Clinical trial NCT02603328: Atorvastatin Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Cerebral Cavernous Malformation
Keywords: Cerebral cavernous malformation
Statins
MRI
Permeability
Quantitative susceptibility mapping
Lead sponsor: University of Chicago
Sponsor class: OTHER
Collaborators: name: Johns Hopkins University
First posted: 2015-11-11
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: mean percent change in lesional QSM per year (called the change score)
timeFrame: End of study (24-month) MRI scan
measure: Percent QSM change per year
timeFrame: End of study (24-month) MRI scan
Secondary outcomes:
measure: Changes in DCEQP vascular permeability measurements in the index lesion and in brain (white matter far from lesion)
timeFrame: End of study (24-month) MRI scan
measure: Rates of QSM and DCEQP biomarker events
timeFrame: End of study (24-month) MRI scan
measure: Adverse event rates
timeFrame: End of study (24-month) MRI scan
measure: Serious adverse event rates
timeFrame: End of study (24-month) MRI scan
measure: Drug compliance by tracking daily medication log in study app
timeFrame: End of study (24-month) MRI scan
measure: Changes in functional outcome as measured using the modified Rankin scale which measures the degree of disability or dependence in patients with neurological disability.
timeFrame: End of study (24-month) MRI scan
measure: Impact of sex on primary and secondary outcomes (pre specified subgroup analyses)
timeFrame: End of study (24-month) MRI scan
measure: Impact of genotype on primary and secondary outcomes (pre specified subgroup analyses)
timeFrame: End of study (24-month) MRI scan
measure: Impact of lesion location on primary and secondary outcomes (pre specified subgroup analyses)
timeFrame: End of study (24-month) MRI scan
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
Study officials:
affiliation: Director of Neurovascular Surgery University of Chicago Medicine and Biological Sciences
name: Issam A Awad, MD
role: STUDY_CHAIR
affiliation: Director, Division of Brain Injury Outcomes Service The Johns Hopkins Medical Institutions
name: Daniel F Hanley, MD
role: STUDY_CHAIR
References: