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

Phase 1

Completed

• Conditions: Cerebral Cavernous Malformation
• Interventions: Other: Placebo; Drug: Atorvastatin

• Registration Number: NCT02603328
• Lead Sponsor: University of Chicago

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.

Detailed Description

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. Subjects will also be assessed by lesional and brain vascular permeability MRI using dynamic contrast enhanced quantitative perfusion (DCEQP) and a number of clinical evaluation tools. Subjects shall be followed for 2 years from randomization, the period of highest likelihood of rebleed after a recent CCM hemorrhage. Subjects will undergo clinical and MRI evaluations at baseline, and at 12 and 24 months during the study period. Enrolled subjects and the treating team will be blinded to treatment group allocation.

Study Timeline

• Study First Submitted: 2015-11-09
• Study First Submitted QC: 2015-11-09
• Study First Posted: 2015-11-11
• Study Start: 2018-07-17
• Primary Completion: 2024-07-31
• Study Completion: 2025-03-31
• Results First Submitted: 2025-06-10
• Status Verified: 2025-07
• Results First Submitted QC: 2025-08-20
• Last Update Submitted: 2025-08-20
• Results First Posted: 2025-08-22
• Last Update Posted: 2025-08-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

1. Diagnosis of CCM of any genotype supported by relevant imaging studies.
2. Symptomatic CCM bleeding event within 1 year prior to enrollment.
3. 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.

Exclusion Criteria

1. Pre-menopausal women who are breastfeeding, pregnant or likely to get pregnant during the study period.
2. Previous cranial irradiation or surgical/radiosurgical treatment of CCM lesion.
3. Failure to pass MRI safety screening (claustrophobia, metal implant . . . etc)
4. Known allergy or intolerance to gadolinium.
5. Severely impaired renal function (eGFR < 60ml/min), active renal disease or status post-kidney transplants.
6. Statin therapy, for any indication, for more than 7 continuous days or greater than 14 total days within 12 months preceding enrollment.
7. Indication to use statin medication for current approved indication, unrelated to CCM
8. Known allergy or intolerance to statins
9. Liver dysfunction or active liver disease (including chronic viral hepatitis) defined as baseline serum transaminases levels twice the upper range of normal.
10. Previous diagnosis of skeletal muscle disorders of any cause (myopathy), or baseline creatine kinase level five times the upper range of normal.
11. Currently treated with or likely to need treatment with one or more of prohibited medications listed in the protocol.
12. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
13. 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.
14. 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).
15. In the investigator's opinion, the patient is unstable, and would benefit from a specific intervention rather than treatment with atorvastatin.
16. Inability or unwillingness of subject or legal guardian/representative to give written informed consent.
17. No documentation of valid healthcare insurance.
18. No medical record confirmation of primary care physician.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Identically looking capsules containing no active ingredient
Treatment	Atorvastatin	Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events.

Primary Outcome Measures

Name	Time	Method
Percent Change in Mean Lesional QSM (QSM Change Score)	2 years of follow-up	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.

Secondary Outcome Measures

Name	Time	Method
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 1 follow-up visit.; The mRS is a simple global measure of functional disability. Scores range from 0 (no symptoms) to 6 (death). An mRS score of 0 to 1 is considered a minimal clinical disability, and 0 to 2 is independent.
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)	Compare the changes in modified Rankin Score between atorvastatin and placebo groups at the year 2 follow-up visit (change between mRS score at year 1 follow up visit and year 2 follow up visit).; The mRS is a simple global measure of functional disability. Scores range from 0 (no symptoms) to 6 (death). An mRS score of 0 to 1 is considered a minimal clinical disability, and 0 to 2 is independent.
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)	Mean score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the year 2 follow-up visit; The EQ-VAS is a vertical visual analogue scale that takes values between 100 (best imaginable health) and 0 (worst imaginable health), on which patients provide a global assessment of their health.
Compare Rate of Drug Compliance in Atorvastatin vs Placebo Group	2 years of follow-up	Compare number of subjects with 90% or greater protocol compliance throughout the 2 year follow-up period
Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 2	2 year follow-up	Compare the mean percent change in peripheral blood leukocyte ROCK activity between atorvastatin and placebo groups from baseline to year 2
Percent Change in Dynamic Contrast-enhanced Quantitative Perfusion (DCEQP) Value (Vascular Permeability) in Index Lesion (Lesional DCEQP Change Score)	2 years of follow-up	DCEQP change score is the absolute value of the Percent Change in DCEQP value of the index lesion, presented as a mean value across all participants from baseline to year 1 and year 1 to year 2 follow-up MRIs; DCEQP measures vascular permeability and perfusion, in this case as measured in the index lesion. A higher DCEQP value reflects higher permeability in the lesion.
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 1 follow-up visit; The EQ-VAS is a vertical visual analogue scale that takes values between 100 (best imaginable health) and 0 (worst imaginable health), on which patients provide a global assessment of their health.
Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 1	1 year of follow-up	Compare the mean percent change in peripheral blood leukocyte ROCK activity between atorvastatin and placebo groups from baseline to year 1

Trial Locations

Locations (1)

University of Chicago; 🇺🇸 Chicago, Illinois, United States