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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Communicating Hydrocephalus; Cerebral Intraventricular Hemorrhage; Secondary Normal Pressure Hydrocephalus; Post Hemorrhagic Hydrocephalus
• Intervention / Treatment: Drug: Rapamycin

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.

• Study Type: Interventional
• Enrollment (Estimated): 53
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Guoyi Gao, MD; Phone Number: +86 13801874393; Email: gao3@sina.com
• Study Contact Backup: Name: Runfa Tian, MD; Phone Number: +86 15910996812; Email: trftc@126.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100070
      • Recruiting
      • Beijing Tiantan Hospital, Capital Medical University
      • Contact: Guoyi Gao, MD; Phone Number: +86 13801874393; Email: gao3@sina.com
      • Contact: Runfa Tian, MD; Phone Number: +86 15910996812; Email: trftc@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Rapamycin treatment group; 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.

Drug: Rapamycin; All enrolled patients receive treatment with sirolimus (rapamycin)#The prescribed regimen involved a daily oral dosage of 1.5 mg for a duration of four weeks.; Other Names: Sirolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Disease relief: Improvement of >1 point on the Idiopathic Normal Pressure Hydrocephalus Grading Scale (iPNHGS) in patients after four weeks of rapamycin treatment compared to pre-treatment. Objective remission rate: The ratio of the number of patients who have achieved disease remission to the total number of patients enrolled in the study.	From the commencement of treatment to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	All events are determined based on CTCAE V5.0	From the commencement of treatment to 12 weeks after discontinuation of dosing
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).	Disease relief: Improvement of >1 point on the Idiopathic Normal Pressure Hydrocephalus Grading Scale (iPNHGS) in patients after four weeks of rapamycin treatment compared to pre-treatment. Objective remission rate: The ratio of the number of patients who have achieved disease remission to the total number of patients enrolled in the study.	From the commencement of treatment to 2 weeks of dosing and 12 weeks after discontinuation of dosing
The objective remission rates of 3 clinical domains is evaluated using the Idiopathic Normal Pressure Hydrocephalus Grading Scale (IPNHGS).	The 3 clinical domains include: gait, urinary incontinence, and cognition. For gait, positive outcome was defined that improvement of >1 point in the gait section of iNPHGS; for urinary incontinence, a positive outcome was defined that improvement of >1 point in the urinary section of iNPHGS; For cognition, positive outcome was defined that improvement of >1 point in the cognition section of iNPHGS	From the commencement to 2 weeks of dosing, 4 weeks of dosing and 12 weeks after discontinuation of dosing
Changes in plasma biomarkers	Change in plasma levels of TNF-α, IL-1β, IL-6, IL-10, IL-8 and IL-2R.	From the commencement to 2 weeks of dosing, 4 weeks of dosing and 12 weeks after discontinuation of dosing
Change in CSF biomarkers	Change in plasma levels of TNF-α, IL-1β, IL-6, IL-10, IL-8 and IL-2R.	From the commencement to 2 weeks of dosing, 4 weeks of dosing and 12 weeks after discontinuation of dosing
Change in Euro-Quality of Life-5 dimension-5L (EQ-5D-5L) descriptive system	Measured using EQ-5D-5L using the descriptive system.	From the commencement to 2 weeks of dosing, 4 weeks of dosing and 12 weeks after discontinuation of dosing

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Screening of potential beneficiary population	Identification of a patient population with secondary communicating hydrocephalus after intraventricular hemorrhage that may benefit from rapamycin therapy.	From the commencement of treatment to 4 weeks

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Investigators: Study Director: Runfa Tian, MD, Beijing Tiantan Hospital; Study Chair: Guoyi Gao, MD, Beijing Tiantan Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2024
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: August 9, 2024
• First Submitted That Met QC Criteria: August 18, 2024
• First Posted (Actual): August 21, 2024

Study Record Updates

• Last Update Posted (Actual): August 21, 2024
• Last Update Submitted That Met QC Criteria: August 18, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Rapamycin; Communicating Hydrocephalus; Cerebral Intraventricular Hemorrhage; Secondary Normal Pressure Hydrocephalus; Post Hemorrhagic Hydrocephalus
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplastic Processes; Intracranial Hemorrhages; Neoplasm Metastasis; Hemorrhage; Cerebral Hemorrhage; Hydrocephalus; Hydrocephalus, Normal Pressure; Cerebral Intraventricular Hemorrhage; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: HX-A-2024025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No