Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage

NCT07662174 | Not Yet Recruiting Phase 1 FDA Drug

• 1 other identifier: 2026P001357
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Post-hemorrhagic Hydrocephalus (PHH)

Keywords

hydrocephalus; brain hemorrhage; mTOR Inhibition

Outcome Measures

Primary Outcomes (1)

• CSF rapamycin concentration

  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 Outcomes (4)

• Change in Evans Index

  Baseline, 7 days, and 14 days after rapamycin treatment.

• Change in Frontal-Occipital Horn Ratio (FOHR)

  Baseline, 7 days, and 14 days after rapamycin treatment.

• Change in Third Ventricular Width

  Baseline, 7 days, and 14 days after rapamycin treatment.

• Change in Ventricular Volume

  Baseline, 7 days, and 14 days after rapamycin treatment.

Study Arms (1)

Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage

EXPERIMENTAL

The investigators 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®)

Interventions

Sirolimus (Rapamune®) DRUG

Ventricular delivery

Also known as: Rapamycin

Ventricular mTOR Inhibition to Prevent Hydrocephalus After Brain Hemorrhage

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (1)

Massachusetts General Hospital Lunder 4 OR for adult surgeries

Boston, Massachusetts, 02114, United States

Location

Related Publications (15)

• 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 BACKGROUND

• Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet. 2001;40(8):573-85. doi: 10.2165/00003088-200140080-00002.

  PMID: 11523724 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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):1591-1608.e4. doi: 10.1016/j.neuron.2023.02.020. Epub 2023 Mar 8.

  PMID: 36893755 BACKGROUND

• 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 BACKGROUND

• Zhang J, Bhuiyan MIH, Zhang T, Karimy JK, Wu Z, Fiesler VM, Zhang J, Huang H, Hasan MN, Skrzypiec AE, Mucha M, Duran D, Huang W, Pawlak R, Foley LM, Hitchens TK, Minnigh MB, Poloyac SM, Alper SL, Molyneaux BJ, Trevelyan AJ, Kahle KT, Sun D, Deng X. Modulation of brain cation-Cl- cotransport via the SPAK kinase inhibitor ZT-1a. Nat Commun. 2020 Jan 7;11(1):78. doi: 10.1038/s41467-019-13851-6.

  PMID: 31911626 BACKGROUND

• Mukumbya B, Adeleye AO, Siddig AHE, Mbilinyi RH, Woo J, Agwu C, Min Htike WY, Mustapha MJ, Dada OE, Ramos S, Adereti C, Ssembatya JM, Petitt Z, Still MEH, Blackwood ER, von Isenburg M, Haglund MM, Ukachukwu AK. Outcomes of ventriculoperitoneal shunt surgery for hydrocephalus in children in low- and middle-income countries: a systematic review. J Neurosurg Pediatr. 2025 Aug 15;36(5):570-581. doi: 10.3171/2025.4.PEDS24598. Print 2025 Nov 1.

  PMID: 40815859 BACKGROUND

• Vinchon M, Rekate H, Kulkarni AV. Pediatric hydrocephalus outcomes: a review. Fluids Barriers CNS. 2012 Aug 27;9(1):18. doi: 10.1186/2045-8118-9-18.

  PMID: 22925451 BACKGROUND

• Karimy JK, Reeves BC, Damisah E, Duy PQ, Antwi P, David W, Wang K, Schiff SJ, Limbrick DD Jr, Alper SL, Warf BC, Nedergaard M, Simard JM, Kahle KT. Inflammation in acquired hydrocephalus: pathogenic mechanisms and therapeutic targets. Nat Rev Neurol. 2020 May;16(5):285-296. doi: 10.1038/s41582-020-0321-y. Epub 2020 Mar 9.

  PMID: 32152460 BACKGROUND

• Kahle KT, Klinge PM, Koschnitzky JE, Kulkarni AV, MacAulay N, Robinson S, Schiff SJ, Strahle JM. Paediatric hydrocephalus. Nat Rev Dis Primers. 2024 May 16;10(1):35. doi: 10.1038/s41572-024-00519-9.

  PMID: 38755194 BACKGROUND

• Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, Furey CG, Zhou X, Mansuri MS, Montejo J, Vera A, DiLuna ML, Delpire E, Alper SL, Gunel M, Gerzanich V, Medzhitov R, Simard JM, Kahle KT. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat Med. 2017 Aug;23(8):997-1003. doi: 10.1038/nm.4361. Epub 2017 Jul 10.

  PMID: 28692063 BACKGROUND

• 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.

  PMID: 36803604 BACKGROUND

MeSH Terms

Conditions

Hydrocephalus; Intracranial Hemorrhages

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Kristopher Kahle, MD, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kristopher Kahle, M.D., Ph.D.

CONTACT

14143057506; kahle.kristopher@mgh.harvard.edu

Carla Fortes, BA

CONTACT

16175489679; CFORTES@MGH.HARVARD.EDU

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Nicholas T. Zervas Endowed Chair and Associate Professor of Neurosurgery

Model Details: The investigators 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 investigators anticipate enrollment of approximately 10-15 adults with Hunt-Hess grade IV-V aneurysmal SAH over the 12-month study period.

Study Record Dates

• First Submitted: May 29, 2026
• First Posted: June 23, 2026
• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: June 25, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)