Cavernous MalformationsPhase 2CALMNCT06091332
Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: aSingle Centre, Randomized, Placebo-controlled Pilot Trial
A Phase 2 study testing Sirolimus and Starch flake in people with Cavernous Malformations and Intracerebral Hemorrhage, run by Huashan Hospital at 2 sites in China.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Cavernous Malformations, Intracerebral Hemorrhage, Brainstem Stroke
- What is being tested?
- Sirolimus and Starch flake
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 75 participants
- Where
- 2 sitesChina
- Study dates
- 5 Jan 2024to 31 Dec 2026
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
Show all 14Show fewer
- 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).
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
China2 sites, 1 recruiting
- Active, not recruiting
Huashan Hospital, Fudan University
Shanghai, Shanghai Municipality, 200040
- Recruiting
Huashan Hospital, Fudan University
Shanghai, Shanghai Municipality, 200040
Wei Zhu, Doctor, +86 021 52887718 ext. +86 1312122658, lizongze666@aliyun.com
About this study
Official title: 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.
- Being tested
- Sirolimus, Starch flake
- Keywords
- Cavernous Malformations, Brainstem, Rebleeding rate, Sirolimus
- Medical subject headings
- Cerebral Hemorrhage, Brain Stem Infarctions
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SirolimusDrug
Also called Rapamycin
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.
Starch flakeDrug
The placebo is composed of starch material and is formulated at 0.5 grams per tablet.
| Study group | Role | What they receive |
|---|---|---|
| High-dose sirolimus group | Experimental | Participants will receive oral sirolimus with a target blood concentration of 9-15ng/ml continuously for 12 months. Receives: 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 Receives: Drug: Sirolimus |
| Placebo control group | Placebo comparator | Participants will receive oral placebo(starch formulation) for 12 months. Receives: Drug: Starch flake |
What is being measured
The primary outcome is the main question the study is designed to answer.
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:
- 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.
Measured: 24 months
Secondary outcomes (4)
We will measure the tolerability of sirolimus in the management of BSCMs.
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.
Measured: 24 months
We will measure the occurrence of recurrent ICH from the BSCM within 24 months.
- 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.
Measured: 24 months
We will measure the efficacy outcomes in MR
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.
Measured: 24 months
We will measure several the quality of life
Quality of Life (mRS score and EuroQOL five dimensions questionnaire (EQ-5D) scale) within 24 months after enrollment
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2023
- Study start5 Jan 2024
- Primary completion31 Dec 2025 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Cavernous MalformationsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 75 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Huashan Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Wei Zhu, Huashan Hospital
- Investigators
- Wei Zhu, Doctor, Principal investigator, Huashan Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06091332
- Sponsor's protocol ID
- 2023-816
- Acronym
- CALM
- Status last verified
- Dec 2024
- First submitted
- 13 Oct 2023
- Last updated
- 20 Dec 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 33910229Flemming 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.
PubMed 28492932Ren 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.
PubMed 36995941Yan C, Ye Y, Liu N, Zhang D, Du W, Li Y, Li G, Li C, Li J, Ma S, Dai Z, Xiong Z, Wang Y, Men C, Bi R, Duan Q, Xu W, Husilengtu, Cao Y, Du J, Shi C. Metformin limits cerebral cavernous malformation development by targeting KLF4-mediated mitochondrial damage. Biochem Biophys Res Commun. 2025 Sep 1;777:152241. doi: 10.1016/j.bbrc.2025.152241. Epub 2025 Jun 24.
PubMed 40570636
Study at a glance
From the registry record, last updated by the sponsor on 20 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Hemorrhagic Brainstem Cavernous Malformations Treatment With Sirolimus: a Randomized, Placebo-controlled Pilot Trial
- ClinicalTrials.gov ID
- NCT06091332
- Acronym / sponsor ID
- CALM / 2023-816
- Keywords
- Cavernous Malformations, Brainstem, Rebleeding rate, Sirolimus
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 75 participants (estimated)
- Lead sponsor
- Huashan HospitalUniversity, hospital or other
- Study start
- 5 Jan 2024 (actual)
- Primary completion
- 31 Dec 2025 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 19 Oct 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| High-dose sirolimus group | Experimental | Drug: SirolimusParticipants will receive oral sirolimus with a target blood concentration of 9-15ng/ml continuously for 12 months. |
| Low-dose sirolimus group | Experimental | Drug: SirolimusParticipants will receive oral sirolimus with a target blood concentration of 3-7ng/ml continuously for 12 months |
| Placebo control group | Placebo comparator | Drug: Starch flakeParticipants will receive oral placebo(starch formulation) for 12 months. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (14 listed)
- 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);
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SirolimusAlso: RapamycinSirolimus 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. | Drug | High-dose sirolimus group, Low-dose sirolimus group |
| Starch flakeThe placebo is composed of starch material and is formulated at 0.5 grams per tablet. | Drug | Placebo control group |
Primary outcome
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.
4 secondary outcomes
We will measure the tolerability of sirolimus in the management of BSCMs.
Time frame: 24 months
We will measure the occurrence of recurrent ICH from the BSCM within 24 months.
Time frame: 24 months
We will measure the efficacy outcomes in MR
Time frame: 24 months
We will measure several the quality of life
Time frame: 24 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Dec 2024.
- Background: PubMed 33910229Ren 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.
- Background: PubMed 28492932Flemming 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.
- Background: PubMed 36995941Ren 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.
- Derived from this study: PubMed 40570636Yan C, Ye Y, Liu N, Zhang D, Du W, Li Y, Li G, Li C, Li J, Ma S, Dai Z, Xiong Z, Wang Y, Men C, Bi R, Duan Q, Xu W, Husilengtu, Cao Y, Du J, Shi C. Metformin limits cerebral cavernous malformation development by targeting KLF4-mediated mitochondrial damage. Biochem Biophys Res Commun. 2025 Sep 1;777:152241. doi: 10.1016/j.bbrc.2025.152241. Epub 2025 Jun 24.
- Individual participant dataSharing planned: No
Related trials for Cavernous Malformations
RecruitingPhase 2/3
Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.
Lymphatic Malformations
Not yet recruiting
Biological Collection of the Rare Diseases of the Brain and Eye Vessels Cohort - 2
CADASIL, Cavernous Angioma
Active, not recruitingObservational study
Biomarkers of CASH
Cerebral Cavernous Malformation, Cavernous Angioma
RecruitingObservational study
Study on Treatment Decision-Making and Prognostic Follow-Up for Untreated Cerebral Cavernous Malformations
Hemangioma, Cavernous, Central Nervous System
Not yet recruitingEarly Phase 1
Daratumumab for Familial Cerebral Cavernous Malformations: A Single-Arm Safety and Efficacy Study
Cavernous Malformation, Cerebral
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Wei Zhu, Doctor principal investigator
Huashan Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sirolimus and Starch flake in people with Cavernous Malformations and Intracerebral Hemorrhage, run by Huashan Hospital at 2 sites in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 20 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Zongze Li, Doctor (+8613121226581, lizongze666@aliyun.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary outcome is to explore the safety of sirolimus in the management of BSCMs. (time frame: 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06091332, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Dec 2024.