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

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ClinicalTrials.gov Identifier: NCT02603328
Recruitment Status : Recruiting
First Posted : November 11, 2015
Last Update Posted : October 4, 2018
Sponsor:
Collaborator:
Johns Hopkins University
Information provided by (Responsible Party):
University of Chicago

November 9, 2015
November 11, 2015
October 4, 2018
July 17, 2018
August 2022   (Final data collection date for primary outcome measure)
  • mean percent change in lesional QSM per year (called the change score) [ Time Frame: End of study (24-month) MRI scan ]
    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 [ Time Frame: End of study (24-month) MRI scan ]
    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.
lesional iron concentration [ Time Frame: End of study (36-month) MRI scan ]
Lesional iron load measured by QSM protocol during the end of trial visit.
Complete list of historical versions of study NCT02603328 on ClinicalTrials.gov Archive Site
  • 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 ]
    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 [ Time Frame: End of study (24-month) MRI scan ]
    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 [ Time Frame: End of study (24-month) MRI scan ]
  • Serious adverse event rates [ Time Frame: End of study (24-month) MRI scan ]
  • Drug compliance by tracking daily medication bottle opening [ Time Frame: End of study (24-month) MRI scan ]
    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. [ Time Frame: End of study (24-month) MRI scan ]
    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) [ Time Frame: End of study (24-month) MRI scan ]
  • Impact of genotype on primary and secondary outcomes (pre specified subgroup analyses) [ Time Frame: End of study (24-month) MRI scan ]
  • Impact of lesion location on primary and secondary outcomes (pre specified subgroup analyses) [ Time Frame: End of study (24-month) MRI scan ]
Rebleeding Rate [ Time Frame: Three years ]
Number of recurrent hemorrhagic events on Atorvastatin Vs Placebo
Not Provided
Not Provided
 
Atorvastatin Treatment of Cavernous Angiomas With Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial
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.
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.
Interventional
Phase 1
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Cerebral Cavernous Malformation
  • Drug: Atorvastatin
    40-80 mg OD
  • Other: Placebo
    inactive
  • Active Comparator: Treatment
    Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events.
    Intervention: Drug: Atorvastatin
  • Placebo Comparator: Placebo
    Identically looking capsules containing no active ingredient
    Intervention: Other: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
80
60
August 2022
August 2022   (Final data collection date for primary outcome measure)

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, 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.
Sexes Eligible for Study: All
18 Years to 80 Years   (Adult, Older Adult)
No
Contact: Kristina Piedad, BSN, RN 7733269839 ATCASH@uchospitals.edu
Contact: Agnieszka Stadnik, MS, CCRP 7733269839 ATCASH@uchospitals.edu
United States
 
 
NCT02603328
IRB16-0024
Yes
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
Not Provided
University of Chicago
University of Chicago
Johns Hopkins University
Study Chair: Issam A Awad, MD Director of Neurovascular Surgery University of Chicago Medicine and Biological Sciences
Study Chair: Daniel F Hanley, MD Director, Division of Brain Injury Outcomes Service The Johns Hopkins Medical Institutions
University of Chicago
October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP