Cerebral Cavernous MalformationPhase 1/2AT CASH EPOCNCT02603328
Atorvastatin Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial
A Phase 1/2 study testing Atorvastatin in people with Cerebral Cavernous Malformation, run by University of Chicago at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Cerebral Cavernous Malformation
- What is being tested?
- Atorvastatin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 80 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Jul 2018to 31 Mar 2025
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 18Show fewer
- 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.
- Inability or unwillingness of subject or legal guardian/representative to give written informed consent.
- No documentation of valid healthcare insurance.
- No medical record confirmation of primary care physician.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase I-II Randomized, Placebo-Controlled, Single-Blinded, Single-Site Clinical Trial of Atorvastatin in the Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC)
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.
Read the 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.
- Conditions
- Cerebral Cavernous Malformation
- Being tested
- Atorvastatin, Placebo
- Keywords
- Cerebral cavernous malformation, Statins, MRI, Permeability, Quantitative susceptibility mapping
- Medical subject headings
- Hemangioma, Cavernous, Central Nervous System
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtorvastatinDrug
40-80 mg OD
PlaceboOther
inactive
| Study group | Role | What they receive |
|---|---|---|
| Treatment | Active comparator | Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events. Receives: Drug: Atorvastatin |
| Placebo | Placebo comparator | Identically looking capsules containing no active ingredient Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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)
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.
Measured: 2 years of follow-up
Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit
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.
Measured: 1 year of follow-up
Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit.
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.
Measured: 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.
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.
Measured: 1 year of follow up
Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 2 Follow-up Visit
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.
Measured: 1 year of follow up (from year 1 to year 2)
Compare Rate of Drug Compliance in Atorvastatin vs Placebo Group
Compare number of subjects with 90% or greater protocol compliance throughout the 2 year follow-up period
Measured: 2 years of follow-up
Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 1
Compare the mean percent change in peripheral blood leukocyte ROCK activity between atorvastatin and placebo groups from baseline to year 1
Measured: 1 year of follow-up
Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 2
Compare the mean percent change in peripheral blood leukocyte ROCK activity between atorvastatin and placebo groups from baseline to year 2
Measured: 2 year follow-up
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Nov 2015 (estimated)
- Study start17 Jul 2018
- Primary completion31 Jul 2024
- Study completion31 Mar 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Cerebral Cavernous MalformationStudies of the same condition, open and under way.
- More trials run by University of ChicagoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 80 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Chicago
- Sponsor type
- University, hospital or other
- Collaborators
- Johns Hopkins University
- Responsible party
- Sponsor
- Investigators
- Issam A Awad, MD, Study chair, Director of Neurovascular Surgery University of Chicago Medicine and Biological SciencesDaniel F Hanley, MD, Study chair, Director, Division of Brain Injury Outcomes Service The Johns Hopkins Medical Institutions
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02603328
- Sponsor's protocol ID
- IRB18-0445
- Acronym
- AT CASH EPOC
- Status last verified
- Jul 2025
- First submitted
- 9 Nov 2015
- Last updated
- 22 Aug 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
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 Feb 3;15(3):e46943. doi: 10.1161/JAHA.125.046943. Epub 2026 Jan 29.
PubMed 41608890Alcazar-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. 2026 Jun 1;98(6):1395-1401. doi: 10.1227/neu.0000000000003814. Epub 2025 Oct 21.
PubMed 41117517Awad 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.
PubMed 40120614
Study at a glance
From the registry record, last updated by the sponsor on 22 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I-II Randomized, Placebo-Controlled, Single-Blinded, Single-Site Clinical Trial of Atorvastatin in the Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC)
- ClinicalTrials.gov ID
- NCT02603328
- Acronym / sponsor ID
- AT CASH EPOC / IRB18-0445
- Conditions
- Cerebral Cavernous Malformation
- Keywords
- Cerebral cavernous malformation, Statins, MRI, Permeability, Quantitative susceptibility mapping
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 80 participants (actual)
- Lead sponsor
- University of ChicagoUniversity, hospital or other
- Collaborators
- Johns Hopkins University
- Study start
- 17 Jul 2018 (actual)
- Primary completion
- 31 Jul 2024 (actual)
- Study completion
- 31 Mar 2025 (actual)
- First posted
- 11 Nov 2015 (estimated)
- Results
- Posted 22 Aug 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment | Active comparator | Drug: AtorvastatinAtorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events. |
| Placebo | Placebo comparator | Other: PlaceboIdentically looking capsules containing no active ingredient |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (18 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Atorvastatin40-80 mg OD | Drug | Treatment |
| Placeboinactive | Other | Placebo |
Primary outcome
Percent Change in Mean Lesional QSM (QSM Change Score)
Time frame: 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.
8 secondary outcomes
Percent Change in Dynamic Contrast-enhanced Quantitative Perfusion (DCEQP) Value (Vascular Permeability) in Index Lesion (Lesional DCEQP Change Score)
Time frame: 2 years of follow-up
Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit
Time frame: 1 year of follow-up
Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit.
Time frame: 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.
Time frame: 1 year of follow up
Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 2 Follow-up Visit
Time frame: 1 year of follow up (from year 1 to year 2)
Compare Rate of Drug Compliance in Atorvastatin vs Placebo Group
Time frame: 2 years of follow-up
Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 1
Time frame: 1 year of follow-up
Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 2
Time frame: 2 year follow-up
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Aug 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41608890Ali 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 Feb 3;15(3):e46943. doi: 10.1161/JAHA.125.046943. Epub 2026 Jan 29.
- Derived from this study: PubMed 41117517Alcazar-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. 2026 Jun 1;98(6):1395-1401. doi: 10.1227/neu.0000000000003814. Epub 2025 Oct 21.
- Derived from this study: PubMed 40120614Awad 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Issam A Awad, MD study chair
Director of Neurovascular Surgery University of Chicago Medicine and Biological Sciences
Daniel F Hanley, MD study chair
Director, Division of Brain Injury Outcomes Service The Johns Hopkins Medical Institutions
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Atorvastatin in people with Cerebral Cavernous Malformation, run by University of Chicago at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Aug 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent Change in Mean Lesional QSM (QSM Change Score) (time frame: 2 years of follow-up). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02603328, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Aug 2025.