ABSTRACT & COMMENTARY
No Evidence Supporting Coenzyme Q10 Use in Parkinson’s Disease
By Claire Henchcliffe, MD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
Dr. Henchcliffe reports she is on the speakers bureau and advisory board for GE, Teva Pharmaceutical Industries, and UCB; advisory board for Allergan and USWorldmeds; receives grant/research support from Biogen and Kaneka; and does CME program development and presentation for MedIQ.
SYNOPSIS: This large, randomized Phase 3 clinical trial of high-dose coenzyme Q10 failed to show any neuroprotective benefit in early Parkinson’s disease.
Source: Parkinson Study Group QE3 Investigators. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: No evidence of benefit. JAMA Neurol 2014;71:543-552.
This Phase 3, double-blind, placebo-controlled trial, nicknamed QE3, was designed to test the hypothesis that high-dose coenzyme Q10 is neuroprotective in Parkinson’s disease (PD). Individuals with early unmedicated PD (n = 600) were randomized to placebo, 1200 mg coenzyme Q10 (CoQ10) daily, or 2400 mg CoQ10 daily for 16 months or until there was a need for dopaminergic therapy. All received 1200 IU vitamin E in the combination wafers, thus reproducing the intervention in the preceding Phase 2 (QE2) study. Mean age at enrollment was 62.5 years, one-third were women, and 7.5% were minorities. There were no differences between groups when analyzed based on sex, age, or severity of PD. Mean baseline total Unified Parkinson’s Disease Rating Scale (UPRDS) at baseline was 22.7, corresponding to a mild degree of symptomatology, and mean disease duration ranged between 2.0 ± 1.5 and 2.2 ± 1.9 years in the different treatment groups. At study completion, no statistically significant differences were found between groups in primary and secondary outcome variables. In fact, treatment groups had marginally worse changes from baseline to endpoint when compared with the placebo group. Change (worsening) in total UPDRS score from baseline to endpoint was: + 6.92 ± 0.63 points (placebo); + 7.50 ± 0.62 points (1200 mg CoQ10 daily); and + 8.01 ± 0.63 points (2400 mg CoQ10 daily). No imaging biomarkers were included. Although 72.5% of participants reported side effects, they were mild in 62.7% and did not markedly differ between the three groups. The most common adverse events reported were back pain, constipation, and insomnia. In the CoQ10 arms, 3% had treatment reduced and 8.3% had treatment suspended, compared with 1% and 6.4%, respectively, in the placebo arm. Serious adverse events were reported in 33 individuals: Of these, one event of severe gastrointestinal bleeding was considered possibly related to the study intervention (this was in association with angiodysplasia). There was one death from cardiac arrest 8 days after completing the study (1200 mg CoQ10 daily).
Despite a robust rationale for a potential neuroprotective effect of CoQ10 in PD, this large Phase 3 QE3 study has failed to demonstrate any benefit. The result is disappointing, to say the least. Several lines of evidence had supported CoQ10 as a promising candidate for neurprotection. CoQ10 is a potent antioxidant and is critical in the mitochondrial electron transport chain, and therefore was predicted to "correct" increased oxidative stress and mitochondrial dysfunction in PD. Robust preclinical data in cell culture and animal models have supported its neuroprotective activity. A Phase 2 study of doses of CoQ10 up to 1200 mg daily (nicknamed QE2) demonstrated safety and tolerability in 80 subjects with early PD, and importantly also suggested that it might slow PD progression. CoQ10 has also been studied in a futility design study, conducted by the NINDS Neuroprotection Exploratory Trials in PD (NET-PD) program. CoQ10 administered to 213 patients did not meet futility criteria and was deemed worthy of further study. On the other hand, MitoQ, a coenzyme Q10 derivative, failed to show benefit in a recent study in 128 early PD patients. Moreover, the NET-PD trial results noted above have been criticized, based on use of historical control subjects. Although a "failure," mitochondrial medicine may yet prove beneficial and the QE3 study highlights a number of critical issues in developing neuroprotective therapies. Potential reasons for a negative result include limitations of animal models as predictors of success for neuroprotective strategies in humans, heterogeneity of PD etiopathogenesis, and limited readouts available for use in clinical trials. The study should therefore encourage ongoing efforts in the field to 1) improve disease modeling, for example using genetic animal models and iPS cells; 2) determine the "best" study population for an intervention; and 3) identify objective biomarkers that will measure disease progression as well as demonstrate target engagement.