To our knowledge, this is the first RCT examining the long-term efficacy of zonisamide for weight reduction. Zonisamide 400 mg/d led to 3.3 kg greater weight loss than diet and lifestyle intervention alone. Zonisamide 200 mg/d was not efficacious.
A unique feature of this trial is the high retention. Of 48 patients who dropped out, 41 returned at 1-year time-point, leaving only 7 of 225 randomized patients lost to follow-up. Not surprisingly, MI and LOCF imputation procedures showed almost identical results as few data were missing. Historically, dropout rates have generally been in the range of 30–50% in pharmaceutical weight loss trials, including recent long-term trials.16–19
Interestingly, in the COR-BD trial that tested the addition of naltrexone + bupropion or placebo to intensive behavior modification, 42% withdrew early in the behavior modification (plus placebo) group and 12% cited an adverse event for discontinuation,20
Simons-Morton et al21
criticized obesity trials with the argument that high attrition introduces a bias, and randomization does not serve its purpose when data from patients who have not adhered to treatment are not analyzed. A counter argument is that physicians are interested in treatment effects among patients that adhere to it and not the effect of being assigned to a treatment.
Various statistical models are employed in obesity RCTs to make up missing data, the most common being LOCF. Food and Drug Administration (FDA), in its guidance to industry,22
recommends LOCF, which implicitly assumes that patients who withdraw early in a trial would have maintained the same weight at study exit as at the time of withdrawal. Other statistical imputation procedures make less restrictive assumptions for the individual patient or the assigned group based on patterns of weight change prior to dropout. Although some imputation procedures are superior to others, it is important to recognize that all imputation approaches make assumptions, some of which are inherently untestable (e.g., that data are missing at random).15
Observations of weight change among the 41 patients in this trial, who dropped out early, but returned for final assessment at 1-year, demonstrate that most obese patients gain weight or regain their lost weight after they drop out from a clinical trial, calling into question the results from trials with high dropout rates and the validity of commonly used imputation procedures in obesity RCTs. As seen in , many patients who lost substantial weight prior to drop out regained considerable weight by 1-year visit. The 11 dropouts in the 400 mg group gained almost 5% weight on the average when they returned at 1-year.
There were no extraordinary efforts in this trial that could explain the high retention. There were no extended screening visits to ensure patients were serious about participation. Patients were educated about time and commitment required for participation, and that they needed to make changes to their diet and lifestyle without which drug therapy would not help. They were counseled to have realistic expectations about what could be achieved over a year. Very few patients were excluded during screening. They were told that if they withdrew early, they would be requested to return for 1-year visit to complete final assessments, which would be valuable for the study’s success. There was no coercion and the stipend offered was minimal.
Historically, most obesity RCTs enrolled primarily white women. This trial enrolled a fair number of men (40%) and ethnic minorities (37%).
A notable limitation of this trial is that most patients did not have significant weight-related comorbidities. At baseline, patients had normal blood pressure, lipids, and glycemic measures. Reduction in risks associated with obesity is most demonstrable when patients with risk factors are enrolled. This is a consideration for future investigation.
In a preliminary trial by Gadde et al.,8
zonisamide achieved 5 kg greater weight loss than placebo (5.9 kg vs
0.9 kg) over 16 weeks. The current RCT examined whether zonisamide, could enhance long-term weight loss achievable with a good quality diet and lifestyle intervention that is implementable in a primary care clinical setting. In contrast to the previous trial, placebo group in the current RCT achieved an impressive 4 kg weight loss. Our lifestyle intervention was not as intensive as the ones administered in DPP,3
trials, and could be easily incorporated into primary care practices.
Although, zonisamide 400 mg/d demonstrated moderate efficacy of a magnitude similar to orlistat6
neuropsychiatric adverse events (mood changes and memory problems) occurred at a higher frequency relative to placebo. Hence, for treatment of obesity, the drug’s benefit-to-risk ratio needs thoughtful and cautious assessment. The results of our trial must be considered in the context of our follow-up procedures, which were markedly different from those of typical weight loss trials.