Introduction: Brainstem cavernous malformations (BSCMs) frequently cause intracerebral hemorrhage (ICH). Microsurgery is the primary treatment option to prevent ICH recurrence, but microsurgery may have high risks and result in postoperative death or disability. Stereotactic radiosurgery is sometimes used for BSCM that cannot be approached safely with microsurgery, but its effects are uncertain. Preclinical studies have indicated that sirolimus (also known as rapamycin), which is an mTORC1 inhibitor that has been used to treat lymphatic malformations and venous/lymphatic malformations, may have a beneficial therapeutic effect on cavernous malformations, though clinical experience is limited. This pilot randomized controlled trial (RCT) aims to investigate, for the first time, the feasibility of sirolimus treatment for BSCMs.
Methods: We will perform a pilot phase double-blind RCT involving about seventy-five people in China aged 18-65 years with mental capacity to give consent and solitary BCSM diagnosed by brain MRI within six months of their first ICH (confirmed by brain imaging) due to BCSM. Participants will be randomized into three groups (oral sirolimus with a target blood concentration of 9 – 15 ng / ml, oral sirolimus with a target blood concentration of 3 – 7 ng / ml, and matching oral placebo) in a 1:1:1 ratio. Participants will receive their assigned treatment for one year, followed by one-year follow-up.
Results: The primary outcome will be the safety of sirolimus treatment of BSCM (serious and non-serious adverse events). Secondary outcomes will include the incidence of recurrent symptomatic ICH from the qualifying BSCM, and the mean susceptibility as assessed by MRI (CCM size and signal characteristics, iron deposition and quantitative susceptibility mapping) and health-related quality of life.
Conclusion : The objective of this pilot trial is to assess the safety and tolerability, and estimate the efficacy of sirolimus for BCSM. The magnitude and direction of effect on the primary outcome and the consistency of effects on the secondary outcomes will inform the design and sample size of a larger definitive phase III trial.
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