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

NCT06091332 | Recruiting Phase 2 DMC

• 1 other identifier: 2023-816
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Cavernous Malformations; Intracerebral Hemorrhage; Brainstem Stroke

Keywords

Cavernous Malformations; Brainstem; Rebleeding rate; Sirolimus

Outcome Measures

Primary Outcomes (1)

• The primary outcome is to explore the safety of sirolimus in the management of BSCMs.

  A serious adverse event is an SAE occurring during any study phase that fullfils one or more of the following criteria: i. Results in death, ii. Is life-threatening, iii. Requires inpatient hospitalization or prolongation of existing hospitalization, iv. Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, v. Is an important medical event that may jeopardize the patient or may require medical intervention to prevent one of the outcomes listed above. SAE will be assessed at each follow-up visit (15 days, 2 months, 6 months, 12 months, 18 months, 24 months). During the trial, participants can promptly report potential SAEs to the research team via the telephone. We will establish continuous, real-time communication with patients via the telephone, facilitating round-the-clock reporting of potential endpoints or adverse reactions to the clinical trial investigators.

  24 months

Secondary Outcomes (4)

• We will measure the tolerability of sirolimus in the management of BSCMs.

  24 months

• We will measure the occurrence of recurrent ICH from the BSCM within 24 months.

  24 months

• We will measure the efficacy outcomes in MR

  24 months

• We will measure several the quality of life

  24 months

Study Arms (3)

High-dose sirolimus group

EXPERIMENTAL

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

Drug: Sirolimus

Low-dose sirolimus group

EXPERIMENTAL

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

Drug: Sirolimus

Placebo control group

PLACEBO COMPARATOR

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

Drug: Starch flake

Interventions

Sirolimus 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.

Also known as: Rapamycin

High-dose sirolimus group; Low-dose sirolimus group

Starch flake DRUG

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

Placebo control group

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Cancer history;
• Pregnancy or lactation;
• Sirolimus/starch allergy;
• Modified Rankin Scale (mRS) score 5, respiratory failure or currently severe bleeding requiring life support treatment;
• 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);
• History of previous immunosuppressive therapy;
• History of prior surgical intervention for CCM ;
• History of prior cranial radiation therapy ;
• Familial CCM or people with multiple CCM;
• Patients with concurrent acute active infections (e.g., severe bacterial, viral, or fungal infections);
• Uncontrolled diabetes mellitus;
• Currently participating in another clinical trial;
• Patient unwilling/unable to undergo MRI.
• Co-administration of drugs affecting CYP3A4 enzymes (ketoconazole, voriconazole, itraconazole, telithromycin, clarithromycin).

Sponsors & Collaborators

• Huashan Hospital: lead

Study Sites (2)

Huashan Hospital, Fudan University

Shanghai, Shanghai Municipality, 200040, China

ACTIVE NOT RECRUITING

Huashan Hospital, Fudan University

Shanghai, Shanghai Municipality, 200040, China

RECRUITING

Related Publications (3)

• 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.

  PMID: 33910229 BACKGROUND

• 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.

  PMID: 28492932 BACKGROUND

• 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.

  PMID: 36995941 BACKGROUND

MeSH Terms

Conditions

Cerebral Hemorrhage; Brain Stem Infarctions

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Brain Infarction; Brain Ischemia; Stroke; Infarction; Ischemia; Necrosis

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Wei Zhu, Doctor

  Huashan Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zongze Li, Doctor

CONTACT

+8613121226581; lizongze666@aliyun.com

Wei Zhu, Doctor

CONTACT

+8613121226581; drzhuwei@fudan.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Vice director of neurosurgey department

Model Details: 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.

Study Record Dates

• First Submitted: October 13, 2023
• First Posted: October 19, 2023
• Study Start: January 5, 2024
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: December 20, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

CN (2)