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A Randomized Controlled Trial of Etilevodopa in Patients with Parkinson Disease Who Have Motor Fluctuations

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A Randomized Controlled Trial of Etilevodopa in Patients with Parkinson Disease Who Have Motor Fluctuations ORIGINAL CONTRIBUTION A Randomized Controlled Trial of Etilevodopa in Patients With Parkinson Disease Who Have Motor Fluctuations Parkinson Study Group Background: Motor fluctuations are a common com- Intervention: Treatment with either etilevodopa- plication in patients with Parkinson disease (PD) receiv- carbidopa or levodopa-carbidopa for 18 weeks. ing long-term levodopa therapy. Slowed gastric empty- ing and poor solubility of levodopa in the gastrointestinal Main Outcome Measure: Change from baseline in total tract may delay the onset of drug benefit after dosing. Eti- daily TTON as measured using home diaries. levodopa is an ethyl-ester prodrug of levodopa that has Results: The reduction in mean total daily TTON from greater gastric solubility, passes quickly into the small baseline to treatment was 0.58 hour in the etilevodopa- intestine, is rapidly hydrolyzed to levodopa, and has a carbidopa group and 0.79 hour in the levodopa- shortened time to maximum levodopa concentration. carbidopa group (P=.24). There was no significant Objective: To determine the efficacy, safety, and tol- difference between the etilevodopa-carbidopa and erability of etilevodopa in patients with PD who have mo- levodopa-carbidopa groups in the reduction of response tor fluctuations. failures (−6.82% vs −4.69%; P=.20). Total daily “off” time improved in the etilevodopa-carbidopa (−0.85 hour) and Design: A double-blind, randomized, comparative clini- levodopa-carbidopa (−0.87 hour) groups without an in- cal trial. crease in on time with troublesome dyskinesias. Setting: Forty-four sites in the United States and Canada. Conclusion: Despite the theoretical pharmacokinetic ad- vantage of etilevodopa, there was no improvement in TTON, Patients: Three hundred twenty-seven patients with PD response failures, or off time compared with levodopa. who had a latency of at least 90 minutes total daily time to “on” (TTON) after levodopa dosing. Arch Neurol. 2006;63:210-216 EVODOPA REMAINS THE MOST ride, liquid levodopa suspensions, and duo- effective symptomatic treat- denal levodopa infusions.7,8 ment for Parkinson disease Etilevodopa (TV-1203) is an ethyl-ester (PD), but motor complica- prodrug of levodopa that is rapidly hydro- tions arise in many levodopa- lyzed to levodopa and ethanol by nonspecific treated patients with PD after 3 to 5 years esterases in the gastrointestinal tract. Com- L1,2 of use. Motor complications can be cat- pared with standard levodopa, etilevodopa egorized into dyskinesias and response fluc- has greater solubility in the stomach, faster tuations, which include end-of-dose wear- passage to the small intestine, and a short- ing “off,” sudden “on”/offs, delayed time to ened time to maximum levodopa concentra- on (TTON), and response failures, where tion.9 In an early clinical study10 of eti- no symptomatic benefit occurs after receiv- levodopa,62patientswithadvancedPDwere ing a levodopa dose.3 randomized to either continue standard le- Multiple mechanisms, including the vodopa treatment or replace the first dose of poor solubility of levodopa in the gastro- levodopa in the morning and the first dose intestinal tract and delayed gastric empty- after lunch with etilevodopa. The mean ing, likely contribute to delayed TTON and TTON for the first morning dose decreased response failures.4,5 One study6 found a gas- by 21% in the etilevodopa group and 9% in tric emptying time of 56 minutes in healthy the standard levodopa group. The mean la- individuals, 85 minutes in patients with tency to on for the first dose after lunch de- nonfluctuating early PD, and 221 minutes creased by 17% in the etilevodopa group and in patients with advanced PD and motor 0% in the standard levodopa group. The re- Group Information: A complete fluctuations. The options for treating de- sponse failure rate for the dose after lunch list of the Parkinson Study layed TTON and response failure compli- decreasedfrom23%to19%intheetilevodopa Group investigators appears in cations are presently limited but include group vs an increase from 17% to 23% in the a box on page 215. subcutaneous apomorphine hydrochlo- levodopa group.10 The objective of the pres- (REPRINTED) ARCH NEUROL / VOL 63, FEB 2006 WWW.ARCHNEUROL.COM 210 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 ent study is to determine the efficacy, safety, and tolerabil- ity of etilevodopa when administered in place of all daily A immediate-release levodopa doses in a double-blind man- RAPID (TV-1203/111) 22 “TIME TO ON” DIARY (DIA2) Page __ of __ ner to patients with advanced PD and motor fluctuations. One Diary is to be completed each day. Leave entries blank if fewer than 12 doses are taken each day. If you are “ON” at the time of taking medication, do not mark any of the boxes in the shaded area. SUBJECT NO SITE NO VISIT NO METHODS DATE NAME/DOB CODE DIARY (1st three letters of last name, 1st initial, year of birth) COMPLETED MM DD YEAR PATIENTS If “OFF” at the time of taking medication: Consenting patients with PD and chronic levodopa-related mo- If No What is your status at the Exact time Mark the exact time “ON” time time of taking tor fluctuations (n=327) were enrolled at 44 participating Par- medication taken “ON” Began before the next medication? dose kinson Study Group sites in the United States and Canada. Pa- DOSE DAILY check box ( ) tients had idiopathic PD, a modified Hoehn and Yahr stage11 ON OFF of less than 5 in the off state, at least 2.5 hours per day in the 9 Hour Minutes Hour Minutes off state (confirmed by a 3-day home diary),12 aTTONof30 AM PM AM PM 10 ON OFF minutes or longer for at least 1 dose of levodopa per day, and Hour Minutes Hour Minutes an average daily total TTON after all daily levodopa-carbidopa AM PM AM PM doses of at least 90 minutes (based on a second 3-day home 11 Hour Minutes ON OFF Hour Minutes diary completed before baseline). Patients were required to re- AM PM AM PM ceive a minimum daily dose of 300 mg of immediate-release 12 Hour Minutes ON OFF Hour Minutes levodopa divided into at least 4 doses. Sustained-release le- AM PM AM PM vodopa-carbidopa was allowed in combination with immediate- release levodopa doses during the day and without immediate- B release levodopa-carbidopa only at bedtime and during the night, RAPID (TV-1203/111) 20 and the sustained-release levodopa dosage was held constant 24 - HOUR DIARY (DIA1) Page 1 of 1 during the trial. Concomitant treatment with dopamine ago- One Diary is to be completed each day. nists, amantadine hydrochloride, anticholinergics, selegiline hy- SUBJECT NO SITE NO VISIT NO DATE NAME/DOB CODE drochloride, and entacapone was allowed in cases in which stable DIARY dosages were maintained for 4 weeks before baseline and (1st three letters of last name, 1st initial, year of birth) COMPLETED MM DD YEAR Time ON1 ON2 OFF3 A Time ON1 ON2 OFF3 A WITH WITH NO dyskinesia S NO dyskinesia S throughout the study. Patients with atypical or secondary par- Troublesome Troublesome OR L OR L dsyskinesia dsyskinesia 13 WITHOUT E WITHOUT E kinsonism, a Mini-Mental State Examination score of 24 or Troublesome E Troublesome E Midnight dyskinesia P4 Noon dyskinesia P4 less, or unstable neurologic, psychiatric, and medical disor- 1. 12:00am - 12:30am 25. 12:00pm - 12:30pm ders were excluded. Patients were also excluded if they had sur- 2. 12:30am - 1:00am 26. 12:30pm - 1:00pm gical treatment for PD in the 12 months preceding the base- 3. 1:00am - 1:30am 27. 1:00pm - 1:30pm 4. 1:30am - 2:00am 28. 1:30pm - 2:00pm line visit, had deep brain stimulation programming changes 5. 2:00am - 2:30am 29. 2:00pm - 2:30pm within 1 month of screening, or anticipated having changes in 6. 2:30am - 3:00am 30. 2:30pm - 3:00pm deep brain stimulation programming during the study. 7. 3:00am - 3:30am 31. 3:00pm - 3:30pm 8. 3:30am - 4:00am 32. 3:30pm - 4:00pm 9. 4:00am - 4:30am 33. 4:00pm - 4:30pm DESIGN AND PROCEDURES 10. 4:30am - 5:00am 34. 4:30pm - 5:00pm 11. 5:00am - 5:30am 35. 5:00pm - 5:30pm We conducted a randomized, parallel-group, double-blind com- parison of etilevodopa and immediate-release levodopa in pa- tients with PD and motor fluctuations receiving optimized le- Figure 1. Time to “on” (A) and 24-hour (B) diary forms. vodopa therapy. After a screening visit to ensure that the participants met the enrollment criteria, existing immediate- or placebo for etilevodopaϩimmediate-release levodopa- release levodopa formulations were switched to generic 4:1 im- carbidopa tablets. The computer-generated randomization plan, mediate-release levodopa-carbidopa (100 mg/25 mg), and pa- created by Parkinson Study Group biostatisticians, provided for tients were optimized on this drug regimen for 2 to 6 weeks stratification by medical center and blocking to ensure approxi- before the baseline visit. The optimal dose of levodopa- mate balance among the treatment groups within each center. The carbidopa was defined as the dose that provided maximal clini- levodopa/etilevodopa dosage could be adjusted during the first cal benefit to the patient. During the screening visit and opti- 8 weeks of the study at the discretion of the investigator, but it mization period, patients underwent standardized diary training was held constant for the last 10 weeks. Patients had visits 4, 8, to ensure that they could reliably complete the home diaries. 13, and 18 weeks after baseline for safety and efficacy monitor- Two separate diaries were used, one to quantify the daily TTON ing.
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