Atorvastatin Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial (AT CASH EPOC)
Primary Purpose
Cerebral Cavernous Malformation
Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Atorvastatin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Cerebral Cavernous Malformation focused on measuring Cerebral cavernous malformation, Statins, MRI, Permeability, Quantitative susceptibility mapping
Eligibility Criteria
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.
Sites / Locations
- University of Chicago
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Treatment
Placebo
Arm Description
Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events.
Identically looking capsules containing no active ingredient
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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)
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
Adverse event rates
Serious adverse event rates
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.
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.
Impact of sex on primary and secondary outcomes (pre specified subgroup analyses)
Impact of genotype on primary and secondary outcomes (pre specified subgroup analyses)
Impact of lesion location on primary and secondary outcomes (pre specified subgroup analyses)
Full Information
NCT ID
NCT02603328
First Posted
November 9, 2015
Last Updated
October 4, 2023
Sponsor
University of Chicago
Collaborators
Johns Hopkins University
1. Study Identification
Unique Protocol Identification Number
NCT02603328
Brief Title
Atorvastatin Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial
Acronym
AT CASH EPOC
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
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 17, 2018 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
June 30, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Chicago
Collaborators
Johns Hopkins University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cerebral Cavernous Malformation
Keywords
Cerebral cavernous malformation, Statins, MRI, Permeability, Quantitative susceptibility mapping
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
80 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment
Arm Type
Active Comparator
Arm Description
Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Identically looking capsules containing no active ingredient
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Intervention Description
40-80 mg OD
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
inactive
Primary Outcome Measure Information:
Title
mean percent change in lesional QSM per year (called the change score)
Description
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.
Time Frame
End of study (24-month) MRI scan
Title
Percent QSM change per year
Description
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.
Time Frame
End of study (24-month) MRI scan
Secondary Outcome Measure Information:
Title
Changes in DCEQP vascular permeability measurements in the index lesion and in brain (white matter far from lesion)
Description
Changes in DCEQP vascular permeability measurements in the index lesion and in brain (white matter far from lesion)
Time Frame
End of study (24-month) MRI scan
Title
Rates of QSM and DCEQP biomarker events
Description
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
Time Frame
End of study (24-month) MRI scan
Title
Adverse event rates
Time Frame
End of study (24-month) MRI scan
Title
Serious adverse event rates
Time Frame
End of study (24-month) MRI scan
Title
Drug compliance by tracking daily medication bottle opening
Description
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.
Time Frame
End of study (24-month) MRI scan
Title
Changes in functional outcome as measured using the modified Rankin scale which measures the degree of disability or dependence in patients with neurological disability.
Description
Using the modified Rankin scale, we will track subjects' functional outcome changes over the course of the trial.
Time Frame
End of study (24-month) MRI scan
Title
Impact of sex on primary and secondary outcomes (pre specified subgroup analyses)
Time Frame
End of study (24-month) MRI scan
Title
Impact of genotype on primary and secondary outcomes (pre specified subgroup analyses)
Time Frame
End of study (24-month) MRI scan
Title
Impact of lesion location on primary and secondary outcomes (pre specified subgroup analyses)
Time Frame
End of study (24-month) MRI scan
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Issam A Awad, MD
Organizational Affiliation
Director of Neurovascular Surgery University of Chicago Medicine and Biological Sciences
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Daniel F Hanley, MD
Organizational Affiliation
Director, Division of Brain Injury Outcomes Service The Johns Hopkins Medical Institutions
Official's Role
Study Chair
Facility Information:
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Atorvastatin Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial
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