Unified Parkinson’s Disease Rating Scale (UPDRS) part II and III (activities of daily living [ADL] and motor scales) sum score (primary outcome measure). The sum scores of all randomized patients (last observation carried forward) are expressed as mean ± SD. Higher scores indicate more severe features of parkinsonian syndrome. Statistical analyses using a t test revealed statistically significant reduction of the scores from baseline (month 0) to month 3 (end of treatment period) in both groups (P < .001 and P = .007 for the placebo and coenzyme Q10 groups, respectively) but no statistically significant differences between both treatment groups (P = .82).
Box plots of plasma coenzyme Q10 levels from the placebo and coenzyme Q10 groups. The plots show the minimum, first quartile, median, third quartile, and maximum of coenzyme Q10 levels for each group of patients at baseline, at the interim visit at end of month 3 (end of treatment period), and after 2 months of follow-up. Circles represent the mean values. The numbers of samples available from the baseline, treatment phase, and follow-up visit were 51, 46, and 42 for the placebo group and 51, 46, and 44 for the coenzyme Q10 group. Diamonds indicate the outliers.
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Storch A, Jost WH, Vieregge P, et al. Randomized, Double-blind, Placebo-Controlled Trial on Symptomatic Effects of Coenzyme Q10 in Parkinson Disease. Arch Neurol. 2007;64(7):938–944. doi:10.1001/archneur.64.7.nct60005
Major hallmarks in the pathophysiology of Parkinson disease are cellular energy depletion and oxidative stress leading to cellular dysfunction and death. Coenzyme Q10 (CoQ10) is an electron acceptor bridging mitochondrial complexes I and II/III and a potent antioxidant that consistently partially recovers the function of dopaminergic neurons.
To determine whether nanoparticular CoQ10 is safe and displays symptomatic effects in patients with midstage Parkinson disease without motor fluctuations.
Multicenter, randomized, double-blind, placebo-controlled, stratified, parallel-group, single-dose trial.
Academic and nonacademic movement disorder clinics.
One hundred thirty-one patients with Parkinson disease without motor fluctuations and a stable antiparkinsonian treatment.
Random assignment to placebo or nanoparticular CoQ10 (100 mg 3 times a day) for a treatment period of 3 months. Stratification criterion was levodopa treatment.
Main Outcome Measure
The subjects underwent evaluation with the Unified Parkinson’s Disease Rating Scale (UPDRS) at each visit on a monthly basis. The primary outcome variable was the change of the sum score of the UPDRS parts II and III between the baseline and 3-month visits.
One hundred thirty-one subjects were randomized according to the protocol. The mean changes of the sum UPDRS parts II/III score were −3.69 for the placebo group and −3.33 for the CoQ10 group (P = .82). Statistical analysis according to the stratification did not result in significant changes of the primary outcome variable. No secondary outcome measure showed a significant change between the placebo group and the CoQ10 group. The frequency and quality of adverse events were similar in both treatment groups.
Nanoparticular CoQ10 at a dosage of 300 mg/d is safe and well tolerated and leads to plasma levels similar to 1200 mg/d of standard formulations. Add-on CoQ10 does not display symptomatic effects in midstage Parkinson disease.
clinicaltrials.gov Identifier: NCT00180037Published online May 14, 2007 (doi:10.1001/archneur.64.7.nct60005).
Parkinson disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons within the substantia nigra pars compacta.1 Although the pathogenesis of PD is not fully understood, the recognition that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce a parkinsonian syndrome by inhibiting mitochondrial complex I activity generated the idea that a disorder of the mitochondrial respiratory chain is involved in PD.2 Indeed, a 30% to 40% reduction of complex I activity in substantia nigra of PD brains has been found,3 a defect that does not affect other parts of the brain.4 Coenzyme Q10 (CoQ10) is an antioxidant, an obligatory cofactor of mitochondrial uncoupling proteins, and a bioenergetic agent in the mitochondrial respiratory chain, where it transfers electrons from complexes I/II to complex III.5,6 Because of these functions, CoQ10 has attracted attention concerning neuroprotective actions in neurodegenerative disorders linked to mitochondrial defects or oxidative stress, such as Huntington disease and PD.7 Beal et al8 demonstrated that taking oral CoQ10 reduces the loss of dopamine and dopaminergic axons in the striatum of aged parkinsonian mice treated with MPTP. On the other hand, CoQ10 might also improve dysfunctions of cells suffering from energy depletion and subsequently generate symptomatic effects as demonstrated in various mitochondrial disorders.9-11
The study of the Parkinson Study Group12 investigating possible protective effects of CoQ10 in early PD demonstrated that high doses of CoQ10 slow the progressive deterioration of functions in PD measured by the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS) but neither improve motor functions nor postpone the start of levodopa treatment.12 Due to the lack of a washout phase and the fast and predominant effects of CoQ10 on activities of daily living (ADL) scores, it is not yet fully clear whether these effects might be a consequence of functional or antidepressive effects rather than neuroprotective actions.12-14 We therefore undertook a randomized, double-blind, placebo-controlled trial on symptomatic effects of nanoparticular CoQ10 in stable patients with midstage PD. We assumed that CoQ10 showed a symptomatic effect by improving cellular functions, including their synthesis capacity of dopamine from levodopa, and therefore stratified our study by a comedication of levodopa.
Our multicenter, placebo-controlled, randomized, stratified, double-blind, parallel-group, single-dose clinical trial was conceived and organized by the German Coenzyme Q10 Study Group and sponsored by the German Parkinson Association (Neuss, Germany) and MSE Pharmazeutika GmbH (Bad Homburg, Germany). The subjects were enrolled between September 2003 and January 2005 at 13 movement disorder clinics. The study was approved by the institutional review boards at participating sites, and all subjects gave written informed consent. An independent contract research organization monitored all data, the patients' safety, and the tolerability of the study drug and continuously informed the principal investigator (H.R.) about all safety issues. There was no prespecified guideline for recommending either modification or termination of the trial. The trial was registered in a public trials registry on September 9, 2005.
Subjects were between 40 and 75 years of age, had received the diagnosis of PD according to the UK Brain Bank criteria,15 had a rating on the modified Hoehn-Yahr scale16 between II and III and 16 points or more on the UPDRS motor score,16 and were on stable antiparkinsonian medication with or without levodopa for at least 4 weeks prior to study enrollment. Patients were excluded if they had been exposed to CoQ10 during the last 3 months prior to study inclusion; were taking more than 149 IU of vitamin E (100 mg of D-α-tocopherol) or calcium, magnesium, and/or other vitamins for more than 3 months prior to study inclusion; were receiving cholesterol-lowering drugs, thyroid hormones, antiarrhythmic compounds, warfarin, metformin, or clozapine; had an identifiable cause of parkinsonism or signs for atypical parkinsonian disorders; had hypothyroidism or current evidence of epilepsy or psychosis; or had levodopa-induced motor fluctuations or dyskinesias.
Subjects were randomly assigned to nanoparticular CoQ10 suspension (100 mg 3 times a day; Nanoquinon from MSE Pharmazeutika) or matching placebo for a treatment period of 3 months centrally by the contract research organization according to a randomization list generated by 1 of us (R.K.). Randomization was stratified by comedication of levodopa. After 3 months, the subjects underwent a withdrawal from study drug for 2 months and a final assessment of the severity of the symptoms of PD was made. Doses of levodopa and all other antiparkinsonian medications were kept constant throughout the study.
Efficacy assessments were made by treating investigators, who were blinded to the treatment assignment, at the screening, baseline, and interim visits (at the end of months 1, 2, and 3) and at the end of the washout phase at the end of month 5. The prespecified primary efficacy variable was the change of the sum of the UPDRS parts II and III (ADL and motor components)16 between baseline to interim visit at month 3 (end-of-treatment visit). Secondary clinical outcome variables were the scores for 6 instruments: The total UPDRS score,16 the Hoehn and Yahr score,16 the Schwab and England ADL score,16 the Parkinson’s Disease Questionnaire (PDQ39) score,17 the Global Clinical Impression score, and the Montgomery-Asberg Depression Rating Scale.18
Safety evaluations included recording of adverse events, results of laboratory tests (obtained at screening, baseline, the interim visit at the end of month 3, and the end-of-study visit), electrocardiographic results (baseline visit and interim visit after 3 months), and vital signs (all visits). Adverse events were coded with the use of a standard glossary.
Plasma CoQ10 levels were obtained at baseline, at the end-of-treatment visit (after 3 months), and after the washout phase of 2 months. Subjects were asked to refrain from taking the study medication on the day of the mentioned visits to obtain plasma levels representative of a steady state. The samples were kept at each site at −20°C to −80°C until shipped on dry ice to the laboratory at the Department of Pediatrics, University of Witten-Herdecke, Witten, Germany. Assays for plasma levels of total CoQ10 were performed as previously described.19
A sample size of 53 subjects per treatment group (106 total) was calculated to provide 95% power to detect a difference in the mean change of the sum score of UPDRS parts II and III of 7.0 units (20% of baseline score) between the placebo and the CoQ10 group using a 1-tailed t test at the .05 level of significance. The SD was estimated at 11.0 units for this calculation. Allowing a dropout rate of 20% of the subjects enrolled, we chose a sample size of 132 subjects (ie, 66 subjects in each of the 2 treatment groups).
We used the intention-to-treat principle in the analysis of the primary outcome variable and the adverse effects with the last-observation-carried-forward method to enter values if no follow-up information was available. We further analyzed both the primary and all secondary outcome variables using the per-protocol population.
Results are presented as mean ± SD or as median values and the range. Variations in the primary outcome variable (UPDRS ADL and motor sum score) between baseline and end of treatment period were compared between the placebo and CoQ10 groups using a ttest and analysis of covariance, adjusting for the baseline value as a covariate. Variations in all secondary outcome variables were compared between the baseline and end-of-treatment periods and between the placebo and CoQ10 groups using a t test (continuous variables) or a χ2 test (discrete variables). Both tests were adjusted using the Bonferroni technique. Frequencies of adverse effects were compared between groups by means of Fisher exact test. All reported P values are 2-sided.
Of a total of 131 subjects enrolled (randomized) in the study, 106 (81%) completed the trial according to the protocol (Figure 1). Sixty-four subjects were assigned to receive CoQ10 and 67 to receive placebo. The strata consist of 21 subjects without levodopa treatment in both groups and 43 and 46 subjects receiving levodopa in the CoQ10 and placebo groups, respectively. Baseline demographic and background characteristics are summarized in the Table; there were no significant differences in these characteristics between the 2 groups as well as between strata. All randomized patients received at least 1 dose of study drug. One third of patients (37 of 131, or 34.9%) had coexisting medical conditions at baseline. The most common were cardiovascular disorders (in 20 patients, or 15.3%), such as hypertension and arrhythmia, and others (in 15, or 11.5%), such as infections, glaucoma, and sleep apnea. Among the patients who were receiving central nervous system drugs at baseline (130 patients, or 99.3%), all patients were receiving antiparkinsonian medication, and the dose of dopaminergic drugs was kept constant in 60 patients in the CoQ10 group and in 64 patients in the placebo group; changes of antiparkinsonian medication led to exclusion from the per-protocol population in 4 and 3 subjects, respectively. All randomized patients were included in the primary efficacy and safety analysis (intent-to-treat population), but 13 patients were excluded from the CoQ10 group and 12 from the placebo group for additional per-protocol population analyses of primary and all secondary efficacy measures due to protocol violations or discontinuation of the study (Figure 1). The per-protocol population was similarly constituted and matched between groups compared with the intent-to-treat population.
The mean changes of the primary outcome measure (combined UPDRS part II/III scale scores) from baseline visit to the end-of-treatment visit after 3 months for all randomized subjects were −3.69 for the placebo group and −3.33 for the CoQ10 group, indicating an improvement in ADL/motor function in both groups (with P < .001 and P = .007 for the placebo and CoQ10 group, respectively; Figure 2). The prespecified primary efficacy analysis was a t test for the difference between these mean changes, which was not significant with P = .82 (2-sided). Covariance analysis adjusted for baseline values also showed no significant differences between the primary outcome measure of the treatment groups (P = .25). Similar results were obtained with the per-protocol population showing a significant reduction of the UPDRS II/III scale scores (−4.4 and −2.8 for the placebo and CoQ10 groups [P < .001 and P = .03], respectively), but no significant differences between groups (P = .32; t test, 2-sided). Analyzing the primary efficacy data according to the stratifications criterion (levodopa treatment) also revealed no significant difference between treatment groups or strata. Together, the efficacy data demonstrated a significant placebo effect in both treatment groups, which is very well known from clinical trials in PD.20
Analysis of all secondary outcome measures (including ADL and depression scores) of the per-protocol population (with or without stratification) using a covariance analysis adjusted for baseline values revealed no significant differences between the placebo and the CoQ10 group. Solely, the Hoehn and Yahr scale scores decreased significantly in the CoQ10 group (−0.16, P = .008) but not in the placebo group (−0.01, P = .85) with a significant difference between groups (P = .04). Analysis according to the stratification revealed significant changes only in the levodopa stratum of the CoQ10 group (−0.24, P = .007).
In general, CoQ10 was well tolerated. The percentage of subjects receiving CoQ10 who reported any adverse event (20 [31.3%]) was not significantly different from that in the placebo group (19 [28.4%]; P = .44). Most frequently reported adverse events (occurring in at least 2 patients [3%]) included viral infection (affecting 6 patients [9.0%] in the placebo group and 2 [3.1%] of those in the CoQ10 group), diarrhea (affecting 1 [1.5%] and 5 [7.8%]), acute hearing loss (1 [1.5%] and 1 [1.6%]), night sweats (1 [1.5%] and 1 [1.6%]), nausea (1 [1.5%] and 1 [1.6%]), and bronchitis (0 and 3 [4.7%]). Most adverse events were mild or moderate. The occurrence of serious adverse events was similar in both groups (2 patients in the placebo group, 4 patients in the CoQ10 group). There was 1 death 2 days before the end of the washout phase in the CoQ10 group, most likely due to myocardial infarction (patient was included in the analyses). Adverse events that contributed to premature withdrawal or interruption of the study drug included nausea/dizziness (1 patient in each group), diarrhea and hallucinations (1 patient each in the placebo group), and pyrosis (1 patient in the CoQ10 group). There were no significant differences between the groups with respect to clinically relevant changes in the results of laboratory tests, electrocardiograms, and vital sign measurements.
The group receiving CoQ10 had a significant increase in the mean plasma level of CoQ10 from baseline to the end-of-treatment visit after 3 months with a mean ± SD baseline and treatment phase level of 0.99 ± 0.44 mg/L (1.15 ± 0.51 nmol/mL) and 4.46 ± 2.07 mg/L (5.17 ± 2.40 nmol/mL) CoQ10, respectively (P<.001; Figure 3). The mean level in the CoQ10 group returned to baseline level after withdrawal of CoQ10 for 2 months (0.94 ± 0.37 mg/L [1.09 ± 0.43 nmol/mL] CoQ10). There was no significant change of mean CoQ10 plasma level in the placebo group.
Although we demonstrated a significant increase in plasma levels of CoQ10 toward levels observed with high doses of standard CoQ10 formulations in PD and other disorders, our study failed to show improvement of PD symptoms and did not meet its primary or secondary end points. Our study further demonstrated that 300 mg/d of nanoparticular CoQ10 is safe and well tolerated in patients with PD already taking various antiparkinsonian medications.
Shults and colleagues12 aimed to investigate the protective effects of CoQ10 in early PD and showed that 1200 mg/d of CoQ10 slows the progressive deterioration of functions in PD measured by the total UPDRS score but neither alters the UPDRS motor score nor postpones the start of levodopa treatment. However, restoration of mitochondrial respiration and reduction of oxidative stress by CoQ10 could also improve cellular dysfunction induced by cellular energy depletion as observed in PD.3,4,10 Thus, CoQ10 could have symptomatic effects in PD similar to those seen in mitochondrial disorders.9,11 Indeed, Shults and coworkers12 did not fully exclude symptomatic effects because th e CoQ10 had not been washed out before testing the outcome of CoQ10 treatment. Moreover, fast and predominant effects of CoQ10 particularly on the ADL scores might be a consequence of functional or antidepressive effects of CoQ10.12 Consistently, one pilot trial investigating the add-on of 360 mg/d of CoQ10 for 1 month also demonstrated mild improvement of the total UPDRS score but not of motor functions,13 while a small study in patients with early PD using up to 1500 mg/d of CoQ10 for 6 months showed mild improvement of motor functions.14 However, this latter study was open label, it lacked a placebo group, and the data were not statistically significant when using multiple comparison techniques.14 In our trial, we observed no effects of add-on CoQ10 either on motor functions or on ADL or depressive symptoms. However, we chose a short treatment period of 3 months to exclude relevant disease progression interfering with our data on symptomatic effects of CoQ10 and powered our study to detect a mean change of the sum score of UPDRS part II/III of 7 units (20% of baseline score). Therefore, we cannot exclude mild symptomatic changes occurring after a longer treatment period.
The results of various studies indicate that the dosage and the resulting plasma and presumably brain levels of CoQ10 might be important determinants of its effectiveness. The baseline CoQ10 plasma levels of approximately 1 mg/L in both treatment groups were well matched and in the range previously described in healthy controls, PD, and other conditions.14,21,22 Shults and colleagues12,23 reported lower baseline levels of CoQ10 of about 0.5 mg/L, most likely due to different analyzing techniques. We used here an improved lipophilic emulsion of nanoparticular CoQ10 at a dosage of 300 mg/d, leading to a significant increase of the mean plasma level to 4.5 mg/L, which is similar to levels previously described with 1200 mg/d of a standard formulation.12,23 Explanations for the relatively mild increase of CoQ10 plasma levels in the trial by Shults and colleagues12,24 might include different pharmacokinetics and the antagonism of CoQ10 uptake by high doses of vitamin E. However, the CoQ10 plasma levels in the present trial were reported to significantly increase the electron transport chain activity in mitochondria from patients with PD.12 Additionally, case series of patients with hereditary CoQ10 deficiency or mitochondrial disorders showed clinical improvement with dosages of CoQ10 similar to or even less than those used in our study.9,10,25 In vitro data indicate that similar concentrations of CoQ10 could counteract 1-methyl-4-phenylpyridinium toxicity toward dopaminergic cells and partially ameliorate mitochondrial defects in fibroblasts from patients with PD.26,27 Although we do not know the CoQ10 brain levels and do not have good indicators for the CoQ10 action in the brain, these data suggest that insufficient CoQ10 levels are most likely not responsible for the absence of symptomatic effects in PD.
The nanoparticular formulation of CoQ10 used in the present study at high dosages was well tolerated and safe in patients with midstage PD simultaneously treated with their regular antiparkinsonian medication. We found no significant differences in the frequency and quality of adverse events in the CoQ10 group compared with the placebo control group. These data are in line with previous studies using various formulations of CoQ10 in patients with PD12,14,23 and other neurological and nonneurological conditions.9,25,28
To our knowledge, this is the first trial systematically investigating the safety and symptomatic efficacy of high doses of CoQ10 in patients with PD. Since we did not find symptomatic effects of CoQ10 in PD, our study does not support the hypothesis that restoring the impaired energy metabolism of the diseased dopaminergic neurons leads to symptomatic benefits in PD. Future studies will need to explore the protective effects of CoQ10 at the highest effective dose (equivalent to ≈ 2400 mg/d of a standard formulation23) over a long treatment period and in a large cohort of patients both sufficient to clearly define the protective potential of this compound in PD.
Nanoparticular CoQ10 at a dosage of 300 mg/d is safe and well tolerated in patients with PD and leads to plasma levels sufficient to exert intracellular effects and similar to 1200 mg/d of standard formulations. Adding CoQ10 to standard antiparkinsonian medication does not display symptomatic effects in midstage PD without motor fluctuations.
Correspondence: Alexander Storch, MD, Department of Neurology, Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany (Alexander.Storch@neuro.med.tu-dresden.de).
Published Online: May 14, 2007 (doi:10.1001/archneur.64.7.nct60005).
Accepted for Publication: December 15, 2006.
Author Contributions: Drs Storch and Reichmann had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Herting and Reichmann contributed equally to this work. Study concept and design: Storch, Durner, Kuhn, Herting, and Reichmann. Acquisition of data: Storch, Jost, Vieregge, Spiegel, Greulich, Durner, Müller, Kupsch, Henningsen, Oertel, Fuchs, Kuhn, and Herting. Analysis and interpretation of data: Storch, Oertel, Niklowitz, and Koch. Drafting of the manuscript: Storch and Müller. Critical revision of the manuscript for important intellectual content: Jost, Vieregge, Spiegel, Greulich, Durner, Müller, Kupsch, Henningsen, Oertel, Fuchs, Kuhn, Niklowitz, Koch, Herting, and Reichmann. Statistical analysis: Koch. Obtained funding: Spiegel. Administrative, technical, and material support: Storch, Vieregge, Spiegel, Durner, Müller, Kupsch, Oertel, and Herting. Study supervision: Vieregge, Kupsch, Henningsen, Oertel, Kuhn, Herting, and Reichmann.
Financial Disclosure: None reported.
Funding/Support: This study was supported by a grant from the Deutsche Parkinson-Vereinigung eV (German Parkinson Association), Neuss, Germany, and MSE Pharmazeutika GmbH, Bad Homburg, Germany. The coenzyme Q10 and matching placebo were formulated and packaged without charge by MSE Pharmazeutika.
Participating Centers and Investigators
Andreas Kupsch, MD; Elmar Lobsien, MD, Department of Neurology, Charite Berlin, Berlin, Germany; Thomas Müller, MD; Elvira Heitmann, MD; Anita Mackowiak, MD; Ulrike Theodoridis, MD, Department of Neurology, Ruhr-University of Bochum, Bochum, Germany; Heinz Reichmann, MD (principal investigator); Birgit Herting, MD; Verena Fürer, MD; Susann Junghanns, MD, Department of Neurology, Technical University of Dresden, Dresden, Germany; Wolfgang Greulich, MD; Kerstin Schmidt-Dabrock, MD, Department of Neurology, Klinikum Ambrock, Hagen, Germany; Stefan Jung, MD; Jörg Spiegel, MD, Department of Neurology, University of Homburg, Homburg/Saar, Germany; Joachim Durner, MD; Karin Junginger, MD, Department of Neurology, Fachklinik Ichenhausen, Ichenhausen, Germany; Peter Vieregge, MD, Department of Neurology, Klinikum Lemgo, Lemgo, Germany; Henning Henningsen, MD, Department of Neurology, Klinikum Lüneburg, Lüneburg, Germany; Wolfgang H. Oertel, MD, Department of Neurology, University of Marburg, Marburg, Germany; Wilfried Kuhn, MD, Department of Neurology, Leopoldina Krankenhaus, Schweinfurt, Germany; Alexander Storch, MD; Michael Sabolek, MD, Department of Neurology, University of Ulm, Ulm, Germany; Wolfgang H. Jost, MD; Elvira Heitmann, MD, Department of Neurology, Deutsche Klinik fuer Diagnostik, Wiesbaden, Germany; Gerd Fuchs, MD, Fachklinik Wolfach, Wolfach, Germany.
Petra Niklowitz, MD, Department of Pediatrics, Vestische Kinderklinik Datteln, University of Witten-Herdecke, Witten, Germany.
Biostatistics and Clinical Trial Coordination
Rainer Koch, PhD, Department of Biometrics and Medical Informatics, Technical University of Dresden; Birgit Herting, MD; Alexander Storch, MD; Heinz Reichmann, MD (principal investigator), Department of Neurology, Technical University of Dresden; Gert Gammel, PhD; Rainer Koch, PhD, MSE Pharmazeutika GmbH, Bad Homburg, Germany; Gisela Rauch-Petz, MD, independent contract research organization, Munich, Germany.
Safety Monitoring Committee
Gisela Rauch-Petz, MD, independent contract research organization, Munich; Heinz Reichmann, MD, Department of Neurology, Technical University of Dresden.
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