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

This study is not yet open for participant recruitment.
Verified September 2017 by University of Chicago
Sponsor:
ClinicalTrials.gov Identifier:
NCT02603328
First Posted: November 11, 2015
Last Update Posted: September 22, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Johns Hopkins University
Information provided by (Responsible Party):
University of Chicago
  Purpose
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.

Condition Intervention Phase
Cerebral Cavernous Malformation Drug: Atorvastatin Other: Placebo Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by University of Chicago:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 80
Anticipated Study Start Date: July 2018
Estimated Study Completion Date: June 2022
Estimated Primary Completion Date: June 2022 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Treatment
Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events.
Drug: Atorvastatin
40-80 mg OD
Placebo Comparator: Placebo
Identically looking capsules containing no active ingredient
Other: Placebo
inactive

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

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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, 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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02603328


Contacts
Contact: Agnieszka Stadnik, MS, CCRP 773-702-8996 astadnik@surgery.bsd.uchicago.edu

Sponsors and Collaborators
University of Chicago
Johns Hopkins University
Investigators
Study Chair: Issam A Awad, MD, MSc, FACS, MA (hon) 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
  More Information

Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT02603328     History of Changes
Other Study ID Numbers: IRB16-0024
First Submitted: November 9, 2015
First Posted: November 11, 2015
Last Update Posted: September 22, 2017
Last Verified: September 2017

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

Keywords provided by University of Chicago:
Cerebral cavernous malformation
Statins
MRI
Permeability
Quantitative susceptibility mapping

Additional relevant MeSH terms:
Congenital Abnormalities
Hemangioma, Cavernous, Central Nervous System
Hemangioma, Cavernous
Central Nervous System Vascular Malformations
Nervous System Malformations
Vascular Malformations
Cardiovascular Abnormalities
Hemorrhage
Pathologic Processes
Hemangioma
Neoplasms, Vascular Tissue
Neoplasms by Histologic Type
Neoplasms
Nervous System Diseases
Cardiovascular Diseases
Hemostatic Disorders
Vascular Diseases
Hemorrhagic Disorders
Hematologic Diseases
Atorvastatin Calcium
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors