Budipine Provides Additional Benefit in Patients with Parkinson Disease Receiving a Stable Optimum Dopaminergic Drug Regimen

ORIGINAL CONTRIBUTION Budipine Provides Additional Benefit in Patients With Parkinson Disease Receiving a Stable Optimum Dopaminergic Drug Regimen

Horst Przuntek, MD; Stefan Bittkau, MD; Harald Bliesath, MD; Ulrich Bu¨ttner, MD; Gerd Fuchs, MD; Joachim Glass, MD; Harald Haller, MD; Thomas Klockgether, MD; Peter Kraus, MD; Lutz Lachenmayer, MD; Dieter Mu¨ller, MD; Thomas Mu¨ller, MD; Bernhard Rathay, MD; Jo¨rg Sgonina, PhD; Volker Steinijans, PhD; Elemer Teshmar, MD; Gudrun Ulm, MD; Dieter Volc, MD

Background: The complex pharmacological profile of Results: Budipine significantly (PϽ.001) decreased the the antiparkinsonian drug budipine influences neuro- Columbia University Rating Scale sum score (median, transmission beyond the dopaminergic system. Previ- 15.0; 95% confidence interval, 11.3-17.0) compared with ous studies have demonstrated the therapeutic efficacy placebo (median, 4.3; 95% confidence interval, 3.0-7.5) at of budipine on motor symptoms in insufficiently treated study end point. Budipine reduced Columbia University patients with Parkinson disease. Rating Scale subscores for tremor, rigidity, and akinesia.

Objective: To demonstrate the efficacy of 20 mg of bu- Conclusion: The additional application of budipine pro- dipine, 3 times daily, in addition to a stable, prior, opti- vides further therapeutic benefit in subjects with Parkin- mum-titrated dopaminergic substitution consisting of a son disease receiving a stable, prior, optimum-titrated do- combination of levodopa and a dopa decarboxylase in- paminergic drug regimen because of the hypothetical hibitor, bromocriptine mesylate, and optional selegiline positive impact of budipine on altered nondopaminergic hydrochloride in 99 patients with idiopathic Parkinson neurotransmission in patients with Parkinson disease. disease in a multicenter, double-blind, placebo-controlled trial. Arch Neurol. 2002;59:803-806

NTIPARKINSONIAN drug tri- placebo-controlled, double-blind clinical als have mainly focused on trial was to demonstrate the antiparkinso- the substitution of the ni- nian efficacy of budipine in addition to a grostriatal dopaminergic stable, prior, optimally titrated dopaminer- deficit and have mainly re- gic drug regimen consisting of a combina- sultedA in improvement of parkinsonian tion of levodopa and a dopa decarboxylase motor symptoms. But insidious deteriorat- inhibitor, bromocriptine mesylate, and op- ing neurodegeneration also affects other tional selegiline hydrochloride. neurotransmitter systems and extranigral anatomical structures in patients with id- RESULTS iopathic Parkinson disease (PD).1 Thus, the neurodegenerative process causes onset of There was a significant distinct reduction a wide heterogeneous variety of parkinso- of the CURS sum score in the budipine- nian features, all of which limit quality of treated patients compared with the placebo- life.2 Therefore, compounds with a com- treated patients (Table 2 and Figure 2). The plex pharmacological profile, which also in- improvement of the median CURS score fluences neurotransmission beyond the do- corresponded to nearly 40% in the budipine- paminergic system, may hypothetically treated group. Columbia University Rat- provide an additional therapeutic benefit in ing Scale subscores of tremor, rigidity, and patients with PD. Budipine represents such akinesia were significantly more reduced in a drug, because it also influences, for in- the budipine- than the placebo-treated sub- stance, GABAergic, norepinephrinergic, se- jects (Table 2). Scores for depression and rotoninergic, and cholinergic neurotrans- dementia did not significantly change within mission.3-7 Eltze8 provides a review. Previous and between both groups (P=.12 and .29, clinical trials9-12 have demonstrated the respectively; Wilcoxon rank sum test). Diz- therapeutic efficacy of budipine on motor ziness (n=4), dry mouth (n=4), loss of ap- symptoms in subjects with PD who re- petite (n=3), nervousness (n=3), and vi- ceive an insufficient antiparkinsonian drug sual dysfunction (n=3) were reported Author affiliations are listed regimen. Przuntek and Mu¨ ller13 provide a adverse effects of the budipine-treated pa- at the end of this article. review. The objective of this multicenter, tients, whereas only 1 participant in the pla-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 PATIENTS AND METHODS vivid dreams, and cognitive deficits) according to the patients’ and treating physicians’ opinion within 4 PATIENTS weeks. Then, we kept the antiparkinsonian therapy stable for at least 4 weeks. A further 4-week screening period We enrolled 99 patients with idiopathic PD, according to followed. Next, we slowly started titration of budipine the United Kingdom Brain Bank criteria, into the study from the initial application of 20 mg/d up to 60 mg/d, (Figure 1).14 They were randomized to treatment with bu- adding 10 mg/wk (Figure 2). Soon after that, partici- dipine (n=49; Hoehn and Yahr stage II [n=2], III [n=17], pants took budipine, 20 mg 3 times daily, until the end IV [n=18], or V [n=3] [totals reflect patients who com- of the trial for 11 weeks. We allowed reduction of budi- pleted the trial]) or placebo (n=50; Hoehn and Yahr stage II pine to 40 mg/d because of the onset of adverse effects. [n=4], III [n=16], IV [n=20], or V [n=4] [totals reflect One blinded investigator determined the score of the patients who completed the trial]) by chance. Their drug regi- patients. Another blinded independent physician con- men had to consist of a combination of levodopa/a dopa de- trolled patients’ compliance, safety, and tolerability of carboxylase inhibitor, bromocriptine, and optional selegi- budipine. line. Their Columbia University Rating Scale (CURS) score 15 at study enrollment had to be between 24 and 50. Subjects STATISTICAL ANALYSIS with severe unpredictable motor fluctuations; clinically relevant cardiac, hepatic, gastrointestinal, metabolic, renal, al- lergic, or psychiatric disorders; and/or intake of drugs that We computed differences of the CURS score and its sub- affect the dopaminergic system were not allowed to partici- scores of tremor (items [grade, 0-4]: arm [score right pate. Eighty-four patients finished the trial. We excluded 15 and left], head, and leg [score right and left]), rigidity individuals (before unblinding) from the per-protocol analy- (items [grade, 0-4]: arm [score right and left separat- sis because of either premature termination not related to study ely], neck, and leg [score right and left separately]), and medication (5 [10%] of budipine-treated patients and 2 [4%] bradykinesia (items [grade, 0-4]: bradykinesia [combin- of placebo-treated participants) or a major protocol viola- ing slowness and poverty of movement in general], gait tion (4 [8%] of budipine-treated individuals and 4 [8%] of disturbance, posture, postural stability, and arising placebo-treated subjects). There were no clinically relevant from a chair [straight-back wooden or metal chair]) be- differences for the demographic data and clinical character- tween baseline (score: [V−4+V0]/2) and the end of the istics between both groups at baseline (Table 1). trial (score: [V12+V16]/2) in the budipine- and the placebo- treated groups (Figure 2).15,16 (V indicates visit; subscript DESIGN numbers, number of the visit.) Then, we used the Wil- coxon rank sum test for comparison of both treatment We titrated the preexisting dopaminergic drug regimen to its arms. The P value was adjusted to .01 for multiple testing optimum efficacy and tolerability (eg, onset of dyskinesia, of CURS and its subscores.

sonian symptoms compared with placebo in our trial. Registered Patients (N = 103) We confirm the results of another double-blind placebo- Not Registered (n = 4) controlled study on the efficacy of budipine, 20 mg Missing Inclusion Criteria administered in the morning. This study showed a significant decrease of the CURS sum score and ameliora- Randomized (n = 99) tion of rigidity, akinesia, and tremor in 29 patients Budipine (n = 49) Placebo (n = 50) undergoing levodopa and benserazide monotherapy. Two dropouts appeared in this earlier study.9 Previous Followed Up (n = 40) Followed Up (n = 44) open-label monocenter trials9,12 described the tremor-

Withdrawn (n = 9) Withdrawn (n = 6) lytic efficacy of budipine with additionally performed Premature Termination Not Premature Termination Not long-term electromyographic recordings in 20 patients Related to Drug (n = 5) Related to Drug (n = 2) Major Protocol Violation (n = 4) Major Protocol Violation (n = 4) with PD (11 patients in one trial and 9 in another). Our results also confirm those of earlier predominantly Completed Trial (n = 40) Completed Trial (n = 44) open-label and retrospective studies on subjects with PD without a previous stable drug regimen and with an Figure 1. Patient enrollment in the study. insufficiently titrated dopaminergic antiparkinsonian drug regimen. Przuntek and Mu¨ ller13 provide a review. cebo-treated group complained of dizziness. There were In contrast to those earlier studies, we used a higher no clinically relevant changes for blood variables, blood pres- dose of budipine, 20 mg 3 times daily, and titrated with sure, heart rate, and electrocardiographic results (data not certain selected dopaminergic drugs to an optimum shown). response. Finally, our participants were enrolled in the study after receiving a stable dopaminergic drug regimen COMMENT for 4 weeks. Despite this complex design, the addition of budipine further reduced parkinsonian symptoms. Additional treatment with budipine in doses up to 20 Therefore, we hypothesize that budipine, with its com- mg 3 times daily significantly further improved parkin- plex pharmacological profile, also influenced altered

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 tors is at least uncertain in some patients. This could Table 1. Demographic Data of the Participants have biased our results to a certain extent, despite the Who Finished the Study* use of 2 different investigators, one only for scoring and a second for further assessments. Both investigators were Budipine-Treated Placebo-Treated Group Group blinded to each other. Variable (n = 40) (n = 44) In conclusion, our study demonstrates that budipine, 20 mg 3 times daily, provides an additional thera- Age, y 65 (41-76) 67 (54-75) Male-female ratio 27:13 27:17 peutic benefit because of its hypothetic positive impact Body weight, kg 75 (50-113) 75 (45-92) on altered nondopaminergic neurotransmission in pa- Concomitant diseases† 19 (48) 22 (50) tients with PD. CURS sum score 34 (21-63) 35 (26-61) BDI score 9 (0.5-17) 8 (0.5-20) Accepted for publication January 3, 2002. MMSE score 28.5 (24-30) 28.5 (24-30) Antiparkinsonian drugs From the Department of Neurology, Ruhr University of administered, mg/d Bochum, Bochum, Germany (Drs Przuntek, Kraus, and T. Levodopa 400 (150-850) 314 (150-900) Mu¨ller); Byk Gulden Pharmaceuticals, Constance, Germany Bromocriptine 7.5 (1.2-50) 7.5 (1.2-30) (Drs Bliesath and Steinijans); the Department of Neurology, Subjects receiving selegiline 20 (50) 16 (36) Ludwig Maximilian University of Munich, Munich, Ger- hydrochloride† many (Dr Bu¨ttner); Parkinson Clinic, Wolfach (Dr Fuchs); Selegiline hydrochloride 7.5 (5-15) 8.8 (5-15) administered, mg/d the Department of Neurology, University of Bonn, Bonn, Ger- many (Dr Klockgether); the Department of Neurology, Barm- *Data are given as median (range) unless otherwise indicated. CURS bek General Hospital (Dr Lachenmayer), the Department of indicates Columbia University Rating Scale; BDI, Beck Depression Inventory; Neurosurgery, University of Hamburg (Dr D. Mu¨ller), and and MMSE, Mini-Mental State Examination. †Data are given as number (percentage) of participants. Lundbeck GmbH & Co (Dr Sgonina), Hamburg, Germany; Paracelsus-Elena Clinic, Kassel, Germany (Dr Ulm); and Josephstadt Neurological Outpatient Clinic, Vienna, Austria 40 160 (Dr Volc). Drs Bittkau, Glass, Haller, Rathay, and Teshmar are in private practice in Germany. 35 140 Author contributions: Study concept and design (Drs 30 120

Budipine Dose, mg/d Przuntek, Bliesath, Bu¨ ttner, Fuchs, Kraus, T. Mu¨ ller, and

25 100 Sgonina); acquisition of data (Drs Bittkau, Fuchs, Glass, Haller, Kraus, Lachenmayer, D. Mu¨ller, T. Mu¨ller, Rathay, 20 80 Sgonina, Teshmar, Ulm, and Volc); analysis and inter-

15 60 pretation of data (Drs Przuntek, Bittkau, Bliesath, Klock-

Median CURS Score gether, Kraus, Sgonina, and Steinijans); drafting of the 10 40 Placebo-Treated Group manuscript (Drs Przuntek, Bittkau, Bliesath, Kraus, 5 Budipine-Treated Group 20 T. Mu¨ ller, Sgonina, and Steinijans); critical revision of Budipine Dose, mg/d the manuscript for important intellectual content (Drs 0 0 –4 0 1 2 4 612168 Przuntek, Bliesath, Bu¨ ttner, Fuchs, Glass, Haller, Klock- Visits, wk gether, Kraus, Lachenmayer, D. Mu¨ ller, Rathay, Sgonina, Figure 2. Daily dosages of budipine and placebo and decrease of the Teshmar, Ulm, and Volc); statistical expertise (Drs Columbia University Rating Scale (CURS) sum score during the trial. Przuntek, Bliesath, T. Mu¨ ller, and Steinijans); obtained funding (Drs Przuntek, Bittkau, Bliesath, Kraus, and Ulm); administrative, technical, and material support (Drs Table 2. Total Point Reduction of the CURS Score Przuntek, Bu¨ ttner, Fuchs, Glass, Haller, Klockgether, After 16 Weeks* Kraus, D. Mu¨ ller, Rathay, Sgonina, Ulm, and Volc); and study supervision (Drs Przuntek, Klockgether, Kraus, CURS Budipine-Treated Placebo-Treated Lachenmayer, T. Mu¨ ller, and Sgonina). Component Group Group P Value† This study was supported by Byk Gulden Pharmaceu- Total score 15.0 (11.3-17.0) 4.3 (3.0-7.5) Ͻ.001 ticals, Constance, Germany; and Lundbeck GmbH & Co, Subscores Hamburg, Germany. Tremor 2.5 (2.0-3.5) 0.5 (0.3-2.0) .002 Corresponding author and reprints: Horst Przuntek, Rigidity 3.0 (2.3-3.8) 1.3 (0.5-1.8) Ͻ.001 MD, Department of Neurology, Ruhr University of Akinesia 7.0 (5.3-8.5) 2.0 (1.3-3.8) Ͻ.001 Bochum, Gudrunstrass 56, 44791 Bochum, Germany (e-mail: [email protected]). *Data are given as median (95% confidence interval) unless otherwise indicated. CURS indicates Columbia University Rating Scale. †Wilcoxon rank sum test. REFERENCES

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