Neurology Central

Study of stroke therapy highlights the potential value of preclinical trials in solving the ‘reproducibility crisis’ in clinical trials

In an effort to bridge the gap between the lab and the clinical setting, the European Consortium has put a potential new stroke therapy to the test in an animal study matching the requirements of a human clinical trial. The results, which were published recently in Science Translational Medicine, indicate that preclinical randomized controlled trials (pRCT) could aid in choosing the most promising drug candidates from lab-based studies before commencing potentially ineffective and costly clinical trials.

The European Consortium sought to investigate the efficacy of the candidate stroke drug termed CD49d-specific antibody therapy (natalizumab), which is currently in a Phase II trial in stroke patients, in a mouse model pRCT.

Following conflicting outcomes from five preceding rodent studies, in which four identified suppression of brain inflammation subsequent to ischemic stroke with the CD49d-specific antibody therapy and one demonstrated no benefit, the team wanted to determine whether a pRCT could have better guided the decision to advance to human clinical trials of the drug.

On the initiation of the Phase II trial senior author Arthur Liesz (University Medical Center Munich, Germany) commented: “I think most researchers in the field — including me — had the feeling that this clinical study was somewhat prematurely initiated.”

Six independent European research teams collaborated in order to conduct the multicenter, blinded pRCT. Two different mouse models of stroke were utilized and the rigorous methodologies implemented for human trials were adopted. The trial was carried out on mouse models over 1 year and 4 months and at a total cost of $180,000, of which >$30,000 was drug costs. In total results were based on a pool of 315 mice.

In mouse models with confined stroke the CD49d-specific antibody therapy reduced brain inflammation and therefore damage to the brain following stroke. In contrast, models of severe stroke showed no evidence of a protective effect as a result of the drug. The results therefore highlighted that potentially only a subset of stroke patients may benefit from the therapy depending on the type and severity of the stroke.

The team believe that knowledge such as this would not only be useful in guiding future studies on the stroke therapy tested in their own pCRT, but importantly may also act as a powerful and useful new step that could be incorporated into the established drug pipeline. “…from basic research [to]preclinical drug testing to clinical trials,” stated Liesz.

“Our study unequivocally proved that preclinical randomized multicenter trials are feasible, which has been doubted over the last decade,” commented lead author Gemma Llovera (University Medical Center Munich).

“Compared to the enormous financial and scientific loss caused by a negative clinical trial, preventing a single unnecessary or even harmful clinical trial by conducting a pRCT…will outweigh the costs and time of a pRCT manifold,” added Liesz.

International research consortia that seek to perform pRCTs have already been established, including the European Union-funded Multicentre Preclinical Animal Research Team (Multi-PART) for stroke research and the U.S. National Institutes of Health-funded Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR) for cardiac research.

Looking forward, the research team plan to compare the findings of the pRCT with the results of the Phase II clinical trial for CD49d-specific antibody therapy, which are scheduled to be released by the end of 2015. Concurrence between the results of the preclinical and clinical trials would support the role of pRCT as a useful research step in deciding drug advancement to clinical testing.

“If supported by funding agencies and the pharmaceutical industry, pRCTs [may]become a mandatory step before testing a drug candidate in a clinical trial,” concluded Liesz.

Source: American Association for the Advancement of Science press release