Credulity of exploratory trials for cerebral cavernous malformations

• Published in: Lancet neurology Vol. 22; no. 1; pp. 2 - 3
• Main Authors: Shenkar, Robert, Awad, Issam A
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01-01-2023
• Subjects: Atorvastatin; Biomarkers; Clinical trials; Drug dosages; Hemangioma, Cavernous, Central Nervous System; Hemorrhage; Humans; Magnetic Resonance Imaging; Patients; Propranolol; Rare diseases; Simvastatin; Surgery; Therapeutic targets
• ISSN: 1474-4422; 1474-4465
• DOI: 10.1016/s1474-4422(22)00440-9

Preclinical studies have suggested potential pharmacological strategies that are based on modification of molecular signaling pathways.1 Clinical trials to date have included a small pilot trial that showed safety of simvastatin,2 and an ongoing phase 1/2a trial of atorvastatin for rebleeding.3 The participants who should be included in clinical trials of pharmacotherapies (eg, familial vs sporadic disease, symptomatic vs asymptomatic cases) and the outcomes that should be used as therapeutic targets (eg, lesion growth, bleeding) remain unclear. Investigators and patients in the Treat_CCM study were aware of treatment group assignments; therefore, the reporting of focal neurological deficit events (which accounted for half of the outcome events) might have been biased, with transient symptoms noted in the absence of imaging correlates.4 Preclinical studies have shown an effect on lesion development of propranolol at high doses but not at low doses,5,6 meaning that the attribution of outcome events to propranolol might also have been biased in people who received a potentially subtherapeutic dose (many participants did not show any detectable drug in blood samples). [...]MRI findings were missing for one patient who had surgery. [...]symptomatic haemorrhage or other events leading to surgery might not have been counted.