Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage

Official title

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

Overview

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.

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.

Interventions

• Drug Sirolimus (Rapamune®)
  Ventricular delivery

Primary outcome measures

• CSF rapamycin concentration [Time frame: Baseline, 7 days, and 14 days after rapamycin treatment.]

Secondary outcome measures (4)

• Change in Evans Index [Time frame: 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.]
• Change in Third Ventricular Width [Time frame: Baseline, 7 days, and 14 days after rapamycin treatment.]
• Change in Ventricular Volume [Time frame: Baseline, 7 days, and 14 days after rapamycin treatment.]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Massachusetts General Hospital Lunder 4 OR for adult surgeries — Boston

Publications

• Ziai WC, Parry-Jones AR, Thompson CB, Sansing LH, Mullen MT, Murthy SB, Mould A, Nekoovaght-Tak S, Hanley DF. Early Inflammatory Cytokine Expression in Cerebrospinal Fluid of Patients with Spontaneous Intraventricular Hemorrhage. Biomolecules. 2021 Jul 30;11(8):1123. doi: 10.3390/biom11081123. PMID 34439789
• Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet. 2001;40(8):573-85. doi: 10.2165/00003088-200140080-00002. PMID 11523724
• Foerster P, Daclin M, Asm S, Faucourt M, Boletta A, Genovesio A, Spassky N. mTORC1 signaling and primary cilia are required for brain ventricle morphogenesis. Development. 2017 Jan 15;144(2):201-210. doi: 10.1242/dev.138271. Epub 2016 Dec 19. PMID 27993979
• Kuo LT, Huang AP. The Pathogenesis of Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage. Int J Mol Sci. 2021 May 10;22(9):5050. doi: 10.3390/ijms22095050. PMID 34068783
• Holste KG, Xia F, Ye F, Keep RF, Xi G. Mechanisms of neuroinflammation in hydrocephalus after intraventricular hemorrhage: a review. Fluids Barriers CNS. 2022 Apr 1;19(1):28. doi: 10.1186/s12987-022-00324-0. PMID 35365172
• Lolansen SD, Rostgaard N, Barbuskaite D, Capion T, Olsen MH, Norager NH, Vilhardt F, Andreassen SN, Toft-Bertelsen TL, Ye F, Juhler M, Keep RF, MacAulay N. Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters. Fluids Barriers CNS. 2022 Aug 10;19(1):62. doi: 10.1186/s12987-022-00360-w. PMID 35948938
• Sadegh C, Xu H, Sutin J, Fatou B, Gupta S, Pragana A, Taylor M, Kalugin PN, Zawadzki ME, Alturkistani O, Shipley FB, Dani N, Fame RM, Wurie Z, Talati P, Schleicher RL, Klein EM, Zhang Y, Holtzman MJ, Moore CI, Lin PY, Patel AB, Warf BC, Kimberly WT, Steen H, Andermann ML, Lehtinen MK. Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus. Neuron. 2023 May 17;111(10): PMID 36893755
• Strahle J, Garton HJ, Maher CO, Muraszko KM, Keep RF, Xi G. Mechanisms of hydrocephalus after neonatal and adult intraventricular hemorrhage. Transl Stroke Res. 2012 Jul;3(Suppl 1):25-38. doi: 10.1007/s12975-012-0182-9. PMID 23976902

Identifiers

NCT: NCT07662174 · 2026P001357

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗