test, with Bonferroni- tion) to − 3 (marked increase), was used to evaluate dys- Holm adjustment. For each dose of tolcapone, the null hy- kinesia. The SIP was assessed at baseline and after 6 weeks pothesis (that mean changes are the same for placebo and to evaluate quality of life; UPDRS subscale II was also used the dose of tolcapone) was tested against the alternative as a measure of quality of life. hypothesis (that mean changes are different between pla- The planned total sample size for this study was 180 cebo and the dose of tolcapone). For each treatment, least- patients (60 per treatment group) because 30% of the pa- squares estimates of the actual treatment mean (least- tients were expected to have unevaluable data or to be un- squares means) were reported. The difference between available because of withdrawal. This would provide a estimates for placebo and each tolcapone treatment group sample of 126 patients (42 patients per treatment group). was also calculated. The 95% confidence intervals of treat- This sample size allows a power of 80% at the 2-sided ␣ ment differences were constructed on the basis of the least- level of 0.05 in detecting a 30% difference (which we judged squares means. Data were entered and analyzed by statis- to be a clinically relevant change) between an active treat- ticians at Hoffmann-La Roche, Nutley, NJ.

A significant reduction was seen in total levodopa with only 19 (26%) of 72 patients taking placebo (PϽ.001). dose and number of intakes of levodopa per day in both The IGAs of change in wearing off and symptom severity tolcapone groups compared with the placebo group (Table also improved significantly compared with placebo 2; Figure 3). The total daily dose of levodopa de- (PϽ.001). The score for the UPDRS subscale III (motor creased in the tolcapone groups by 23% in those receiv- function in the on state) was reduced in tolcapone-treated ing 100 mg tid (PϽ.01 vs placebo) and by 29% in those patients, but the reductions were not significantly differ- receiving 200 mg tid (PϽ.001 vs placebo). The mean num- ent from those in placebo-treated patients. The UPDRS sub- ber of daily levodopa intakes decreased by 0.5 in the 100- scale II (activities of daily living), total UPDRS subscales I mg tid group (PϽ.01 vs placebo) and by 1.2 in the 200- to III, and SIP scores showed no significant difference be- mg tid group (PϽ.001 vs placebo). tween the tolcapone and placebo groups. Tolcapone-treated patients had significant improvements on IGAs of change compared with placebo (Table TOLERABILITY 2). Investigators judged 50 (72%) of 69 patients who received tolcapone, 100 mg tid, and 57 (77%) of 74 who re- Of the 215 patients entered into the study, 13 with- ceived tolcapone, 200 mg tid, to be improved, compared drew, 11 because of adverse events (5 [7%] in the pla-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Eligible Patients Table 1. Baseline Patient Characteristics and Parkinson (n = 215) Disease History for the Intention-to-Treat Population, Last-Observation-Carried-Forward Analysis*

Randomized (n = 215) Tolcapone

Placebo 100 mg tid 200 mg tid Received Tolcapone, Received Tolcapone, Received Placebo Patients, No. 72 69 74 100 mg tid, 200 mg tid, as Allocated Male-female ratio, No. 52:20 46:23 51:23 as Allocated as Allocated (n = 72) (n = 69) (n = 74) Age, y 64 ± 8 62 ± 12 61 ± 10 Duration of disease, y 10.6 ± 5.2 10.5 ± 4.8 10.5 ± 4.6 Duration of previous 8.6 ± 5.2 8.3 ± 4.6 8.7 ± 4.8 Withdrawn During Withdrawn During levodopa treatment, y Treatment (n = 6) Withdrawn During Treatment (n = 4) Patients receiving 52 53 62 Unavailable for Treatment (n = 2) Adverse Events (n = 3) selegiline or a Follow-up (n = 1) Adverse Events (n = 2) Withdrawal of dopamine agonist, No. Adverse Events (n = 5) Consent (n = 1) Hoehn and Yahr stage: “on” state, No. 0-1.5 6 5 4 Assessment of Primary Assessment of Primary Assessment of Primary 2444248 and Secondary and Secondary and Secondary Efficacy Measures; Efficacy Measures; Efficacy Measures; 2.5 10 10 10 Safety Assessments: Safety Assessments: Safety Assessments: 311109 Week 6 Week 6 Week 6 4-5 1 2 2 Proportion of waking 40.8 (1.6) 40.8 (1.6) 42.5 (1.6) day spent “off,” % Completed Trial Completed Trial Completed Trial Proportion of waking 56.1 (1.6) 56.7 (1.6) 56.1 (1.6) (n = 66) (n = 67) (n = 69) day spent “on,” % Dyskinesia, No. 56 46 61 Figure 1. Profile of study; tid indicates 3 times daily UPDRS subscales 26.5 ± 13.5 25.9 ± 13.9 27.4 ± 14.2 I to III total score cebo group and, in the tolcapone groups, 2 [3%] of those *Data are means ± SDs or least-squares means (SEM), based on analysis receiving 100 mg tid and 4 [5%] of those receiving 200 of covariance, or analysis of variance for baseline values. UPDRS indicates mg tid). In the placebo group, most withdrawals oc- Unified Parkinson’s Disease Rating Scale; tid, 3 times daily. No significant curred within 4 weeks of starting treatment, whereas in differences were seen between the groups. the tolcapone groups, most withdrawals occurred after 4 to 6 weeks. Adverse events were reported by 53 (74%) of 72 treatment groups showed similar incidences at baseline patients in the placebo group, compared with 59 (86%) and week 6 in duration of dyskinesia and painful dyski- of 69 receiving tolcapone, 100 mg tid, and 72 (97%) of nesia according to the UPDRS subscale IVa (dyskinesia 74 receiving tolcapone, 200 mg tid. Most adverse events ratings). The degree of disability resulting from dyski- were mild or moderate; of the 658 events reported over- nesia was also similar in all 3 groups. No difference in all, only 95 (14%) were rated as severe (an adverse early-morning dystonia was observed between the treat- event was classified as severe even if it was usually mild ment groups. but reached a peak of severity at some point during the Worsening of dyskinesia, as with most dopaminer- patient’s treatment). The frequency of severe adverse gic symptoms, occurred most often at the start of treat- events was 11% in the placebo group and 11% in those ment. The prevalence diminished with time, so that by receiving 100 mg tid and 19% in those receiving 200 the end of the study 5 (7%) of 72 patients in the placebo mg tid. group; 23 (33%) of 69 in the tolcapone, 100-mg tid group; Twelve adverse events were reported at an inci- and 25 (34%) of 74 in the tolcapone, 200-mg tid group dence of at least 5% greater in 1 or both tolcapone groups had developed dyskinesia or had worse dyskinesia than than in the placebo group (Table 3). The most fre- at baseline (Figure 4). Dyskinesia was not, however, cited quent adverse events in tolcapone-treated patients were as the reason for withdrawal by any patient who with- dopaminergic-related events: dyskinesia, nausea, dysto- drew because of an adverse event and was therefore not nia, anorexia, confusion, hallucination, and excessive regarded as treatment limiting. dreaming. The most frequent nondopaminergic adverse The IGA of overall tolerability showed that, in the events were dizziness (nonorthostatic), increased sweat- tolcapone groups, 19 (26%) of 69 patients receiving 100 ing, and dry mouth (Table 3). Dopaminergic-related mg tid and 27 (36%) of 74 receiving 200 mg tid showed events tended to occur more often in patients receiving improvement, compared with 11 (15%) of 72 in the pla- tolcapone, 200 mg tid; most resolved with decreases in cebo group. However, the proportion of patients who levodopa dosage. showed deterioration was also higher in the tolcapone Dyskinesia was by far the most frequent adverse treatment groups (15/69 [22%] in the 100-mg tid group, event, occurring at some point during the study in 14 19/74 [26%] in the 200-mg tid group) than in the pla- (19%) of 72 patients in the placebo group; 43 (62%) of cebo group (7/72 [10%]). No consistent changes in vital 69 in the tolcapone, 100-mg tid group; and 49 (66%) of signs, electrocardiogram, or laboratory tests were asso- 74 in the tolcapone, 200-mg tid group. However, all 3 ciated with tolcapone treatment.

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 2. Efficacy Results: Changes in “Wearing Off”/Fluctuations, Levodopa Dosage, Motor Function, Quality of Life, and IGAs of Efficacy Between Baseline and Week 6 in the Intention-to-Treat Population, Last-Observation-Carried-Forward Analysis*

Tolcapone

Placebo 100 mg tid 200 mg tid “On” time, h 0.3 (0.3) 2.1 (0.3)† 2.3 (0.3)† “Off” time, h −0.3 (0.3) −2.0 (0.3)† −2.5 (0.3)† Total daily levodopa dose, mg −0.5 (20.1) −185.5 (20.6)† −251.5 (19.9)† Daily intakes of levodopa, No. 0.0 (0.1) −0.5 (0.1)‡ −1.2 (0.1)† Unified Parkinson’s Disease Rating Scale Subscale II (activities of daily living) −0.7 (0.4) −0.4 (0.4) −0.5 (0.4) Subscale III (motor function during “on” time) −1.2 (0.7) −2.3 (0.7) −2.4 (0.7) Total (subscales I to III) −2.2 (0.9) −2.9 (0.9) −2.9 (0.9) Sickness Impact Profile Physical −1.1 (0.9) −2.9 (0.9) −2.6 (0.9) Psychosocial −2.2 (1.1) −2.7 (1.1) −2.8 (1.1) IGAs of efficacy, No. (%) improved “Wearing off” 19 (26) 54 (78)† 58 (78)† Symptom severity 15 (21) 47 (68)† 59 (80)† Overall efficacy 19 (26) 50 (72)† 57 (77)†

*Data are least-squares means (SEM) based on analysis of covariance or number (percentage) of patients improved. IGAs indicates Investigator’s Global Assessments; tid, 3 times daily. †PϽ.001 for pairwise comparison with placebo after adjustment for multiple comparisons. ‡P = .01 for pairwise comparison with placebo after adjustment for multiple comparisons.

50 900 Placebo Tolcapone, 100 mg tid 45 Tolcapone, 200 mg tid 850

40 800

35 750 Placebo 30 700 Tolcapone, 100 mg tid ∗ Tolcapone, 200 mg tid ∗

“Off” Time, % of Waking Day % of Waking “Off” Time, 25 650 Total Daily Levodopa Dose, mg Total ∗ ∗ 20 600

80 6

∗ 70 ∗ 5.5

65 †

60 5 ∗ 55 ∗ Daily Levodopa Intakes, No. “On” Time, % of Waking Day % of Waking “On” Time, 50 4.5 Baseline1562 3 4 Baseline1562 3 4 Time, wk Time, wk

Figure 2. Change in “off” time (top) and “on” time (bottom) between Figure 3. Change in levodopa dosage between baseline and week 6 of the baseline and week 6 of the study. Data are means. Intention-to-treat study. Top, Total daily levodopa dose. Bottom, Number of daily intakes. population, last-observation-carried-forward analysis. Asterisk indicates Intention-to-treat population, last-observation-carried-forward analysis. PϽ.001 for pairwise comparison with placebo after adjustment for multiple Asterisk indicates PϽ.001; dagger, PϽ.01 for pairwise comparison with comparisons; tid, 3 times daily. placebo after adjustment for multiple comparisons; and tid, 3 times daily.

COMMENT In the present study, treatment with tolcapone was associated with rapid decreases in off time and increases The present study showed significant reductions in wearing- in on time, assessed by patient diaries and IGAs; indeed, off effects in patients with fluctuating Parkinson disease who improvement was noticeable within the first 2 weeks of were treated with tolcapone, and findings were consistent treatment. These data indicate a rapid onset of response with previous studies.4-9 The results obtained with the 2 dos- to tolcapone in patients with fluctuating disease receiv- ages of tolcapone were similar, although both the therapeu- ing levodopa therapy. No significant treatment effect was ticeffectandtheincidenceofadverseeventstendedtobesome- seen on the UPDRS subscale II (activities of daily living what greater in the group receiving tolcapone, 200 mg tid. during on time) or the SIP scores during the short du-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Tolcapone Fluctuator Study Group III Table 3. Adverse Events Occurring in at Least 5% More Patients Receiving Tolcapone Than Placebo* Mayo Clinic Scottsdale, Scottsdale, Ariz: Charles H. Tolcapone, No. (%) Adler, MD, PhD; Manfred D. Muenter, MD; John N. Placebo, Caviness, MD. Vanderbilt University, Nashville, Tenn: No. (%) 100 mg tid 200 mg tid Thomas Davis, D. A. Shearon. Albany Medical College, Adverse Event (n = 72) (n = 69) (n = 74) Albany, NY: Stewart Factor, DO, Eric S. Molho, MD. Dyskinesia 14 (19.4) 43 (62.3) 49 (66.2) Tampa General Hospital, Tampa, Fla: Robert A. Hauser, Nausea 8 (11.1) 19 (27.5) 21 (28.4) MD; Theresa Zesiewicz, MD. Barrow Neurological Insti- Dystonia 10 (13.9) 8 (11.6) 23 (31.1) tute, Phoenix, Ariz: Matt Kurth, MD; Abraham Lieber- Anorexia 4 (5.6) 10 (14.5) 17 (23.0) man, MD; Susan Imke, RN. Yale Movement Disorders, Excessive dreaming 7 (9.7) 11 (15.9) 9 (12.2) New Haven, Conn: Kenneth L. Marek, MD; J. Cellar; Confusion 5 (6.9) 8 (11.6) 10 (13.5) B. Fassell. Colorado Neurological Institute Movement Dizziness 6 (8.3) 11 (15.9) 4 (5.4) Hallucination 2 (2.8) 4 (5.8) 12 (16.2) Disorders Center, Englewood: Christopher O’Brien, MD; Increased sweating 2 (2.8) 3 (4.3) 10 (13.5) Lauren C. Seeberger, MD. Washington University School Xerostomia 3 (4.2) 1 (1.4) 7 (9.5) of Medicine, St Louis, Mo: Joel Perlmutter, MD. Boston Urine discoloration 1 (1.4) 1 (1.4) 8 (10.8) University School of Medicine, Boston, Mass: Marie- Vomiting 0 (0) 4 (5.8) 5 (6.8) Helene Saint-Hilaire, MD; Robert G. Feldman, MD. The Parkinson’s Institute, Sunnyvale, Calif: Caroline Tanner, *Patients are counted only once for an adverse event, even if the event MD; James W. Tetrud, MD; Heidi Shale, MD. Sinai Clini- occurred more than once; tid indicates 3 times daily. cal Neuroscience Center, West Bloomfield, Mo: Richard Trosch, MD; Peter A. LeWitt, MD; R. C. Berchou; K. L. Mistura. University of Southern California, Los Angeles:

60 Placebo Cheryl Waters, MD; Mark Lew, MD. University of Tolcapone, 100 mg tid Miami School of Medicine, Miami, Fla: William Weiner, 50 Tolcapone, 200 mg tid MD; Carlos Singer, MD; Lisa M. Shulman, MD. Univer- 40 sity of Ottawa, Ottawa, Ontario: Lynn Barclay, MD; J. David Grimes, MD; T. Mandis. Markham Stouffville Hospital, 30 Markham, Ontario: Mark Guttman, MD.

Patients, % 20

0 Baseline1562 3 4 Time, wk ported by approximately 28% of patients in both active treatment groups, compared with 11% in the placebo Figure 4. Percentage of patients reporting new onset or worsening of their initial dyskinesia at each assessment point plotted over time. Adjustments to group. This is consistent with studies of other dopamin- dopaminergic medications resulted in a reduction in this side effect. tid ergic agents used as adjunctive therapy with levodopa in indicates 3 times daily. patients having motor fluctuations.14,15 These dopaminergic adverse events were managed by adjusting the le- ration of the study. The reduction in off time in itself might vodopa dosage: the prevalence of dyskinesia decreased be considered as an improvement in patients’ quality of from week 2 of treatment onward. They were not re- life. ported as a cause of withdrawal from treatment, indicat- The clinical improvements associated with tolca- ing that they were not treatment limiting. The increased pone treatment occurred despite a mean decrease in to- prevalence of dyskinesias in tolcapone-treated patients tal daily levodopa dose. Both the total levodopa dose and might conceivably have led to unblinding; however, dys- the number of daily intakes were reduced. This is con- kinesias also occurred in one fifth of the patients who sistent with previous findings that treatment with tolca- received placebo, indicating that these adverse events were pone increases levodopa bioavailability2,12 and, hence, not exclusive to tolcapone-treated patients. Therefore, the leads to reduced levodopa requirements in parkinso- extent of potential unblinding and any consequent in- nian patients. These patients had already undergone le- troduction of bias would have been limited. vodopa adjustments, so it is believed that these benefits In conclusion, the present study shows that adjunc- could not be obtained by further levodopa dose manipu- tive treatment with tolcapone was well tolerated, rap- lation. The mechanism of action for tolcapone appears idly and significantly reduced off time and increased on to be its inhibition of catechol-O-methyltransferase,1 which time in patients with fluctuating Parkinson disease, and may occur in both the peripheral and the central ner- resulted in reduced daily levodopa requirements. No defi- vous system, because the drug penetrates the blood- nite advantage in terms of efficacy was observed with the brain barrier.13 200-mg tid dose, which was also associated with a slightly In general, tolcapone was well tolerated; the prin- higher incidence of adverse events, suggesting that treat- cipal adverse events were dopaminergic-related and may ment should be initiated with the lower dose. Whether be secondary to increased levodopa bioavailability or to adjunct therapy with tolcapone has advantages over a do- tolcapone itself. New-onset or an increase in dyskinesia pamine agonist is unclear, although 1 study has shown occurred in more than 65% of tolcapone-treated pa- that tolcapone is more effective than bromocriptine tients, compared with 19% in the placebo group. Nau- in reducing off time and levodopa dose and was better sea was the second most frequent adverse event, re- tolerated.16

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Accepted for publication January 22, 1998. administration of levodopa-benserazide and tolcapone, a COMT inhibitor, in Par- From the Parkinson’s Disease and Movement Disor- kinson’s disease. Clin Neuropharmacol. 1995;18:258-265. 6. Roberts JW, Cora-Locatelli G, Bravi D, Amantea MA, Mouradian MM, Chase TN. ders Center, Mayo Clinic, Scottsdale, Ariz (Dr Adler); Move- Catechol-O-methyltransferase inhibitor tolcapone prolongs levodopa/carbidopa ment Disorders Center, University of Miami, Miami, Fla action in parkinsonian patients. Neurology. 1994;44:2685-2688. (Dr Singer); Colorado Neurological Institute Movement Dis- 7. Kurth MC, Adler CH, Saint Hilaire M, et al. Tolcapone improves motor function orders Center, Englewood (Dr O’Brien); Department of Neu- and reduces levodopa requirement in patients with Parkinson’s disease experi- encing motor fluctuations: a multicenter, double-blind, randomized, placebo- rology, University of South Florida, Tampa (Dr Hauser); controlled trial. Neurology. 1997;48:81-87. Department of Neurology, Division of Movement Disor- 8. Myllyla¨ VV, Jackson M, Larsen JP, Baas H, Tolcapone International Parkinson’s Dis- ders, University of Southern California, Los Angeles ease Study (TIPS) Group I. Efficacy and safety of tolcapone in levodopa-treated Par- (Dr Lew); Yale Movement Disorders Center, Yale Univer- kinson’s disease patients with “wearing-off” phenomenon: a multicentre, double- sity, New Haven, Conn (Dr Marek); and Hoffmann-La Roche, blind, randomized, placebo-controlled trial. Eur J Neurol. 1997;4:333-341. 9. Rajput A, Martin W, Saint-Hilaire M-H, Dorflinger E, Pedder S. Tolcapone improves Nutley, NJ (Drs Dorflinger, Pedder, Deptula, and Yoo). motor function in parkinsonian patients with “wearing-off” phenomenon: a double- This work was supported by F. Hoffmann-La Roche, blind, placebo-controlled, multicenter trial. Neurology. 1997;49:1066-1071. Basel, Switzerland. 10. Fahn S, Elton RL, members of the UPDRS Development Committee. Unified Par- We thank all the site coordinators and patients for their kinson’s disease rating scale. In: Fahn S, Marsden CD, Goldstein M, Calne D, eds. Recent Developments in Parkinson’s Disease. Florham Park, NJ: MacMil- dedication and persistence. lan Healthcare Information; 1987:153-163. Reprints: Charles H. Adler, MD, PhD, Parkinson’s Dis- 11. Bergner M, Bobbitt RA, Carter WB, Gilson SB. The Sickness Impact Profile: de- ease and Movement Disorders Center, Mayo Clinic Scottsdale, velopment and final revision of a health status measure. Med Care. 1981;19: 13400 E Shea Blvd, Scottsdale, AZ 85259. 787-805. 12. Zu¨rcher G, Dingemanse J, Da Prada M. Ro 40-7592, a potent inhibitor of extracerebral and brain catechol-O-methyltransferase: preclinical and clinical find- REFERENCES ings. In: Agnoli A, Campanella G, eds. New Developments in Therapy of Parkin- son’s Disease. Rome, Italy: John Libbey; 1991:37-43. 13. Napolitano A, Zu¨rcher G, Da Prada M. Effects of tolcapone, a novel catechol-O- 1. Zu¨rcher G, Colzi A, Da Prada M. Ro 40-7592: inhibition of COMT in rat brain and methyltransferase inhibitor, on striatal metabolism of L-dopa and dopamine in extracerebral tissues. J Neural Transm Suppl. 1990;32:375-380. rats. Eur J Pharmacol. 1995;273:215-221. 2. Dingemanse J, Jorga K, Zu¨rcher G, et al. Pharmacokinetic-pharmacodynamic in- 14. Lieberman A, Ranhosky A, Korts D. Clinical evaluation of pramipexole in ad- teraction between the COMT inhibitor tolcapone and single-dose levodopa. Br J vanced Parkinson’s disease: results of a double-blind, placebo-controlled, parallel- Clin Pharmacol. 1995;40:253-262. group study. Neurology. 1997;48:162-168. 3. Levodopa. In: Dollery C, ed. Therapeutic Drugs. Edinburgh, Scotland: Churchill 15. Olanow CW, Fahn S, Muenter M, et al. A multicentre double-blind placebo- Livingstone; 1991:L10-L15. controlled trial of pergolide as an adjunct to Sinemet in Parkinson’s disease. Mov 4. Davis TL, Roznoski M, Burns RS. Acute effects of COMT inhibition on L-dopa Disord. 1994;9:40-47. pharmacokinetics in patients treated with carbidopa and selegiline. Clin Neuro- 16. Agid Y, Destee A, Durif F, Montastruc JL, Pollak P, on behalf of the French Tol- pharmacol. 1995;18:333-337. capone Study Group. Tolcapone, bromocriptine, and Parkinson’s disease. Lan- 5. Limousin P, Pollak P, Pfefen JP, Tournier-Gervason CL, Dubuis R, Perret JE. Acute cet. 1997;350:712-713.

Images In Neurolo Images In Neurology

We are pleased to announce the addition of a new feature, Images in Neurology, to the ARCHIVES. For this section we invite your submission of interesting images of patients, tissue biopsy samples, and radiographic images, including magnetic reso- nance imaging, positron emission tomography, and x-ray scans, etc. With your image, please send a brief summary (300 words or less) describing its uniqueness and importance. Also, indicate the magnification and stain where appropriate. Both black-and-white and color images (at no charge to the author) are welcome. Submissions should be sent in triplicate to: Roger N. Rosenberg, MD, Editor, Archives of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9108.

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