BACKGROUND AND PURPOSE:

• Doxylamine-pyridoxine is a first-line treatment for nausea during pregnancy
• Well-designed studies for medications to treat nausea and vomiting in pregnancy are limited
• One published RCT (see ‘Learn More – Primary Sources’ below), known as DIC-301, is the basis for the FDA approval as well as positive guideline recommendations
• Meaney et al. (Plos one, 2018) reanalyzed unpublished DIC-301 methods and results data that had been submitted to Health Canada

METHODS:

• Authors re-analyzed individual level data from the DIC-301 RCT
  • The timing of primary outcome ascertainment, the analysis plan for the primary outcome, the secondary outcomes, and the sample size justification were changed after the study was completed
  • Unclear if changes to the analysis plan were made prior to or after initiating analysis
• DIC-301: Randomized controlled trial (RCT)
  • Pregnant women between 7 and 14 weeks of gestation
  • Moderate nausea and vomiting during pregnancy
  • Women were randomized to take either
    • One tablet doxylamine 10 mg/pyridoxine 10 mg between 2 and 4 times per day for 14 days depending on symptoms
    • An identical placebo tablet taken using the same instructions
  • The primary outcome was improvement in nausea and vomiting of symptoms scores using the 13-point pregnancy unique quantification of emesis (PUQE) scale between baseline and 14 days
  • Prespecified minimal clinically important difference was defined as an “expected difference” of 3 points

RESULTS:

• Data for 131 active treatment participants and 125 control participants were analyzed
  • On the final day of the trial, 101 active treatment participants and 86 control participants provided primary outcome measures
• There was greater improvement in symptoms scores with doxylamine-pyridoxine compared with placebo (0.73 points; 95% CI 0.21 to 1.25), but only when ‘last observation carried forward imputation’ was used to populate missing values with the subject’s previous non-missing values
• When using any other methods to deal with missing data, there was no statistical difference

CONCLUSION:

• Doxylamine-pyridoxine trended toward efficacy, but depends on how missing data is evaluated
• Even if statistically significant, the authors did not find a clinically significant difference meeting the prespecified threshold
• The FDA statistical review of the DIC-301 accepted the difference between groups of 0.73 from the ‘last carried forward imputation’ methodology
  • The FDA summary stated that there was a “small, but statistically significant improvement” and “although the treatment effect is small, there are no other FDA-approved treatments for nausea and vomiting of pregnancy”
• The authors suggest that due to small clinical impact and the fact that this trend is only seen if using one particular approach to dealing with missing data, recommendation for first-line usage of doxylamine-pyridoxine should be reevaluated

Learn More – Primary Sources:

Doxylamine-pyridoxine for nausea and vomiting of pregnancy randomized placebo controlled trial: Prespecified analyses and reanalysis

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