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A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit

Parkinson Study Group QE3 Investigators, M Flint Beal, David Oakes, Ira Shoulson, Claire Henchcliffe
JAMA Neurology 2014 71(5):543-552

Bibliography

PubMed
PMID 24664227
DOI
10.1001/jamaneurol.2014.131
Funding
Funded by National Institute of Neurological Disorders and Stroke grants U01 NS050324 (Cornell University) and U01 NS050573 (University of Rochester); Parkinson’s Disease Foundation support facilitated minority enrollment.
Competing interests
Conflict-of-interest disclosures: none reported.

Study snapshot

DesignPhase III randomized double-blind placebo-controlled multicenter trial
ModelLarge multicenter, randomized, double-blind, placebo-controlled phase III-style futility-monitored trial (QE3) in untreated early Parkinson disease across 67 US/Canadian sites.
Sample600 randomized: placebo n=203; CoQ10 1200 mg/day n=201; CoQ10 2400 mg/day n=196. Sixty-five withdrew prematurely (29 placebo, 19 at 1200 mg, 17 at 2400 mg).
InterventionPlacebo, CoQ10 1200 mg/day, or CoQ10 2400 mg/day; all three groups also received vitamin E 1200 IU/day. Follow-up planned to 16 months or until disability requiring dopaminergic therapy.
DurationUp to 16 months; terminated for futility
EndpointsChange in total UPDRS Parts I-III; Time to disability requiring dopaminergic therapy; UPDRS mental/ADL/motor subscales; Hoehn and Yahr stage; Schwab and England ADL; PD quality-of-life scale; Modified Rankin score; Symbol digit score; Safety/adverse events; Plasma CoQ10; Futility interim analysis

What the study showed, in plain terms

QE3 is the strongest direct test of high-dose CoQ10 as a disease-modifying treatment in early Parkinson disease. Six hundred untreated patients were randomized to placebo, 1,200 mg/day CoQ10 or 2,400 mg/day CoQ10, with all groups also receiving 1,200 IU/day vitamin E.

The trial was stopped for futility. Total UPDRS worsened by an adjusted mean 6.9 points with placebo, 7.5 with 1,200 mg/day (p=0.49 vs placebo), and 8.0 with 2,400 mg/day (p=0.21). Both active arms trended slightly worse rather than better, and secondary outcomes also showed no benefit.

High-dose CoQ10 was generally well tolerated and produced expected plasma exposure, so the negative efficacy result cannot be dismissed as inadequate dosing or poor absorption. The authors concluded that CoQ10 should not be recommended to treat early Parkinson disease on the basis of QE3.

Key findings

Primary outcome—total UPDRS change: placebo +6.92 (SE 0.63), 1200 mg/day +7.50 (SE 0.62; p=0.49 vs placebo), 2400 mg/day +8.01 (SE 0.63; p=0.21 vs placebo). Lower worsening would have favored CoQ10; neither dose did.

Futility: both active arms crossed the prespecified futility threshold; DSMB informed investigators on 29 April 2011 and the study was terminated for futility in May 2011, without a safety-driven stop.

Clinical endpoint: 267 participants required dopaminergic treatment—94 placebo, 87 at 1200 mg/day, 86 at 2400 mg/day.

Secondary outcomes: no meaningful benefit on UPDRS subscales, Hoehn and Yahr stage, Schwab-England ADL, quality of life or repeated-measures analyses; no favorable subgroup interaction by sex, age or disease severity.

Safety/exposure: high doses were well tolerated with no major safety concern; treatment groups had expected plasma CoQ10 separation and generally excellent medication-log compliance.

Attrition: 65 premature withdrawals—29 placebo, 19 at 1200 mg/day, 17 at 2400 mg/day.

What this study can and cannot tell us

All groups received high-dose vitamin E (1200 IU/day), so the trial tests CoQ10 added to that shared background rather than CoQ10 versus a completely supplement-free placebo.

The study was terminated early for futility, reducing the amount of complete 16-month follow-up, although futility stopping was prespecified and the direction of effect did not favor CoQ10.

The trial enrolled untreated early Parkinson disease, so it does not directly answer symptom-specific supplementation questions in later disease. However, it is highly informative for the proposed disease-modifying/neuroprotective claim.

Despite strong mechanistic rationale and earlier small positive signals, this large trial did not confirm clinical efficacy; those earlier studies should not override QE3.

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