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Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: aSingle Centre, Randomized, Placebo-controlled Pilot Trial

NCT ID: NCT06091332

Last Updated: 2024-12-20

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

75 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-01-05

Study Completion Date

2026-12-31

Brief Summary

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The aim of this pilot phase trial is to assess the safety and tolerability, and estimate the efficacy of sirolimus in reducing the incidence of ICH during high-risk periods for rebleeding, compared to placebo. This pilot trial will inform the design of a future definitive clinical trial on sirolimus treatment for CCM.

Detailed Description

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Conditions

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Cavernous Malformations Intracerebral Hemorrhage Brainstem Stroke

Keywords

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Cavernous Malformations Brainstem Rebleeding rate Sirolimus

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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.
Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors
A double-blind design means that throughout the entire study, neither the participating patients nor the investigators are aware of which treatment group the patients are assigned to, in order to minimize potential biases. The blinding level is double-blind, which means that both the patients in the treatment group and those in the control group, as well as the investigators, are unaware of the treatment the patients receive, ensuring objectivity and reliability of the study results.

Study Groups

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High-dose sirolimus group

Participants will receive oral sirolimus with a target blood concentration of 9-15ng/ml continuously for 12 months.

Group Type EXPERIMENTAL

Sirolimus

Intervention Type DRUG

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.

Low-dose sirolimus group

Participants will receive oral sirolimus with a target blood concentration of 3-7ng/ml continuously for 12 months

Group Type EXPERIMENTAL

Sirolimus

Intervention Type DRUG

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.

Placebo control group

Participants will receive oral placebo(starch formulation) for 12 months.

Group Type PLACEBO_COMPARATOR

Starch flake

Intervention Type DRUG

The placebo is composed of starch material and is formulated at 0.5 grams per tablet.

Interventions

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Sirolimus

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.

Intervention Type DRUG

Starch flake

The placebo is composed of starch material and is formulated at 0.5 grams per tablet.

Intervention Type DRUG

Other Intervention Names

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Rapamycin

Eligibility Criteria

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Inclusion Criteria

1. Age 18-65 years, any gender;
2. Patients who have experienced their first symptomatic BSCM ICH within the six months before randomisation;
3. Diagnosed with solitary BSCM through T2, GRE/T2\*, or SWI MR imaging;
4. ICH within or around the BSCM confirmed by CT /MR;
5. Capable of signing an informed consent form with the accompaniment and understanding of a guardian.

Exclusion Criteria

1. Cancer history;
2. Pregnancy or lactation;
3. Sirolimus/starch allergy;
4. Modified Rankin Scale (mRS) score 5, respiratory failure or currently severe bleeding requiring life support treatment;
5. Abnormal liver and/or kidney function (transaminase levels greater than 50, creatinine greater than 110), abnormal white blood cell/platelet counts (white blood cell count below 3.5 or above 9.5 x 109/L or exceeding normal values, platelet count below 100 or above 300);
6. History of previous immunosuppressive therapy;
7. History of prior surgical intervention for CCM ;
8. History of prior cranial radiation therapy ;
9. Familial CCM or people with multiple CCM;
10. Patients with concurrent acute active infections (e.g., severe bacterial, viral, or fungal infections);
11. Uncontrolled diabetes mellitus;
12. Currently participating in another clinical trial;
13. Patient unwilling/unable to undergo MRI.
14. Co-administration of drugs affecting CYP3A4 enzymes (ketoconazole, voriconazole, itraconazole, telithromycin, clarithromycin).
Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Huashan Hospital

OTHER

Sponsor Role lead

Responsible Party

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Wei Zhu

Vice director of neurosurgey department

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Wei Zhu, Doctor

Role: PRINCIPAL_INVESTIGATOR

Huashan Hospital

Locations

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Huashan Hospital, Fudan University

Shanghai, Shanghai Municipality, China

Site Status ACTIVE_NOT_RECRUITING

Huashan Hospital, Fudan University

Shanghai, Shanghai Municipality, China

Site Status RECRUITING

Countries

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China

Central Contacts

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Zongze Li, Doctor

Role: CONTACT

Phone: +8613121226581

Email: [email protected]

Wei Zhu, Doctor

Role: CONTACT

Phone: +8613121226581

Email: [email protected]

Facility Contacts

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Wei Zhu, Doctor

Role: primary

References

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Ren AA, Snellings DA, Su YS, Hong CC, Castro M, Tang AT, Detter MR, Hobson N, Girard R, Romanos S, Lightle R, Moore T, Shenkar R, Benavides C, Beaman MM, Muller-Fielitz H, Chen M, Mericko P, Yang J, Sung DC, Lawton MT, Ruppert JM, Schwaninger M, Korbelin J, Potente M, Awad IA, Marchuk DA, Kahn ML. PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism. Nature. 2021 Jun;594(7862):271-276. doi: 10.1038/s41586-021-03562-8. Epub 2021 Apr 28.

Reference Type BACKGROUND
PMID: 33910229 (View on PubMed)

Flemming KD, Graff-Radford J, Aakre J, Kantarci K, Lanzino G, Brown RD Jr, Mielke MM, Roberts RO, Kremers W, Knopman DS, Petersen RC, Jack CR Jr. Population-Based Prevalence of Cerebral Cavernous Malformations in Older Adults: Mayo Clinic Study of Aging. JAMA Neurol. 2017 Jul 1;74(7):801-805. doi: 10.1001/jamaneurol.2017.0439.

Reference Type BACKGROUND
PMID: 28492932 (View on PubMed)

Ren J, Huang Y, Ren Y, Tu T, Qiu B, Ai D, Bi Z, Bai X, Li F, Li JL, Chen XJ, Feng Z, Guo Z, Lei J, Tian A, Cui Z, Lindner V, Adams RH, Wang Y, Zhao F, Korbelin J, Sun W, Wang Y, Zhang H, Hong T, Ge WP. Somatic variants of MAP3K3 are sufficient to cause cerebral and spinal cord cavernous malformations. Brain. 2023 Sep 1;146(9):3634-3647. doi: 10.1093/brain/awad104.

Reference Type BACKGROUND
PMID: 36995941 (View on PubMed)

Other Identifiers

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2023-816

Identifier Type: -

Identifier Source: org_study_id