Knowing the underlying etiology of intellectual disability in genetic disorders holds great promise for developing targeted treatments. Although successful preclinical studies and many positive clinical studies have been reported, it is unclear how many purported therapies have become established treatments. The quality of the clinical trials may be an important determinant for achieving clinical impact.
To evaluate clinical impact, strengths, and weaknesses of clinical trials of diet or drug treatments to improve cognitive function in patients with a genetic disorder.
MEDLINE, EMBASE, PsycINFO, and Cochrane databases were searched from inception date to January 26, 2014, for clinical trials with cognitive outcomes in patients with genetic disorders. Outcome measures of randomized clinical trials (RCTs) were compared between trial registries and reports, and trials were evaluated for the quality of design using the Jadad score and Consolidated Standards of Reporting Trials (CONSORT) criteria.
We identified 169 trial reports of 80 treatments for 32 genetic disorders. Seventy-five trials (44.4%) reported potential efficacy, of which only 2 therapies are now established treatments, namely, dietary restriction for phenylketonuria and miglustat for Niemann-Pick disease type C. The median sample size for RCTs was 25 (range, 2-537). Only 30 of 107 RCTs (28.0%) had acceptable Jadad scores exceeding 3. Reporting of key CONSORT items was poor. Reported outcome measures matched preregistered outcome measures in trial registries in only 5 of 107 RCTs (4.7%).
Conclusions and Relevance
The number of trials in the field of cognitive genetic disorders is rapidly growing, but clinical impact has been limited because few drugs have become established treatments and the benefit of most drugs remains unclear. Most trials have small sample sizes and low quality of design. Predefinition of outcome measures, improved trial reporting and design, and international collaboration to increase recruitment are needed to unequivocally determine efficacy of drugs identified in preclinical research.