Atorvastatin Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial

NCT02603328 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: IRB18-0445
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/II randomized, placebo-controlled, double-blinded, single-site clinical trial is designed to investigate the effect of a prolonged course of atorvastatin versus placebo on CCM lesional iron deposition assessed by validated quantitative susceptibility mapping (QSM) MRI studies in patients who suffered a symptomatic bleed within the preceding one year.

Conditions

Cerebral Cavernous Malformation

Keywords

Cerebral cavernous malformation; Statins; MRI; Permeability; Quantitative susceptibility mapping

Outcome Measures

Primary Outcomes (1)

• Percent Change in Mean Lesional QSM (QSM Change Score)

  QSM change score is the Percentage Change in mean lesional iron deposition per year (QSM score) according to assigned treatment (modified intention-to-treat cohort), presented as a mean value across all participants from baseline to year 1 and year 1 to year 2 follow-up MRIs. Quantitative susceptibility mapping (QSM) is a noninvasive MRI technique that assesses iron content by quantifying the magnetic susceptibility of local tissues. A higher QSM value corresponds to a larger amount of iron in the lesion, which means more blood is present in the lesion.

  2 years of follow-up

Secondary Outcomes (8)

• Percent Change in Dynamic Contrast-enhanced Quantitative Perfusion (DCEQP) Value (Vascular Permeability) in Index Lesion (Lesional DCEQP Change Score)

  2 years of follow-up

• Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit

  1 year of follow-up

• Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit.

  1 year of follow-up (from year 1 to year 2)

• Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 1 Follow-up Visit.

  1 year of follow up

• Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 2 Follow-up Visit

  1 year of follow up (from year 1 to year 2)

Study Arms (2)

Treatment

ACTIVE COMPARATOR

Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events.

Drug: Atorvastatin

Placebo

PLACEBO COMPARATOR

Identically looking capsules containing no active ingredient

Other: Placebo

Interventions

Atorvastatin DRUG

40-80 mg OD

Treatment

Placebo OTHER

inactive

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of CCM of any genotype supported by relevant imaging studies.
• Symptomatic CCM bleeding event within 1 year prior to enrollment.
• Must be willing/able to travel to the study site for all study visits (baseline, 12 months, and 24 months) over the course of the study period.

You may not qualify if:

• Pre-menopausal women who are breastfeeding, pregnant or likely to get pregnant during the study period.
• Previous cranial irradiation or surgical/radiosurgical treatment of CCM lesion.
• Failure to pass MRI safety screening (claustrophobia, metal implant . . . etc)
• Known allergy or intolerance to gadolinium.
• Severely impaired renal function (eGFR \< 60ml/min), active renal disease or status post-kidney transplants.
• Statin therapy, for any indication, for more than 7 continuous days or greater than 14 total days within 12 months preceding enrollment.
• Indication to use statin medication for current approved indication, unrelated to CCM
• Known allergy or intolerance to statins
• Liver dysfunction or active liver disease (including chronic viral hepatitis) defined as baseline serum transaminases levels twice the upper range of normal.
• Previous diagnosis of skeletal muscle disorders of any cause (myopathy), or baseline creatine kinase level five times the upper range of normal.
• Currently treated with or likely to need treatment with one or more of prohibited medications listed in the protocol.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Serious illness (requiring systemic treatment and/or hospitalization) until subject either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 30 days prior to study entry.
• Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated, including conditions resulting in or precipitating myopathy (e.g. HIV, uncontrolled hypothyroidism).
• In the investigator's opinion, the patient is unstable, and would benefit from a specific intervention rather than treatment with atorvastatin.

Sponsors & Collaborators

• University of Chicago: lead
• Johns Hopkins University: collaborator

Study Sites (1)

University of Chicago

Chicago, Illinois, 60637, United States

Location

Related Publications (3)

• Ali B, Shenkar R, Lee J, Alcazar-Felix RJ, Thompson RE, Stadnik A, Sader G, Polster SP, Flemming KD, Liao JK, Sorrentino M, Girard R, Hanley DF, Awad IA. Recurrent Symptomatic Hemorrhage in Cerebral Cavernous Malformations After Discontinuation of Atorvastatin or Placebo. J Am Heart Assoc. 2026 Jan 29:e46943. doi: 10.1161/JAHA.125.046943. Online ahead of print.

  PMID: 41608890 DERIVED

• Alcazar-Felix RJ, Thompson RE, Stadnik A, Kinkade S, Sader G, Jhaveri A, Lee J, Iqbal J, Polster SP, Shenkar R, Flemming KD, Girard R, Carroll TJ, Hanley DF, Awad IA. Relevance of Lesion Volume as an Outcome in Cerebral Cavernous Malformation Drug Trial: Exploratory Analyses in Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept. Neurosurgery. 2025 Oct 21. doi: 10.1227/neu.0000000000003814. Online ahead of print.

  PMID: 41117517 DERIVED

• Awad IA, Alcazar-Felix RJ, Stadnik A, Kinkade S, Jhaveri A, Lee J, Hage S, Iqbal J, Polster SP, Shenkar R, Treine K, McBee N, Ostapkovich N, Lane K, Liao JK, Sorrentino M, Lee C, Flemming KD, Girard R, Carroll TJ, Thompson RE, Hanley DF. Safety and efficacy of atorvastatin for rebleeding in cerebral cavernous malformations (AT CASH EPOC): a phase 1/2a, randomised placebo-controlled trial. Lancet Neurol. 2025 Apr;24(4):295-304. doi: 10.1016/S1474-4422(25)00036-5.

  PMID: 40120614 DERIVED

MeSH Terms

Conditions

Hemangioma, Cavernous, Central Nervous System

Interventions

Atorvastatin

Condition Hierarchy (Ancestors)

Hemangioma, Cavernous; Hemangioma; Neoplasms, Vascular Tissue; Neoplasms by Histologic Type; Neoplasms; Cavernous Sinus Syndromes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Central Nervous System Vascular Malformations; Nervous System Malformations; Vascular Malformations; Cardiovascular Abnormalities; Cardiovascular Diseases; Hemostatic Disorders; Vascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Results Point of Contact

• Title: Agnieszka Stadnik
• Organization: University of Chicago, Medicine and Biological Sciences Division

astadnik@bsd.uchicago.edu

773-702-8996

Study Officials

• Issam A Awad, MD

  Director of Neurovascular Surgery University of Chicago Medicine and Biological Sciences

  STUDY CHAIR

• Daniel F Hanley, MD

  Director, Division of Brain Injury Outcomes Service The Johns Hopkins Medical Institutions

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 9, 2015
• First Posted: November 11, 2015
• Study Start: July 17, 2018
• Primary Completion: July 31, 2024
• Study Completion: March 31, 2025
• Last Updated: August 22, 2025
• Results First Posted: August 22, 2025

Record last verified: 2025-07

Locations

US (1)