Clinical trial NCT06563817: The Safety and Efficacy of Rapamycin on Communicating Hydrocephalus Secondary to Intraventricular Hemorrhage
Official title: A Prospective, Multi-center, Open-label Study to Observe the Efficacy and Safety of Rapamycin in the Treatment of Communicating Hydrocephalus Secondary to Intraventricular Hemorrhage
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Communicating Hydrocephalus
Cerebral Intraventricular Hemorrhage
Secondary Normal Pressure Hydrocephalus
Post Hemorrhagic Hydrocephalus
Keywords: Communicating Hydrocephalus
Cerebral Intraventricular Hemorrhage
Rapamycin
Secondary Normal Pressure Hydrocephalus
Post Hemorrhagic Hydrocephalus
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
First posted: 2024-08-21
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: All enrolled patients receive treatment with sirolimus (rapamycin), administered in capsule form at a dosage of 0.5 mg per capsule. The capsules, provided by North China Pharmaceutical under the trade name Yixinke, were stored at room temperature. The prescribed regimen involved a daily oral dosage of 1.5 mg for a duration of four weeks.
Primary purpose: TREATMENT

Brief summary: This prospective, multicenter, open-label clinical trial is designed to evaluate the safety and efficacy of rapamycin in the treatment of communicating hydrocephalus secondary to intraventricular hemorrhage. Additionally, the underlying pathogenic mechanisms associated with this particular type of hydrocephalus will be investigated in greater depth, and populations that may benefit from rapamycin therapy will be identified.

Detailed description: Communicating hydrocephalus secondary to intraventricular hemorrhage is a serious neurological disorder with the main clinical manifestations of ventricular dilatation, gait disturbance, cognitive dysfunction, and urinary incontinence. At present, the sole treatment option for these patients is cerebrospinal fluid shunting. However, complications resulting from this therapy have necessitated multiple surgeries for some patients, which has a significant impact on their quality of life and financial resources. However, recent studies have identified the PI3K-AKT-mTOR pathway as a key contributor to the sequelae of hemorrhagic hydrocephalus. Furthermore, these studies demonstrated that rapamycin, an inhibitor of the PI3K-AKT-mTOR pathway, inhibited cerebrospinal fluid secretion and ventricular dilation in an animal model of hemorrhagic hydrocephalus sequelae. In light of these findings, we propose a prospective, multicenter, open-label clinical trial to evaluate the efficacy and safety of rapamycin in the treatment of communicating hydrocephalus secondary to intraventricular hemorrhage.

The study design was that of a prospective, multicenter, open-label clinical trial. All patients were administered sirolimus (rapamycin) in a dosage of 0.5 mg per capsule. The capsules were provided by the North China Pharmaceutical Company and were stored at room temperature. The treatment course was four weeks, with a dosage of 1.5 mg orally per day. Efficacy and adverse effects were assessed at two weeks, four weeks, the end of treatment, and 12 weeks after the end of treatment, respectively.

Eligibility criteria: Inclusion Criteria:

1. Patients with ventricular dilatation due to intraventricular hemorrhage who clinically present with any one or more of new gait disturbances, cognitive deficits, and urinary incontinence after remission of intraventricular hemorrhage symptoms, and whose brain imaging shows an Evans index (EI) of ≥0.3
2. Age ≥ 18 years and ≤ 70 years
3. Signed informed consent form

Exclusion Criteria:

1. Participation in another medical trial
2. Have other disease that may affect the patient's symptoms (including gait disturbance, cognitive impairment, urinary incontinence)
3. Allergy to the investigational drug
4. Reduced liver function (increased INR or alanine transaminase concentrations in plasma elevated more than 1.5 times reference values)
5. Reduced kidney function with GFR \< 50
6. Concomitant treatment with strong CYP3A4/5 inducers or inhibitors, such as diltiazem, ketoconazole, or rifampicin.
7. Active or uncontrolled chronic infection
8. Women who are pregnant or breastfeeding
9. Patients who are bedridden or require urinary catheters for extended periods of time.

Primary outcomes:
measure: The objective remission rate of rapamycin for 4 weeks in the treatment of communicating hydrocephalus secondary to intraventricular hemorrhage is evaluated using the Idiopathic Normal Pressure Hydrocephalus Grading Scale (IPNHGS).
timeFrame: From the commencement of treatment to 4 weeks
Secondary outcomes:
measure: Assessment of the incidence and severity of adverse events, serious adverse events, and other safety parameters (e.g., abnormal laboratory results) based on CTCAE V5.0
timeFrame: From the commencement of treatment to 12 weeks after discontinuation of dosing
measure: The objective remission rate of rapamycin treatment of communicating hydrocephalus secondary to intraventricular hemorrhage is evaluated using the Idiopathic Normal Pressure Hydrocephalus Grading Scale (IPNHGS).
timeFrame: From the commencement of treatment to 2 weeks of dosing and 12 weeks after discontinuation of dosing
measure: The objective remission rates of 3 clinical domains is evaluated using the Idiopathic Normal Pressure Hydrocephalus Grading Scale (IPNHGS).
timeFrame: From the commencement to 2 weeks of dosing, 4 weeks of dosing and 12 weeks after discontinuation of dosing
measure: Changes in plasma biomarkers
timeFrame: From the commencement to 2 weeks of dosing, 4 weeks of dosing and 12 weeks after discontinuation of dosing
measure: Change in CSF biomarkers
timeFrame: From the commencement to 2 weeks of dosing, 4 weeks of dosing and 12 weeks after discontinuation of dosing
measure: Change in Euro-Quality of Life-5 dimension-5L (EQ-5D-5L) descriptive system
timeFrame: From the commencement to 2 weeks of dosing, 4 weeks of dosing and 12 weeks after discontinuation of dosing
Other outcomes:
measure: Screening of potential beneficiary population
timeFrame: From the commencement of treatment to 4 weeks
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital, Capital Medical University
state: Beijing
Study officials:
affiliation: Beijing Tiantan Hospital
name: Runfa Tian, MD
role: STUDY_DIRECTOR
affiliation: Beijing Tiantan Hospital
name: Guoyi Gao, MD
role: STUDY_CHAIR
References:
citation: Robert SM, Reeves BC, Kiziltug E, Duy PQ, Karimy JK, Mansuri MS, Marlier A, Allington G, Greenberg ABW, DeSpenza T Jr, Singh AK, Zeng X, Mekbib KY, Kundishora AJ, Nelson-Williams C, Hao LT, Zhang J, Lam TT, Wilson R, Butler WE, Diluna ML, Feinberg P, Schafer DP, Movahedi K, Tannenbaum A, Koundal S, Chen X, Benveniste H, Limbrick DD Jr, Schiff SJ, Carter BS, Gunel M, Simard JM, Lifton RP, Alper SL, Delpire E, Kahle KT. The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus. Cell. 2023 Feb 16;186(4):764-785.e21. doi: 10.1016/j.cell.2023.01.017.