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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Cerebral Cavernous Malformation

Intervention / Treatment
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* Drug: Atorvastatin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment<br>Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events. | Drug: Atorvastatin<br>* 40-80 mg OD<br>|
| Placebo Comparator: Placebo<br>Identically looking capsules containing no active ingredient | Other: Placebo<br>* inactive<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mean percent change in lesional QSM per year (called the change score) | Each patient contributes two outcome measurements (at year 1 and year 2) based on intention-to-treat. Evaluation of the intervention on this outcome will be performed as a time-averaged difference between two arms using a repeated measures analysis implemented as an unadjusted linear mixed model. Patients with outcome measurements in both periods will be included in the initial intention-to-treat analysis. In cases with multiple lesions, only QSM measurements in the lesion with initial hemorrhage (index lesion) shall be considered for the primary outcome assessment. | End of study (24-month) MRI scan | 
| Percent QSM change per year | A secondary analysis of the percent QSM change per year shall be conducted per treatment rendered for all patients with at least one annual epoch of measurements. | End of study (24-month) MRI scan | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in DCEQP vascular permeability measurements in the index lesion and in brain (white matter far from lesion) | Changes in DCEQP vascular permeability measurements in the index lesion and in brain (white matter far from lesion) | End of study (24-month) MRI scan | 
| Rates of QSM and DCEQP biomarker events | Rates of QSM and DCEQP biomarker events, representing increases in index lesional QSM or DCEQP above previously articulated biomarker thresholds; rates of clinically overt hemorrhages in the index lesion per adjudicated criteria; and rates of lesional expansion, defined as an increase in maximum lesion diameter on T2 sequences by 2 or more mm | End of study (24-month) MRI scan | 
| Adverse event rates |  | End of study (24-month) MRI scan | 
| Serious adverse event rates |  | End of study (24-month) MRI scan | 
| Drug compliance by tracking daily medication bottle opening | We plan to use a compliance device that would record every time the bottle was opened, thus allowing the study team to track compliance with the protocol and help keep subjects accountable. | End of study (24-month) MRI scan | 
| Changes in functional outcome as measured using the modified Rankin scale which measures the degree of disability or dependence in patients with neurological disability. | Using the modified Rankin scale, we will track subjects' functional outcome changes over the course of the trial. | End of study (24-month) MRI scan | 
| Impact of sex on primary and secondary outcomes (pre specified subgroup analyses) |  | End of study (24-month) MRI scan | 
| Impact of genotype on primary and secondary outcomes (pre specified subgroup analyses) |  | End of study (24-month) MRI scan | 
| Impact of lesion location on primary and secondary outcomes (pre specified subgroup analyses) |  | End of study (24-month) MRI scan | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MRI, Statins, Cerebral cavernous malformation, Permeability, Quantitative susceptibility mapping