Previously unpublished research calls into question the efficacy of the most commonly prescribed medication for nausea in pregnancy, found a Canadian study.
The now defunct Merrell-National Laboratories conducted a clinical trial in the 1970s to determine whether the drug pyridoxine-doxylamine, sold under the brand name Diclectin, could alleviate morning sickness in the first trimester of pregnancy.
While the results of the trial were never published, Health Canada and the US Food and Drug Administration used the information collected to approve the drug, also known as Bendectin in the US.
Pyridoxine-doxylamine is so popular that it has been prescribed in 33m women worldwide and is used in half of Canadian pregnancies that result in live births. The Society of Obstetricians and Gynaecologists of Canada lists it as the standard of care for women with nausea and vomiting "since it has the greatest evidence to support its efficacy and safety."
The 40-year-old study was published by Dr Nav Persaud, a family physician and researcher at St Michael's Hospital, as part of the restoring invisible and abandoned trials (RIAT) initiative that holds that unpublished or misreported studies make it difficult to determine the true value of a treatment.
Persaud said there were many flaws in the study, which may explain why it was never published and which call into question the benefits of Diclectin. He obtained 36,000 pages of documents from the FDA, including the original study report, the protocol and summary results, and other documents from Health Canada, all as the result of freedom of information requests.
The trial was conducted at 14 clinics in the US and enrolled 2,308 patients in the first 12 weeks of pregnancy who were experiencing nausea and vomiting. The women were randomly assigned to eight groups, one of which received a placebo and the other seven a variety of drugs including the combination for Diclectin. Data from 1,599 participants was analysed. The proportion of participants who were "evaluated moderate or excellent" was greater in each of the seven groups receiving drugs than those receiving the placebo – 14% for Diclectin.
Persaud called into question those conclusions based on what he said were several flaws in the execution and analysis of the trial, including: the final results of the study are not available; the high number of participants who did not complete the trial, even though it lasted only one week; outcome data is unavailable for 37% of participants in the placebo arm that was used as the reference for comparisons; data for 30 patients recruited by one of the investigators was excluded on orders of the Commissioner of Food and Drugs in a 1975 letter that referred to "data recording in absence of patient visits”; and the method by which physicians scored symptoms was not clear
Persaud said he was unable to contact any of the original researchers and there was evidence that many of them had since died.
Abstract
Objectives: We report information about an unpublished 1970s study (“8-way” Bendectin Study) that aimed to evaluate the relative therapeutic efficacy of doxylamine, pyridoxine, and dicyclomine in the management of nausea and vomiting during pregnancy. We are publishing the trial's findings according to the restoring invisible and abandoned trials (RIAT) initiative because the trial was never published.
Design: Double blinded, multi-centred, randomized placebo-controlled study.
Setting: 14 clinics in the United States.
Participants: 2308 patients in the first 12 weeks of pregnancy with complaints of nausea or vomiting were enrolled.
Interventions: Each patient was randomized to one of eight arms: placebo, doxylamine/pyridoxine/dicylcomine, doxylamine/pyridoxine, dicylomine/pyridoxine, doxylamine, dicyclomine/pyridoxine, pyridoxine and dicyclomine. Each patient was instructed to take 2 tablets at bedtime and 1 additional tablet in the afternoon or morning if needed, for 7 nights.
Outcomes: Reported outcomes included the number of hours of nausea reported by patients, the frequency of vomiting reported by patients and the overall efficacy of medication as judged by physicians.
Results: Data from 1599 (69% of those randomized) participants were analyzed. Based on the available summary data of physician evaluation of symptoms and ignoring missing data and data integrity issues, the proportion of participants who were “evaluated moderate or excellent” was greater in each of the seven active treatment groups when compared with placebo (57%): doxylamine/pyridoxine/dicylcomine (14% absolute difference versus placebo; 95% CI: 4 to 24), doxylamine/pyridoxine (21; 95% CI 11 to 30), dicylomine/pyridoxine (21; 95% CI 11 to 30), doxylamine (20; 95% CI 10 to 29), dicyclomine/pyridoxine (4; 95% CI -6 to 14), pyridoxine (9; 95% CI -1 to 19) and dicyclomine (4; 95% CI -6 to 14). Based on incomplete information, the most common adverse events were apparently drowsiness and fatigue. There is a high risk of bias in these previously unpublished results given the high attrition rate in a 7 day trial, the lack of prespecified outcomes or analyses, and the exclusion of some data because of questionable data integrity.
Conclusion: The available information about this “8-way Bendectin” trial indicates it should not be used to support the efficacy of doxylamine, pyridoxine or dicyclomine for the treatment of nausea and vomiting during pregnancy because of a high risk of bias.
Authors
Rujun Zhang, Navindra Persaud
[link url="https://www.sciencedaily.com/releases/2017/01/170104143550.htm"]St Michael’s Hospital material[/link]
[link url="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167609"]PLOS One abstract[/link]