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

December 17, 2024 updated by: Wei Zhu, Huashan Hospital

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

75

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Shanghai
      • Shanghai, Shanghai, China, 200040
        • Recruiting
        • Huashan Hospital, Fudan University
        • Contact:
      • Shanghai, Shanghai, China, 200040
        • Active, not recruiting
        • Huashan Hospital, Fudan University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Low-dose sirolimus group
Participants will receive oral sirolimus with a target blood concentration of 3-7ng/ml continuously for 12 months
Drug: 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.
Other Names:
  • Rapamycin
Placebo Comparator: Placebo control group
Participants will receive oral placebo(starch formulation) for 12 months.
Drug: Starch flake
The placebo is composed of starch material and is formulated at 0.5 grams per tablet.
Experimental: High-dose sirolimus group
Participants will receive oral sirolimus with a target blood concentration of 9-15ng/ml continuously for 12 months.
Drug: 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.
Other Names:
  • Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The primary outcome is to explore the safety of sirolimus in the management of BSCMs.
Time Frame: 24 months

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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
We will measure the tolerability of sirolimus in the management of BSCMs.
Time Frame: 24 months

Based on prior clinical experience and reports from sirolimus trials, adverse events (AE) have included oral ulcers, upper respiratory tract infections, headaches, respiratory illnesses, stomatitis, seizures, and fever. Other commonly reported AEs are nausea, vomiting, fatigue, dizziness, diarrhea, and mild allergic reactions such as rash or itching. Minor infections, mild gastrointestinal disturbances, and fluctuations in blood pressure or heart rate have also been observed.

Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or any life-threatening problem or death caused by or associated with sirolimus, if that effect, problem or death was not previously identified in nature, severity or degree of incidence in the investigational plan, or any other unanticipated serious problem associated with sirolimus that related to the rights, safety or welfare of subjects.
24 months
We will measure the occurrence of recurrent ICH from the BSCM within 24 months.
Time Frame: 24 months
a. The primary efficacy outcome will be the occurrence of recurrent ICH from the BSCM within 24 months. ICH is defined as the presence of new focal neurological dysfunction or new headache symptoms, and confirmed by head CT/MR imaging examinations indicating new cerebral haemorrhage attributed to BSCM. If the primary efficacy outcome occurs, surgery will be considered for participants with a second ICH during follow-up. Radiosurgery or conservative treatment may also be considered for patients with a high risk of surgical intervention.
24 months
We will measure the efficacy outcomes in MR
Time Frame: 24 months
A secondary efficacy outcome will be change in magnetic susceptibility using quantitative susceptibility mapping (QSM) MRI34 at 24 months after randomisation. Recent studies have described the feasibility, reliability, and validity of QSM as a biomarker for the effect of drugs on CCM.
24 months
We will measure several the quality of life
Time Frame: 24 months
Quality of Life (mRS score and EuroQOL five dimensions questionnaire (EQ-5D) scale) within 24 months after enrollment
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Huashan Hospital

Investigators

  • Principal Investigator: Wei Zhu, Doctor, Huashan Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 5, 2024

Primary Completion (Estimated)

December 31, 2025

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

October 13, 2023

First Submitted That Met QC Criteria

October 13, 2023

First Posted (Actual)

October 19, 2023

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

December 17, 2024

Last Verified

December 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2023-816

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Due to the involvement of subject privacy, we have not yet made a decision

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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