Back to resultsHemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: a Pilot Study (CALM)
Primary Purpose
Brainstem Cavernous Malformations
Status
Not yet recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Sirolimus
Sponsored by
About this trial
This is an interventional treatment trial for Brainstem Cavernous Malformations focused on measuring Cavernous Malformations, Brainstem, Rebleeding rate, Sirolimus
Eligibility Criteria
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.
Sites / Locations
- Huashan Hospital, Fudan University
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
High-dose sirolimus group
Low-dose sirolimus group
Placebo control group
Arm Description
Participants will receive oral sirolimus with a target blood concentration of 10-15ng/ml continuously for 12 months.
Participants will receive oral sirolimus with a target blood concentration of 3-7ng/ml continuously for 12 months
Participants will receive oral placebo(starch formulation) for 12 months.
Outcomes
Primary Outcome Measures
To investigate whether Sirolimus can reduce the rebleeding rate of brainstem cavernous malformations within 24 months after the first symptomatic bleeding event.
Through a randomized controlled exploratory study, we aim to assess whether Sirolimus can reduce the risk of rebleeding by 50% within one year after the first symptomatic bleeding event in patients with brainstem cavernous malformations.
Secondary Outcome Measures
To explore the effectiveness assessment of Sirolimus in reducing the occurrence of subclinical bleeding in brainstem cavernous malformations.
Brainstem cavernous malformations may manifest as subclinical microbleeds, undetectable by CT scan with no new hemorrhage seen. We 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.
To explore the treatment dose of Sirolimus and evaluate its side effects in the management of brainstem cavernous malformations.
By dividing the patients into high-dose Sirolimus and low-dose Sirolimus groups, we will assess the therapeutic effects of different doses of Sirolimus in the treatment of brainstem cavernous malformations following bleeding events. This study aims to identify an appropriate treatment dose and evaluate the occurrence of side effects, as well as the safety of Sirolimus in treatment.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT06091332
Brief Title
Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: a Pilot Study
Acronym
CALM
Official Title
Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: a Pilot Study
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
December 1, 2023 (Anticipated)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Huashan Hospital
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brainstem Cavernous Malformations
Keywords
Cavernous Malformations, Brainstem, Rebleeding rate, Sirolimus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
We will recruit subjects from the Neurosurgery Outpatient Department of Huashan Hospital, affiliated with Fudan University.
Masking
ParticipantCare ProviderInvestigator
Masking Description
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.
Allocation
Randomized
Enrollment
60 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
High-dose sirolimus group
Arm Type
Experimental
Arm Description
Participants will receive oral sirolimus with a target blood concentration of 10-15ng/ml continuously for 12 months.
Arm Title
Low-dose sirolimus group
Arm Type
Experimental
Arm Description
Participants will receive oral sirolimus with a target blood concentration of 3-7ng/ml continuously for 12 months
Arm Title
Placebo control group
Arm Type
Placebo Comparator
Arm Description
Participants will receive oral placebo(starch formulation) for 12 months.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamune
Intervention Description
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.
Primary Outcome Measure Information:
Title
To investigate whether Sirolimus can reduce the rebleeding rate of brainstem cavernous malformations within 24 months after the first symptomatic bleeding event.
Description
Through a randomized controlled exploratory study, we aim to assess whether Sirolimus can reduce the risk of rebleeding by 50% within one year after the first symptomatic bleeding event in patients with brainstem cavernous malformations.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
To explore the effectiveness assessment of Sirolimus in reducing the occurrence of subclinical bleeding in brainstem cavernous malformations.
Description
Brainstem cavernous malformations may manifest as subclinical microbleeds, undetectable by CT scan with no new hemorrhage seen. We 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.
Time Frame
24 months
Title
To explore the treatment dose of Sirolimus and evaluate its side effects in the management of brainstem cavernous malformations.
Description
By dividing the patients into high-dose Sirolimus and low-dose Sirolimus groups, we will assess the therapeutic effects of different doses of Sirolimus in the treatment of brainstem cavernous malformations following bleeding events. This study aims to identify an appropriate treatment dose and evaluate the occurrence of side effects, as well as the safety of Sirolimus in treatment.
Time Frame
24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zongze Li, Doctor
Phone
+8613121226581
Email
lizongze666@aliyun.com
First Name & Middle Initial & Last Name or Official Title & Degree
Wei Zhu, Doctor
Phone
+8613121226581
Email
drzhuwei@fudan.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wei Zhu, Doctor
Organizational Affiliation
Huashan Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Huashan Hospital, Fudan University
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200040
Country
China
12. IPD Sharing Statement
Plan to Share IPD
Undecided
IPD Sharing Plan Description
Due to the involvement of subject privacy, we have not yet made a decision
Citations:
PubMed Identifier
33910229
Citation
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.
Results Reference
background
PubMed Identifier
28492932
Citation
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.
Results Reference
background
PubMed Identifier
36995941
Citation
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.
Results Reference
background
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Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: a Pilot Study
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