Another Disappointing Clinical Trial in Neurodegenerative Disease

Summary and Comment |
February 25, 2014

Another Disappointing Clinical Trial in Neurodegenerative Disease

  1. Brandy R. Matthews, MD

Daily doxycycline was no better than placebo in Creutzfeldt-Jakob disease.

  1. Brandy R. Matthews, MD

Creutzfeldt-Jakob disease (CJD) is a rapidly progressive spongiform encephalopathy caused by the conformational conversion of cellular prion proteins. Most cases are sporadic; some are caused by a genetic mutation or through exposure to infectious tissue. Recent trials of molecules effective against CJD in vitro have been disappointing when moved from bench to bedside (NEJM JW Neurol Jan 2 2014).Two independent observational studies suggested that the antimicrobial agent doxycycline improved survival in patients with CJD, prompting this collaborative, randomized, placebo-controlled, double-blind study. Of 663 patients referred to the study, 121 with various forms of CJD were randomized, 62 of these to active treatment with 100 mg of oral doxycycline daily. The primary outcome measure was increased survival time.

The study was halted at 4.5 years when a prespecified interim analysis showed futility (86 of 97 patients were deceased). The final intention-to-treat analysis of all patients and a secondary per-protocol analysis of patients who received at least 30 days of treatment revealed no benefit in the doxycycline group. Other secondary analyses (time to loss of autonomous feeding, to loss of sphincter control, and to akinetic mutism) also failed to demonstrate any benefit from doxycycline. The intervention was well-tolerated overall, and autopsy measurements of doxycycline concentration in 11 patients revealed expected penetration of the blood–brain barrier. Also of note, the diagnosis of CJD was neuropathologically confirmed in all 39 autopsied patients.


The authors of this negative study conclude that similar multinational endeavors will be required to implement effective treatment trials for rare neurodegenerative diseases such as Creutzfeldt-Jakob disease. However, such undertakings have inherent challenges, highlighted in this study by the variability in inclusion criteria across sites (e.g., one cohort allowed patients with disease duration >6 months and several cases of non-sporadic CJD, while such patients were excluded at the other site) and by the necessary adjustment of the WHO criteria to include MRI findings highly sensitive and specific for CJD. As with Alzheimer disease and other neurodegenerative proteinopathies, biomarker detection in advance of neurobehavioral symptoms of prionopathies likely will be needed, so that molecular therapies can be engaged soon enough to affect clinical outcomes, including survival.

Editor Disclosures at Time of Publication

  • Disclosures for Brandy R. Matthews, MD at time of publication Grant / research support National Institute on Aging


Reader Comments (1)

Paula millman Physician, Neurology, Berkeley

That is really a shame

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