QALS
(2009)Objective
To select between two high doses of CoQ10 (1,800 vs 2,700 mg/day) and determine if CoQ10 merits testing in a Phase III clinical trial for ALS using a futility design
Study Summary
• Stage 2 futility test: Primary analysis did not reject null hypothesis that CoQ10 is ≥20% superior to placebo (p=0.14), but sensitivity analysis with alternative death scoring did reject it (p=0.025)
• No significant differences in secondary outcomes; CoQ10 was safe and well-tolerated
• Conclusion: Insufficient evidence to justify Phase III testing
Intervention
CoQ10 2,700 mg/day (or 1,800 mg/day in Stage 1) as chewable wafers (3 wafers TID) vs matching placebo for 9 months
Inclusion Criteria
Age 21-85 years, definite/probable/laboratory-supported probable ALS (El Escorial), sporadic or familial, FVC ≥60%, disease onset ≤5 years
Study Design
Arms: Stage 1: CoQ10 1,800 mg vs CoQ10 2,700 mg vs Placebo (35 each); Stage 2: CoQ10 2,700 mg vs Placebo (75 each)
Patients per Arm: Stage 1: 35 per arm (CoQ10 1,800 mg, CoQ10 2,700 mg, placebo); Stage 2: 75 per arm (CoQ10 2,700 mg, placebo — 35 Stage 1 carry-forwards + 40 newly randomized); Total n=185
Outcome
• Sensitivity analysis with death score=16: CoQ10 8.5 vs placebo 8.4 (p=0.025, futility declared)
• No significant differences in FVC, SF-36, or fatigue severity
Bottom Line
CoQ10 at 2,700 mg/day for 9 months showed insufficient promise to warrant Phase III testing. While the primary futility analysis did not definitively rule out proceeding to Phase III (p=0.14), a pre-specified sensitivity analysis (p=0.025) and secondary analyses showed no benefit. The result was sensitive to how deceased patients were scored on the ALSFRS-R. CoQ10 was safe and well-tolerated. The innovative two-stage adaptive design successfully minimized sample size requirements while providing definitive guidance against further development.
Major Points
- Stage 1 dose selection: 2,700 mg/day selected over 1,800 mg/day based on lower mean 9-month ALSFRS-R decline (9.0 vs 10.9)
- Stage 2 primary futility analysis: Mean ALSFRS-R decline was 8.8 (CoQ10) vs 9.4 (placebo); null hypothesis of ≥20% superiority not rejected (p=0.14)
- Pre-specified sensitivity analysis with death score=16 (10th percentile): Declines were similar (8.5 vs 8.4), futility was declared (p=0.025)
- Mortality during 9-month follow-up: 1 on CoQ10 vs 5 on placebo (not statistically significant); outlying values from deceased placebo patients drove apparent CoQ10 benefit in primary analysis
- Median ALSFRS-R decline was slightly greater for CoQ10 than placebo, insensitive to outliers
- Post hoc slope analysis consistent with futility (p=0.097)
- No significant differences in secondary outcomes (FVC, SF-36 quality of life, fatigue severity)
- CoQ10 plasma levels significantly increased from baseline in active groups but not placebo, confirming compliance and minimal drop-in
- No difference in plasma levels between 1,800 and 2,700 mg doses, consistent with plateau effect
- Innovative adaptive Phase II design required only 185 participants vs ~900 for conventional approach
Study Design
- Study Type
- Phase II, multicenter, randomized, stratified, placebo-controlled, double-blind, two-stage adaptive, bias-corrected, futility design
- Randomization
- Yes
- Blinding
- Double-blind; identical wafers for active and placebo (yellow color, maple flavor); participants, investigators, and evaluators blinded
- Sample Size
- 185
- Follow-up
- 9 months treatment + 1 month post-treatment safety follow-up
- Centers
- 19
- Countries
- United States
Primary Outcome
Definition: Decline in ALSFRS-R score from baseline to 9 months (positive value indicates worsening); Stage 1: dose selection; Stage 2: futility test with null hypothesis that CoQ10 reduces mean decline by ≥20% vs placebo
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & Criticisms
- Primary analysis result was highly sensitive to the choice of score assigned to deceased patients (0 vs 10th percentile vs other values)
- More deaths occurred in placebo group (5 vs 1) driving apparent CoQ10 benefit; difference not statistically significant
- Plasma CoQ10 levels did not differ between 1,800 and 2,700 mg doses, suggesting plateau effect and questioning whether higher doses achieve greater tissue penetration
- Stage 1 dose selection did not include a head-to-head significance test, only a selection procedure
- Gender imbalance in Stage 1 (71% male at 1,800 mg vs 43% at 2,700 mg)
- No single best or correct score for deceased patients can be specified a priori for ALSFRS-R
- Compliance by wafer count was only 71-73% for the protocol-defined threshold of consuming >80% of prescribed medication
- Oxidative stress biomarker (8OH2dG) results not available at time of publication
- Study powered to detect 20% slowing in decline, which may be too ambitious; smaller effects could be missed
- Short 9-month follow-up may miss delayed neuroprotective effects
- Riluzole use differed between groups (76% CoQ10 vs 67% placebo)
Citation
Ann Neurol. 2009;66(2):235-244. doi:10.1002/ana.21743