Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage (VENTURE-PHH)

June 18, 2026 updated by: Kristopher Kahle, Massachusetts General Hospital

VENTURE-PHH: Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage

Hydrocephalus is a serious condition in which fluid builds up inside the brain, often requiring lifelong surgical placement of a shunt to drain excess cerebrospinal fluid (CSF). One of the most common causes of hydrocephalus is bleeding into the brain's fluid spaces after aneurysm rupture, prematurity, or infection. Currently, no medication exists to prevent hydrocephalus from developing after these injuries. The investigators' recent research suggests that hydrocephalus may result not only from blocked fluid pathways but also from harmful inflammation within the brain's ventricular system. The investigators discovered that inflammation activates the choroid plexus, the tissue that produces CSF, causing excessive CSF production and inflammatory injury to the ventricular lining and surrounding brain tissue. The investigators also identified inflammatory biomarkers and extracellular vesicles in human CSF that may enable real-time monitoring of these disease processes.

In this project, the investigators will perform a first-in-human pilot study testing whether targeted "intraventricular mTOR inhibition" can reduce ventricular inflammation and prevent hydrocephalus after severe brain hemorrhage. The medication will be delivered via temporary ventricular drains already in place as part of routine clinical care. The investigators will study safety, inflammation, CSF production, brain imaging changes, and whether patients ultimately require permanent shunts. Although this initial study focuses on adults with hemorrhage-related hydrocephalus, our long-term goal is to develop non-surgical therapies that could help children with hydrocephalus caused by prematurity or infection, especially in regions where access to neurosurgical care and shunt surgery is limited.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Hydrocephalus remains one of the most common neurosurgical disorders worldwide and is currently treated primarily with surgical diversion of CSF using implanted shunts. Although lifesaving, shunts frequently fail, require repeated surgeries, and do not directly address the underlying biological injury occurring within the brain and ventricular system. Many patients continue to experience lifelong neurological complications despite surgical treatment. This project has the potential to shift hydrocephalus treatment from surgical management toward mechanism-guided prevention. By targeting ventricular inflammation early after hemorrhage, the investigators aim to prevent the biological processes that drive excessive CSF accumulation, ventricular remodeling, ependymal injury, and chronic inflammatory scarring. Successful completion of this work could establish the first pharmacologic strategy designed to prevent hydrocephalus rather than simply treat its consequences after it develops.

The impact of this approach could extend far beyond adult hemorrhage-related hydrocephalus. Similar inflammatory mechanisms are believed to contribute to hydrocephalus caused by prematurity, infection, and traumatic brain injury. In particular, post-infectious and neonatal hydrocephalus remain major causes of childhood disability and death in many low-resource regions where access to shunt surgery and specialized neurosurgical care is limited. A scalable medical therapy capable of reducing hydrocephalus progression could therefore have a substantial global health impact. In addition, this project establishes a new translational framework for studying the ventricular neuroimmune microenvironment through real-time analyses of CSF biomarkers and extracellular vesicles. These tools may ultimately enable personalized monitoring and targeted treatment approaches for multiple forms of hydrocephalus and related neuroinflammatory disorders.

Study Type

Interventional

Enrollment (Estimated)

15

Phase

  • Phase 2
  • Phase 1

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

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital Lunder 4 OR for adult surgeries
        • Contact:
        • Principal Investigator:
          • Kristopher Kahle, MD, PhD

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:

  • Age ≥18 years
  • Diagnosis of aneurysmal subarachnoid hemorrhage (aSAH)
  • Hunt Hess grade IV to V
  • Radiographic evidence of intraventricular hemorrhage (IVH)
  • Clinically indicated EVD placement as part of standard neurocritical care
  • Ability to enroll during the acute post-hemorrhagic inflammatory period, ideally within 24 hours of EVD placement

Exclusion Criteria:

  • Pre-existing ventriculoperitoneal shunt dependence
  • Severe baseline immunosuppression
  • Uncontrolled systemic infection unrelated to hemorrhage
  • Pregnancy
  • Anticipated withdrawal of life-sustaining therapy within 24 hours
  • Inability to safely receive investigational ventricular therapy

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: N/A
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage
We will conduct a prospective, single-center, phase Ib/IIa, biomarker-rich translational pilot study evaluating intraventricular mTOR inhibition in adults with severe aneurysmal subarachnoid hemorrhage (aSAH) who require external ventricular drain (EVD) placement as part of routine neurocritical care management. The central objective of the study is to determine whether early modulation of ventricular immune-secretory signaling is feasible, biologically active, and capable of altering inflammatory CSF physiology and ventricular remodeling following hemorrhage.
Drug: Sirolimus (Rapamune®)
Ventricular delivery
Other Names:
  • Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CSF rapamycin concentration
Time Frame: Baseline, 7 days, and 14 days after rapamycin treatment.
The concentration of rapamycin will be measured in serial CSF samples collected longitudinally through EVDs.
Baseline, 7 days, and 14 days after rapamycin treatment.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Evans Index
Time Frame: Baseline, 7 days, and 14 days after rapamycin treatment.
Longitudinal change in the Evans index measured on serial brain MRI to assess ventricular enlargement and progression toward hydrocephalus.
Baseline, 7 days, and 14 days after rapamycin treatment.
Change in Frontal-Occipital Horn Ratio (FOHR)
Time Frame: Baseline, 7 days, and 14 days after rapamycin treatment.
Longitudinal change in the frontal-occipital horn ratio measured on serial brain MRI as a marker of ventricular size.
Baseline, 7 days, and 14 days after rapamycin treatment.
Change in Third Ventricular Width
Time Frame: Baseline, 7 days, and 14 days after rapamycin treatment.
Longitudinal change in third ventricular width measured on serial brain MRI to evaluate ventricular remodeling.
Baseline, 7 days, and 14 days after rapamycin treatment.
Change in Ventricular Volume
Time Frame: Baseline, 7 days, and 14 days after rapamycin treatment.
Change in total ventricular volume quantified by MRI-based volumetric segmentation, when imaging quality permits, to explore treatment effects on ventricular remodeling.
Baseline, 7 days, and 14 days after rapamycin treatment.

Collaborators and Investigators

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

Sponsor

Massachusetts General Hospital

Investigators

  • Principal Investigator: Kristopher Kahle, MD, PhD, Massachusetts General 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 (Estimated)

January 1, 2027

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

December 31, 2027

Study Registration Dates

First Submitted

May 29, 2026

First Submitted That Met QC Criteria

June 18, 2026

First Posted (Actual)

June 23, 2026

Study Record Updates

Last Update Posted (Actual)

June 23, 2026

Last Update Submitted That Met QC Criteria

June 18, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2026P001357

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

We have no plan to share IPD with other researchers.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

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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