Illness impact and adjustment to Parkinson's disease: before and after treatment with tolcapone.

Research on the impact of disease and treatment on health status and quality of life in patients with movement disorders is limited. We studied quality of life in 46 patients with Parkinson's disease (PD) to determine whether the impact of illness and psychosocial adjustment to illness were improved by 42 days of adjunctive therapy with tolcapone (50 mg, 200 mg, or 400 mg three times a day). This study was conducted in parallel with a double-blind, placebo-controlled, dose-response study of the safety and efficacy of tolcapone in combination with levodopa/carbidopa therapy. Only a subset of individuals from the larger study participated. In the quality of life study, illness impact and adjustment to illness were measured subjectively by the Sickness Impact Profile (SIP) and the Psychosocial Adjustment to Illness Scale-Self-Report (PAIS-SR). Patient ratings of total illness impact (p = 0.003), physical illness impact (p = 0.05), and psychosocial illness impact (p = 0.007) improved significantly in individuals receiving tolcapone compared with those receiving placebo. There was no statistically significant difference in adjustment to illness when the tolcapone and placebo groups were compared; however, 17 of 21 adjustment to illness indicators showed improvement.

A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson's disease patients. Tolcapone De Novo Study Group.

Tolcapone is a potent, reversible catechol-O-methyltransferase (COMT) inhibitor with both peripheral and central activity. It has been demonstrated to improve motor function and allow levodopa dose reductions in Parkinson's disease (PD) patients who are experiencing either a stable response or motor fluctuations while on levodopa/dopa decarboxylase inhibitor therapy. Because striatal dopamine is metabolized by COMT and monoamine oxidase (MAO), central COMT inhibition alone or in combination with MAO inhibition might provide symptomatic benefit for patients not receiving levodopa. We conducted a pilot study to evaluate the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in early untreated PD patients. Patients were randomized to receive 200 mg tolcapone three times a day or placebo for the 8 weeks of the study. Open-label oral selegiline (5 mg in the morning and midday) was administered to all patients during the second 4 weeks of the study. There was no difference between treatment groups according to the investigator's assessment of tolerability at week 4. Ninety-five percent of tolcapone-treated patients and 98% of placebo-treated patients experienced excellent or good tolerability during the first 4 weeks (95% confidence interval [CI]: -10.3, 5.7; p = 0.57). A decrease in tolerability occurred in the tolcapone group during the second 4 weeks of the study following the addition of selegiline. The most commonly reported side effects were diarrhea (31% tolcapone, 7% placebo), nausea (21% tolcapone, 2% placebo), urine discoloration (12% tolcapone, 0% placebo), dizziness (12% tolcapone, 5% placebo), headaches (12% tolcapone, 10% placebo), and abdominal pain (10% tolcapone, 5% placebo). We did not identify symptomatic benefit associated with tolcapone alone or in combination with oral selegiline in this group of otherwise untreated PD patients.

Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Tolcapone Fluctuator Study Group III.

OBJECTIVE: To assess the efficacy and tolerability of the catechol-O-methyltransferase inhibitor tolcapone in reducing "off/on" fluctuations in levodopa-treated parkinsonian patients. DESIGN: A randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Fifteen Parkinson disease clinics. PATIENTS: Two hundred fifteen referred outpatients with Parkinson disease who showed predictable end-of-dose motor fluctuations that were not controlled by a stable levodopa-carbidopa (Sinemet) regimen of at least 4 weeks' duration. INTERVENTIONS: In addition to their usual levodopa-carbidopa regimen, patients received placebo or tolcapone, 100 or 200 mg, 3 times daily orally for 6 weeks. PRIMARY OUTCOME MEASURE: Change in daily off/on time. RESULTS: Tolcapone, 100 and 200 mg 3 times daily, reduced off time by 2.0 and 2.5 hours per day, respectively, and increased on time by 2.1 and 2.3 hours per day, respectively (P<.001 vs placebo). Investigators' global measures of disease severity indicated that significantly more tolcapone-treated patients had reduced wearing off and symptom severity (P<.001 vs placebo). No significant change in quality-of-life measures occurred. Clinical improvements occurred despite a reduction in total daily levodopa dose of 185.5 mg (23%) in the tolcapone, 100 mg 3 times daily, group and 251.5 mg (29%) in the 200 mg 3 times daily group. Principal adverse events (mainly dyskinesia and nausea) were levodopa related, were not treatment limiting, and were seldom reported as reasons for withdrawal. The frequency of withdrawals because of adverse events was similar in all groups (3% to 7%). CONCLUSIONS: Tolcapone was well tolerated and substantially increased on time and reduced off time in patients with fluctuating Parkinson disease. Additionally, levodopa requirements were significantly decreased.

Tolcapone in stable Parkinson's disease: efficacy and safety of long-term treatment. Tolcapone Stable Study Group.

In this double-blind, placebo-controlled trial, we investigated the effect of the catechol-O-methyltransferase inhibitor tolcapone 100 or 200 mg three times daily on activities of daily living and motor function in 298 patients with parkinsonism receiving levodopa but without motor fluctuations. At 6 months, both dosages of tolcapone produced significant reductions in the Unified Parkinson's Disease Rating Scale scores for activities of daily living (Subscale II) and motor function (Subscale III) and in the total score for Subscales I to III. These improvements were maintained up to the 12-month assessment. At 6 months, both tolcapone groups had changes in levodopa dosage that were significantly different from placebo: the tolcapone groups had decreases in mean total daily dose of levodopa, whereas the placebo group had a mean increase. Tolcapone was well tolerated. The principal adverse events were levodopa-related, but these were generally mild or moderate. Diarrhea was the most frequent nondopaminergic adverse event. Tolcapone appears to be beneficial in the treatment of patients with parkinsonism who have not yet developed motor fluctuations.

Tolcapone improves motor function in parkinsonian patients with the "wearing-off" phenomenon: a double-blind, placebo-controlled, multicenter trial.

We studied the new catechol-O-methyltransferase inhibitor tolcapone, 100 and 200 mg, three times daily (tid) in a randomized, double-blind, parallel-group trial involving 202 parkinsonian patients who were experiencing the "wearing-off" phenomenon on levodopa therapy. After 3 months, patients receiving tolcapone had a significant decrease in mean daily levodopa dose requirement compared with placebo-treated patients (p < 0.01). In patients treated with tolcapone 200 mg tid, daily "off" time, measured using patient diaries, was reduced from baseline by 3.25 hours; this reduction was significantly different from that seen in the placebo group (p < 0.01). Moreover, the number of daily levodopa intakes was reduced significantly in each tolcapone group compared with placebo (p < 0.01). We found significant improvements in motor function and overall efficacy in the tolcapone groups (p < 0.01). The most frequent adverse events were associated with levodopa treatment. Dyskinesia developed or worsened in 18% of patients receiving placebo, in 51% receiving tolcapone 100 mg tid, and in 64% receiving 200 mg tid, with most cases occurring within the first 30 days of the study. Diarrhea was the most frequent nondopaminergic event, occurring in 14% on placebo, 13% on tolcapone 100 mg tid, and 19% on 200 mg tid. Overall 18% of patients withdrew because of adverse events: 15% on placebo, 17% on tolcapone 100 mg tid, and 22% on 200 mg tid. We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off " phenomenon in levodopa-treated parkinsonian patients.

Tolcapone added to levodopa in stable parkinsonian patients: a double-blind placebo-controlled study. Tolcapone in Parkinson's Disease Study Group II (TIPS II).

The primary objective of this study was to assess the effect of tolcapone on levodopa dosage in parkinsonian patients whose "wearing-off" phenomenon has been controlled with more frequent levodopa dosage. After a 1-week placebo run-in, 97 patients were assigned randomly to receive placebo or tolcapone 200 or 400 mg three times daily (t.i.d.). Levodopa dosage was reduced by -35% on day 1 of study and subsequently retitrated as required. After 6 weeks, the tolcapone groups crossed over to receive the other dose for a further 3 weeks for exploratory purposes. Both tolcapone groups had greater reductions in levodopa dosage than the placebo group at week 6 (not statistically different). The 200-mg t.i.d. group showed greatest improvement in estimated mean scores for all efficacy parameters (p < 0.05 versus placebo for change in Unified Parkinson's Disease Rating Scale Subscale II). Fewer dopaminergic and nondopaminergic adverse events were associated with tolcapone 200 mg t.i.d. than with tolcapone 400 mg t.i.d. The most frequently reported dopaminergic adverse events were nausea, cramps, dyskinesia, and dystonia. The most frequently reported unanticipated adverse event was diarrhea. Tolcapone 200 mg t.i.d. may provide additional benefit to patients with moderately advanced Parkinson's disease with treated "wearing-off" phenomenon.

Tolcapone improves motor function in parkinsonian patients with the "wearing-off" phenomenon: a double-blind, placebo-controlled, multicenter trial.

We studied the new catechol-O-methyltransferase inhibitor tolcapone, 100 and 200 mg, three times daily (tid) in a randomized, double-blind, parallel-group trial involving 202 parkinsonian patients who were experiencing the "wearing-off" phenomenon on levodopa therapy. After 3 months, patients receiving tolcapone had a significant decrease in mean daily levodopa dose requirement compared with placebo-treated patients (p < 0.01). In patients treated with tolcapone 200 mg tid, daily "off" time, measured using patient diaries, was reduced from baseline by 3.25 hours; this reduction was significantly different from that seen in the placebo group (p < 0.01). Moreover, the number of daily levodopa intakes was reduced significantly in each tolcapone group compared with placebo (p < 0.01). We found significant improvements in motor function and overall efficacy in the tolcapone groups (p < 0.01). The most frequent adverse events were associated with levodopa treatment. Dyskinesia developed or worsened in 18% of patients receiving placebo, in 51% receiving tolcapone 100 mg tid, and in 64% receiving 200 mg tid, with most cases occurring within the first 30 days of the study. Diarrhea was the most frequent nondopaminergic event, occurring in 14% on placebo, 13% on tolcapone 100 mg tid, and 19% on 200 mg tid. Overall 18% of patients withdrew because of adverse events: 15% on placebo, 17% on tolcapone 100 mg tid, and 22% on 200 mg tid. We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off" phenomenon in levodopa-treated parkinsonian patients.

Tolcapone in stable Parkinson's disease: efficacy and safety of long-term treatment. The Tolcapone Stable Study Group.

In this double-blind, placebo-controlled trial, we investigated the effect of the catechol-O-methyltransferase inhibitor tolcapone 100 or 200 mg three times daily on activities of daily living and motor function in 298 patients with parkinsonism receiving levodopa but without motor fluctuations. At 6 months, both dosages of tolcapone produced significant reductions in the Unified Parkinson's Disease Rating Scale scores for activities of daily living (Subscale II) and motor function (Subscale III) and in the total score for Subscales I to III. These improvements were maintained up to the 12-month assessment. At 6 months, both tolcapone groups had changes in levodopa dosage that were significantly different from placebo: the tolcapone groups had decreases in mean total daily dose of levodopa, whereas the placebo group had a mean increase. Tolcapone was well tolerated. The principal adverse events were levodopa-related, but these were generally mild or moderate. Diarrhea was the most frequent nondopaminergic adverse event. Tolcapone appears to be beneficial in the treatment of patients with parkinsonism who have not yet developed motor fluctuations.

Tolcapone improves motor function and reduces levodopa requirement in patients with Parkinson's disease experiencing motor fluctuations: a multicenter, double-blind, randomized, placebo-controlled trial. Tolcapone Fluctuator Study Group I.

Tolcapone is a potent catechol-O-methyltransferase inhibitor that prolongs the plasma half-life of levodopa. This multicenter, double-blind, placebo-controlled study used two 10-hour clinical evaluations to compare the efficacy and safety of three doses of tolcapone (50, 200, and 400 mg tid) with placebo in patients with Parkinson's disease (PD) experiencing motor fluctuations from levodopa/carbidopa. One hundred fifty-one patients completed the study. Clinical evaluations lasting 10 hours were performed on day -1 and day 42 using United Parkinson's Disease Rating Scale motor subscale and "on/off" and dyskinesia assessments every 30 minutes. Tolcapone significantly reduced "off" time an average of 40% and increased total "on" time by about 25% at all dose levels, as compared to placebo treatment. Levodopa/carbidopa dosage and frequency were significantly reduced. Tolcapone was well tolerated, with patients experiencing typical dopaminergic side effects that could be reduced or eliminated by lowering levodopa/carbidopa dosages. Tolcapone was effective at prolonging the clinical benefit of levodopa and reducing total levodopa requirements in PD patients with motor fluctuations.

Utility of an objective dyskinesia rating scale for Parkinson's disease: inter- and intrarater reliability assessment.

Although dyskinesia is a frequent and important problem in Parkinson's disease (PD), a reliable assessment measure has not been thoroughly developed and tested. We modified the Obeso dyskinesia scale to create an objective rating scale for dyskinesia assessment during activities of daily living. Thirteen physicians and 15 study coordinators involved in a clinical trial independently reviewed videotape segments of PD patients performing three tasks: walking, putting on a coat, and lifting a cup to the lips for drinking. Raters evaluated the severity of worst dyskinesia seen, the types of all dyskinesias seen, and the type of dyskinesia most associated with motoric disability. For all assessments, the total group showed statistically significant inter- and intrarater reliability. Physicians had a higher consistency than did coordinators, but for most measures the difference was not statistically significant. Physicians and coordinators found the scale easy to use and especially practical for rating dyskinesia severity and for identifying the most disabling dyskinesia. Dyskinesias can be assessed in clinical trials and warrant regular documentation.