Controlled-Release Carbidopa-Levodopa (Sinemet) in Combination with Standard Sinemet in Advanced Parkinson s Disease

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1 ANNALS O F CLINICAL AND LABORATORY SCIEN CE, Vol. 19, No. 2 Copyright 1989, Institute for Clinical Science, Inc. Controlled-Release Carbidopa-Levodopa (Sinemet) in Combination with Standard Sinemet in Advanced Parkinson s Disease MARGERY H. MARK, M.D. and JACOB I. SAGE, M.D. Department o f Neurology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ ABSTRACT Twelve of 23 patients with Parkinson s disease and m otor fluctuations who en tered a double-blind study com paring controlled-release carbidopa/levodopa (Sinemet CR-4) with standard Sinemet (SS) continued into open label follow-up on a combination of CR-4 and SS (C/S); the rest continued on CR-4 alone. Significant im provem ent on C/S compared with CR-4 was noted for shorter duration and reduced disability of dyskinesias, and more hours on without dyskinesias (all p < 0.05). Total num ber of hours off was im proved on C/S over SS (p < 0.01). Sinem et CR-4 proved to be b etter than C/S for sleep disturbance (p < 0.05). Although the total num ber of tablets and doses per day of CR-4 was reduced during the C/S period, total levodopa dosage p er day was not significantly changed from e ith e r of the previous periods. T he C/S th era p y for advanced parkinsonism can be more efficacious for fluctuators than either CR-4 or SS alone. Introduction The com bination of levodopa plus decarboxylase inhibitor has been the mainstay in the treatm ent of Parkinson s disease for m ore than a decade. H ow ever, its long-term use invariably gives way to a variety of undesirable m otor fluctuations, including w earing off (end-of-dose d eterio ratio n ), on-off phenomena, peak-dose dyskinesias, and off dystonia. 1,2 718 The appearance of these phenom ena have been correlated w ith fluctuations in plasm a levodopa c o n c e n tra tio n. 6,9,12,18,19 T h e ra p e u tic objectives in these patients have focused 101 on attem pts to maintain a steady plasma level in th e p ursuit of an even m otor response. Intravenous22 and intraduod e n a l24,25 le v o d o p a in fu sio n s hav e im proved m otor fluctuations in some patients. Trials have been undertaken of o ral c o n tro lle d -re le a s e p r e p a r a tions of benserazide/levodopa21 and of carbidopa/levodopa (Sinemet); the latter has undergone several generations of c lin ic a l tria ls, from C R -1 th ro u g h C R -5. 3,4,5, ,16,17,20,23 Some studies which have exam ined the pharmakokin etics of th e oral c o n tro lle d -re le a se drugs have correlated im provem ent in m otor fluctuations with smoother plasma levels of levodopa. 10, /89/ $00.90 Institute for Clinical Science, Inc.

2 102 MARK AND SAGE Most of the recent trials have studied Sinem et CR-4 (CR), a formulation of 50 mg carbidopa per mg levodopa in an erodable polym eric matrix, in com parison with standard Sinem et (SS).4,5,11,17,23 Following the com pletion of a doubleblind, crossover study, 23 patients in our trial were continued on open label CR in com bination w ith SS according to individual needs. Results are reported here of the open label trial of CR plus SS therapy (C/S) in 12 patients at the end of the first m onth as compared with the results of the final week (week 8 ) of SS and CR therapy during the double blind trial. Patients and M ethods T w en ty -th ree p a tie n ts w ith m otor fluctuations in advanced Parkinson s disease w ho c o m p le te d a d o u b le-b lin d crossover study comparing CR with SS continued to take CR at the conclusion of the 24-week trial. O f these, 12 patients (eight men, four women, age range 51 to 77 years, mean 61.5 years; duration of disease 7 to 18 years, m ean 12.8; duration of fluctuations 1 to 16 years, mean 7.1) continued into open label follow-up on a com bination of CR and SS (C/S). The rem aining 11 patients w ere doing well enough on CR alone at the conclusion of the double-blind trial and did not re q u ire any fu rth e r m anipulations in Sinemet dosage. Requirem ents for entry into the initial study included wearingoff of dose, on-off p h en o m en o n, d o se-related dyskinesias, or freezing despite optim al levodopa therapy. The patients m ust have been taking SS four or m ore tim es p e r day. Patients w ere allowed to continue anticholinergics or am antadine, b u t not direct-acting dopam ine agonists (e.g., brom ocriptine or pergolide). Patients w ere evaluated in the final week of each eight-week period on SS and on CR; results of the comparison of th e double blind trial have been p re viously reported. 23 Scores from the final (8 th) week of CR and SS periods were com pared with information at the end of one m onth for the 1 2 patients who continued with C/S therapy. The end of the double-blind phase was chosen for the CR comparison period as opposed to the earlier, open label phase because the latter had been conducted six months p reviously, and the natural progression of disease in th at tim e could potentially c o m p lic a te e v a lu a tio n of th e data. Patients w ere evaluated using the Unified Parkinson s Disease Scale (UPDS),8 m easu rin g su b je c tiv e p a ra m ete rs of m entation, behavior, and mood, activities of daily living (ADL) for both on and off states, and com plications of therapy (tables I and II). Extrapyramidal motor examination was graded on a 0 to 4 scale (0 = no disability, 4 = maximum disability). Also included in the routine evaluation was the H oehn & Yahr staging, 8,13 the Schwab and England Activities of Daily Living scale for on and off states, 8 and total Sinemet dosage. The patients w ere also asked to record a 24-hour diary twice a week, rating each hour as asleep, on without dyskinesias, on with dyskinesias, or off. For those hours that included more than one of these four descriptions, the single rating that reflected the greatest part of the hour was recorded. At the end of each p e rio d, th e e x a m in e rs g ra d e d th e patients for severity of illness. Statistical analyses were based on all of the previous information as obtained in the final week of each trial. Ratings of m o to r e x a m in a tio n h av e n o t b e e n included as they reflect the condition of the patient only at the time of the brief office visit and are therefore less reliable as m easures of the overall response of the patients to each m edication trial section. Statistical analyses were performed by the chi-square and S tudent s t-test.

3 CONTROLLED-RELEASE AND STANDARD SINEMET 103 TABLE I Parameters Measured - Unified Parkinson's Disease Scale No. Better on C/S NO. Better on CR Mentation, behavior, mood Intellectual impairment 2 2 Thought disorder 1 2 Depression 0 2 Motivation/initiative Activities of daily living (for On and Speech Off) Cfi 0 2 Off 2 3 Salivation On Off 3 0 Swallowing On 2 1 Handwriting On 0 3 Off 1 2 Cutting food and handling utensils On 2 1 Off 1 1 Dressing Cn 2 2 Off 5 1 Hygiene On 3 1 Off 1 3 Turning in bed and adjusting On 2 1 bed clothing Off Falling (unrelated to freezing) On 2 2 Off 3 2 Freezing when walking On 1 1 Off 2 3 Walking On 3 1 Off 2 3 Tremor On 3 0 Sensory complaints related to On 2 2 parkinsonism Off 3 2 Complications of therapy Dyskinesias Duration 5 0* Disability 6 1* Painful dyskinesias 2 0 Presence of early morning dystonia Clinical fluctuations Predictable "Off" periods 2 0 Sudden onset of "Off" periods 0 0 Percent of waking day as "Off" periods Other complications Presence of anorexia, nausea, vomiting 3 1 Presence of sleep disturbance 2 7+ Presence of symptomatic orthostasis 0 1 Schwab and England activities of daily (for On and Off) living On 3 3 Off 5 3 No. hours of sleep per 48 hrs/wk 5 5 No. hours "On" without dyskinesias per 48 hrs/wk 8 3* No. hours "On" with dyskinesias per 48 hrs/wk 5 3 No. hours "Off" per 48 hrs/wk 8 4 Physician's global evaluation 5 4 All information and calculations recorded for final week of CR (double blind) and Week 4 of C/S therapy. C/S = combination of Sinemet CR-4 and standard Sinemet. CR = Sinemet CR-4 (controlled-release). *Statistically significant for C/S>CRi p < 0.05 fstatistically significant for CR>C/S; p < 0.05 Results In the first m onth following the conclusion of the double-blind study, 1 2 of the 23 patients who continued to take CR required the addition or substitution of SS for som e doses. T he p a tie n ts scores for week eight of both the CR and SS periods were recorded and compared with C/S for all 47 param eters in table I and table II, respectively; the num ber of patients who were im proved (vs. worse or unchanged) in each category (C/S vs. CR and C/S vs. SS), with corresponding p values for statistically significant changes, are also recorded. Significant im provem ent on C/S as compared with CR alone was noted for shorter duration and reduced disability of dyskinesias and for more hours on without dyskinesias (p < 0.05). Duration of dyskinesias was reduced in 41.7 p e r cent of patients on C/S as compared with none on CR; less disability owing to dyskinesias was reported for 50 percent on C/S and 8.3 percent on CR. The num ber of hours on w ithout dyskinesias was increased for 66.7 percent of patients on C/S as opposed to 25 percent on CR. The num ber of patients who had fewer hours off during C/S (75 percent) was significantly greater than during the SS p e rio d (16.7 p e rc e n t) (p < 0.01). A lthough tw o -th ird s of th e p a tie n ts reported a similar im provem ent on C/S as com pared w ith Va on CR, the difference is not statistically significant. There was no difference in the total num ber of hours of sleep among all three periods, b ut 58.3 p ercen t of patients reported less sleep disturbance during the CR period as com pared with 16.7 percent reporting improvements during C/S treatm ent (p < 0.05). Nine patients (75 percent) used more total tablets (CR plus SS) and required m ore total daily doses during C/S th e r apy than during CR phase (p < 0.01). The mean num ber of total tablets (CR plus SS) on C/S was 11.9 (range: 4 to 24); when compared with mean total tablets of CR during the CR period (9.0, range:

4 104 MARK AND SAGE 4 to 14), the difference is a significant increase (p < 0.05). It should be noted th a t th e in c re a se in th e to ta l d aily num ber of tablets was at the expense of CR, as eight patients took fewer tablets of CR during the C/S phase than they did during CR; one took more, and three continued on the same amount of CR (p < 0.01). W hen the mean num ber of CR tablets during C/S treatm ent (6.6, range: 1 to 14) is compared with the total during th e CR phase, the decrease is again statistically significant (p < 0.05). However, total daily doses of S inem et did not reveal statistical significance (p = 0.06), with a m ean of 8.0 doses (range: 3 to 12) during C/S therapy and 6.9 doses (range: 3 to 10) on CR alone. D uring the C/S period, added SS was of 25/100 strength in all but one patient, who used / 0 tablets. M ean num ber of added SS tablets was 5.25 (range: 0.5 to 20), while m ean CR tablets during C/S was 6. 6 (range: 1 to 14). D u rin g C/S, m ean num ber of doses was 3.7 (range: 1 to 10) and m ean CR doses was 5.2 (range: 1 to 10). Five patients took their SS doses simultaneously with CR; the other seven took th e tw o ty p es separately. Total am ount of levodopa (mg per day) was not significantly changed among treatm ent sections (C/S: ± SD; CR: ± SD; SS: ± SD). Seven patients took alternating doses of SS and CR while five took th eir SS doses sim ultaneously w ith CR. Five p a t i e n t s a d d e d SS as a m o r n in g booster to circumvent the slow onset and loss of the m orning kick-in that has b e e n c o m m o n ly n o t e d w ith C R usage Two patients took afternoon or late night SS boosters to combat short, predictable offs occurring at those tim es, b u t n e ith e r n e e d ed the addition in the morning. Three people required SS doses in betw een each CR dose throughout the day; another took a SS ta b le t w ith each CR dose. In two TABLE II Parameters Measured - Unified Parkinson's Disease Scale f f o. n o. Better Better on C/S on SS Mentation, behavior, mood Intellectual impairment 1 2 Thought disorder 1 2 Depression 2 1 Mot i vati on/init iat i ve.ctivities of daily living (for On and Speech Off) On 3 3 Off 1 4 Salivation On 2 0 Swallowing On Handwriting On 1 3 Off 0 1 Cutting food and handling utensils On 1 3 Off 0 3 Dressing On 0 2 Off 0 0 Hygiene On 0 2 Off 0 2 Turning in bed and adjusting On 3 2 bed clothing Off 1 1 Falling (unrelated to freezing) On 2 2 Off 3 2 Freezing when walking On 1 2 Off 1 3 Walking On 3 2 Off 2 1 Tremor On 3 1 Off 2 1 Sensory complaints related to On 2 1 parkinsonism Off 1 2 Complications of therapy Dyskinesias Duration Disability Painful dyskinesias Presence of early morning dystonia Clinical fluctuations Predictable "Off" periods Sudden onset of "Off" periods Percent of waking day as "Off" periods Other complications Presence of anorexia, nausea, vomiting Presence of sleep disturbance Presence of symptomatic orthostasis Schwab and England activities of daily living (for On and Off On 1 5 Off 3 6 No. hours of sleep per 48 hrs/wk 5 4 No. hours "On" without dyskinesias per 48 hrs/wk 7 3 No. hours "On" with dyskinesias per 48 hrs/wk 4 3 No. hours "Off per 48 hrs/wk 9 2* Physician's global evaluation 4 3 All information and calculations recorded for final week of SS (double blind) and Week 4 of C/S therapy. C/S * combination of Sinemet CR-4 and standard Sinemet. SS = standard Sinemet. Statistically significant for C/S>SS; p < 0.01 other patients, disturbing dyskinesias on CR caused a return to SS alone for most of the day with CR used only in the evenings.

5 CONTROLLED-RELEASE AND STANDARD SINEMET 105 H oehn & Yahr staging was rated at exam ination in the final w eek of each period and ranged from 2 to 4 (mean: 2.8) on SS, CR, and C/S; there was no difference betw een periods. No adverse effects were reported on C/S or CR beyond those complications of th e ra p y a lre ad y e x p e rien c e d on SS. There w ere no statistically or clinically significant changes in m entation, behavior, and mood, activities of daily living, Schwab and E ngland scale, or physician s global evaluation of severity of illness. Discussion Previous reports of open label4,511 and double-blind studies17,23 of CR compared w ith SS have dem onstrated im provem ent in total daily on tim e on CR. The data in this report suggest that, with the addition and/or su b stitu tio n of SS in com bination w ith CR, th ere is a significant increase in the num ber of patients reporting further im provem ent in the num ber of hours on. On C/S therapy, there is also the added benefit of a significant decrease in duration and disability of dyskinesias; in our double-blind study, dyskinesias w ere worse on CR alone as compared with SS. 23 One possible explanation for this im provem ent is th at, because of the higher plasma levodopa levels m aintained by CR therapy, 10 the tendency toward overdosage phenom ena, including distressing dyskinesias, is m u c h g r e a t e r on C R. T h e r e f o r e, attem pts to decrease the CR dosage may resolve this problem but may cause some minor troughs in plasma levodopa levels, w hich may th en be sm oothed out by addition of small amounts of short-onset, short-duration SS. Total daily off tim e was significantly improved on C/S over SS; although % of the patients reported im provem ent on C/S as com pared with Ya on CR, the difference is not statistically significant. It should be noted that there was no significant difference in the num ber of hours off betw een the CR and SS periods during the double-blind trial, 23 which em phasizes th e im proved efficacy of combination therapy. This also suggests that it may even be possible to improve patients rem aining on CR alone further by adding SS to the regimen. There was no index of predictability as to which patients com pleting the double-blind study would benefit m ost from C/S. L ikew ise, th e 12 p a tie n ts who began on C/S immediately after the double-blind trial had no identifiable characteristics th at w ould distinguish them from those who rem ained on CR alone. One-half of the patients com pleted the double-blind trial in the CR phase; the other half, in the SS phase. The degree of variability and range of severity of illness, duration of disease and flu ctu a tions, num ber of doses and tablets of CR and SS, and total mg of levodopa among individuals differed markedly, and the particular m edication requirem ents of each person had to be addressed and adjusted independently of the others. Because one is not able to categorize patients, it is not yet possible to predict responders in advance of the actual trial of m edications. Based on the findings in a short term, open label trial of C/S therapy, it would appear that, w hen SS is used in com bin a tio n w ith C R, th e r e is f u r th e r im provem ent over CR alone for those patients experiencing the m otor fluctuations associated with long-term levodopa use. However, these conclusions are the result of short-term experience with C/S treatm ent in a small num ber of patients. Ongoing trials with a larger group, along w ith correlation with plasm a levodopa levels, will be necessary to evaluate long-term efficacy of com bination th e r apy of SS and CR. Acknowledgments The authors gratefully acknowledge the assistance of Ms. Vanessa Patterson, Ms. Michele Fabriele, and

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