Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: a Single Centre, Randomised, Placebo-controlled Trial

Study Overview
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Brief Summary
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This study employs a single-center, prospective, randomized controlled, double-blind exploratory research design. To investigate whether Sirolimus can reduce the rebleeding rate of brainstem cavernous malformations within 24 months after the first symptomatic bleeding event.

Official Title
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Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: a Single Centre, Randomised, Placebo-controlled Trial

Conditions
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Cavernous Malformations, Brain Stem Hemorrhage

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Starch flake


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 65 years, any gender. Patients who experienced their first symptomatic bleeding caused by brainstem cavernous malformation within six months. Diagnosed with brainstem cavernous malformation through SWI and MR T2 imaging. Confirmed intracranial or perilesional bleeding by CT scan. Capable of signing an informed consent form with the understanding and accompaniment of a guardian. Exclusion Criteria: History of cancer. Pregnancy or lactation. Hypersensitivity to rapamycin or placebo. Respiratory failure or severe bleeding requiring life support treatment. Abnormal liver or kidney function (transaminases greater than 50, creatinine greater than 110), white blood cell/platelet abnormalities (white blood cell count below 3.5 or above 9.5 x 10^9/L, platelet count below 100 or above 300). History of previous immunosuppressive therapy. History of bleeding more than 6 months ago. History of surgical treatment for cavernous malformation. History of radiation therapy for cerebral cavernous malformation. History of previous statin medication treatment. History of previous propranolol treatment. Presence of intracranial cavernous malformation in a location other than the brainstem. Patients with concurrent acute active infections (such as severe bacterial, viral, or fungal infections). Uncontrolled diabetes. Participation in other clinical trials.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: According to the study protocol, patients were randomly divided into a normal-dose group, low-dose group, and control group at a ratio of 1:1:1. Additionally, to minimize potential bias, this study employed a double-blind approach.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose sirolimus group<br>Participants will receive oral sirolimus with a target blood concentration of 10-15ng/ml continuously for 12 months. | Drug: Sirolimus<br>* Sirolimus is an mTORC1 inhibitor that has received approval from the U.S. Food and Drug Administration (FDA) and has recently been successfully used to treat lymphatic malformations and venous/lymphatic malformations associated with the same PIK3CA GOF mutations.<br>* Other names: Rapamycin;|
| Experimental: Low-dose sirolimus group<br>Participants will receive oral sirolimus with a target blood concentration of 3-7ng/ml continuously for 12 months | Drug: Sirolimus<br>* Sirolimus is an mTORC1 inhibitor that has received approval from the U.S. Food and Drug Administration (FDA) and has recently been successfully used to treat lymphatic malformations and venous/lymphatic malformations associated with the same PIK3CA GOF mutations.<br>* Other names: Rapamycin;|
| Placebo Comparator: Placebo control group<br>Participants will receive oral placebo(starch formulation) for 12 months. | Drug: Starch flake<br>* The placebo is composed of starch material and is formulated at 0.5 grams per tablet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The use of Sirolimus medication can reduce the risk of rebleeding in patients with hemorrhagic brainstem cavernous malformation by 50% within two years. | The rebleeding risk in the Sirolimus medication intervention group (comprising normal-dose or low-dose subgroups) demonstrates a 50% reduction compared to the placebo group. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The use of Sirolimus medication can reduce the risk of subclinical bleeding in patients with hemorrhagic brainstem cavernous malformation within two years based on QSM sequence results. | Brainstem cavernous malformations may manifest as subclinical microbleedings, undetectable by CT scan with no new hemorrhage seen. The investigators will analyze the quantitative susceptibility mapping (QSM) sequence of brainstem cavernous malformations through head MRI to assess whether there is imaging evidence of micro-bleeding, and whether can be reduced by the Sirolimus medication. | 24 months | 
| Therapeutic efficacy of different doses of Sirolimus in the treatment of hemorrhagic brainstem cavernous malformation. | By dividing the patients into high-dose Sirolimus and low-dose Sirolimus groups, the investigators will assess the therapeutic effects of different doses of Sirolimus in the treatment of brainstem cavernous malformation following bleeding events. | 24 months | 
| The side effects of Sirolimus in the management of brainstem cavernous malformations. | The safety assessment will encompass a comprehensive analysis of adverse events, including but not limited to, any unexpected side effects, allergic reactions, or complications arising from the administration of Sirolimus. Adverse events will be categorized based on their nature, severity, duration, and potential relationship to the study drug. Patients enrolled in the trial will be closely monitored for the occurrence of adverse events during the intervention period, as well as during the subsequent follow-up period. The evaluation will involve regular clinical examinations, laboratory assessments, and imaging studies to ensure a thorough and accurate safety profile. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cavernous Malformations, Brainstem, Rebleeding rate, Sirolimus