The Safety and Efficacy of Rapamycin on Communicating Hydrocephalus Secondary to Intraventricular Hemorrhage (Saturn)

Capital Medical University

Status and phase: Enrolling; Phase 2

Conditions: Post Hemorrhagic Hydrocephalus; Cerebral Intraventricular Hemorrhage; Communicating Hydrocephalus; Secondary Normal Pressure Hydrocephalus

Treatments: Drug: Rapamycin

Study type: Interventional

Funder types: Other

Identifiers

NCT06563817

HX-A-2024025

Details and patient eligibility

About

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.

Full 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.

Enrollment: 53 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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53 participants in 1 patient group

Rapamycin treatment group

Experimental group

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. Sirolimus (rapamycin) bioavailability can be affected by food, based on preliminary results of prior drug use. To maintain consistent blood drug concentrations, sirolimus should be taken with or without food on a constant basis. Grapefruit juice slows CYP3A4-mediated metabolism of sirolimus and potentially enhances P-gp-mediated retrograde transport of sirolimus from the small intestinal epithelium to the intestinal lumen. Therefore, it should not be consumed concurrently with sirolimus.

Treatment:

Drug: Rapamycin