Cerebral Cavernous Malformation
Conditions
Keywords
Cerebral cavernous malformation, Statins, MRI, Permeability, Quantitative susceptibility mapping
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.
Interventions
DRUGAtorvastatin
40-80 mg OD
OTHERPlacebo
inactive
Sponsors
Johns Hopkins University
University of Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Mean Lesional QSM (QSM Change Score) | 2 years of follow-up | QSM change score is the Percentage Change in mean lesional iron deposition per year (QSM score) according to assigned treatment (modified intention-to-treat cohort), presented as a mean value across all participants from baseline to year 1 and year 1 to year 2 follow-up MRIs. Quantitative susceptibility mapping (QSM) is a noninvasive MRI technique that assesses iron content by quantifying the magnetic susceptibility of local tissues. A higher QSM value corresponds to a larger amount of iron in the lesion, which means more blood is present in the lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | 1 year of follow-up | Compare the changes in modified Rankin Score between atorvastatin and placebo groups at the year 1 follow-up visit. The mRS is a simple global measure of functional disability. Scores range from 0 (no symptoms) to 6 (death). An mRS score of 0 to 1 is considered a minimal clinical disability, and 0 to 2 is independent. |
| Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | 1 year of follow-up (from year 1 to year 2) | Compare the changes in modified Rankin Score between atorvastatin and placebo groups at the year 2 follow-up visit (change between mRS score at year 1 follow up visit and year 2 follow up visit). The mRS is a simple global measure of functional disability. Scores range from 0 (no symptoms) to 6 (death). An mRS score of 0 to 1 is considered a minimal clinical disability, and 0 to 2 is independent. |
| Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 1 Follow-up Visit. | 1 year of follow up | Mean score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the year 1 follow-up visit The EQ-VAS is a vertical visual analogue scale that takes values between 100 (best imaginable health) and 0 (worst imaginable health), on which patients provide a global assessment of their health. |
| Percent Change in Dynamic Contrast-enhanced Quantitative Perfusion (DCEQP) Value (Vascular Permeability) in Index Lesion (Lesional DCEQP Change Score) | 2 years of follow-up | DCEQP change score is the absolute value of the Percent Change in DCEQP value of the index lesion, presented as a mean value across all participants from baseline to year 1 and year 1 to year 2 follow-up MRIs DCEQP measures vascular permeability and perfusion, in this case as measured in the index lesion. A higher DCEQP value reflects higher permeability in the lesion. |
| Compare Rate of Drug Compliance in Atorvastatin vs Placebo Group | 2 years of follow-up | Compare number of subjects with 90% or greater protocol compliance throughout the 2 year follow-up period |
| Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 1 | 1 year of follow-up | Compare the mean percent change in peripheral blood leukocyte ROCK activity between atorvastatin and placebo groups from baseline to year 1 |
| Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 2 | 2 year follow-up | Compare the mean percent change in peripheral blood leukocyte ROCK activity between atorvastatin and placebo groups from baseline to year 2 |
| Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 2 Follow-up Visit | 1 year of follow up (from year 1 to year 2) | Mean score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the year 2 follow-up visit The EQ-VAS is a vertical visual analogue scale that takes values between 100 (best imaginable health) and 0 (worst imaginable health), on which patients provide a global assessment of their health. |
Countries
United States
Participant flow
Recruitment details
80 participants were randomized and followed for 2 years and all results are provided only for these participants.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events.
Atorvastatin: 40-80 mg OD | 41 |
| Placebo Identically looking capsules containing no active ingredient
Placebo: inactive | 39 |
| Total | 80 |
Baseline characteristics
| Characteristic | Total | Placebo | Treatment |
|---|---|---|---|
| Age, Continuous | 41 Years | 41 Years | 39 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 7 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants | 31 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants |
| European quality of life index Visual Analog Scale | 76.4 units on a scale STANDARD_DEVIATION 14.7 | 78.28 units on a scale STANDARD_DEVIATION 12.67 | 74.59 units on a scale STANDARD_DEVIATION 16.29 |
| Familial cavernous malformation syndrome | 29 Participants | 11 Participants | 18 Participants |
| Location of index CCM lesion with symptomatic hemorrhage Brainstem | 44 participants | 21 participants | 23 participants |
| Location of index CCM lesion with symptomatic hemorrhage Cerebellum | 4 participants | 2 participants | 2 participants |
| Location of index CCM lesion with symptomatic hemorrhage Frontal Lobe | 5 participants | 2 participants | 3 participants |
| Location of index CCM lesion with symptomatic hemorrhage Occipital Lobe | 4 participants | 3 participants | 1 participants |
| Location of index CCM lesion with symptomatic hemorrhage Other location | 5 participants | 1 participants | 4 participants |
| Location of index CCM lesion with symptomatic hemorrhage Parietal Lobe | 3 participants | 2 participants | 1 participants |
| Location of index CCM lesion with symptomatic hemorrhage Temporal Lobe | 8 participants | 6 participants | 2 participants |
| Location of index CCM lesion with symptomatic hemorrhage Thalamus | 7 participants | 2 participants | 5 participants |
| Modified Rankin Scale score 0 | 14 participants | 8 participants | 6 participants |
| Modified Rankin Scale score 1 | 43 participants | 25 participants | 18 participants |
| Modified Rankin Scale score 2-3 | 23 participants | 6 participants | 17 participants |
| Modified Rankin Scale score 4 | 0 participants | 0 participants | 0 participants |
| Modified Rankin Scale score 5-6 | 0 participants | 0 participants | 0 participants |
| MRI characteristics - number of lesions Number of lesions on susceptibility weighted imaging in familial cases | 1 Lesions | 1 Lesions | 1 Lesions |
| MRI characteristics - number of lesions Number of lesions on T2 ≥4mm in familial cases | 1 Lesions | 1 Lesions | 1 Lesions |
| MRI characteristics - size of lesion on T2, mm | 14.80 Size on T2, mm | 16 Size on T2, mm | 14.70 Size on T2, mm |
| Number of symptomatic hemorrhages before enrollment | 1 Number of symptomatic hemorrhages | 1 Number of symptomatic hemorrhages | 1 Number of symptomatic hemorrhages |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 63 Participants | 31 Participants | 32 Participants |
| Sex: Female, Male Female | 51 Participants | 25 Participants | 26 Participants |
| Sex: Female, Male Male | 29 Participants | 14 Participants | 15 Participants |
| Time from most recent symptomatic hemorrhage to enrollment, days | 104 Days | 104 Days | 103 Days |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 1 | 0 / 39 |
| other Total, other adverse events | 27 / 40 | 1 / 1 | 21 / 39 |
| serious Total, serious adverse events | 1 / 40 | 1 / 1 | 0 / 39 |
Outcome results
Primary
Percent Change in Mean Lesional QSM (QSM Change Score)
QSM change score is the Percentage Change in mean lesional iron deposition per year (QSM score) according to assigned treatment (modified intention-to-treat cohort), presented as a mean value across all participants from baseline to year 1 and year 1 to year 2 follow-up MRIs. Quantitative susceptibility mapping (QSM) is a noninvasive MRI technique that assesses iron content by quantifying the magnetic susceptibility of local tissues. A higher QSM value corresponds to a larger amount of iron in the lesion, which means more blood is present in the lesion.
Time frame: 2 years of follow-up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Percent Change in Mean Lesional QSM (QSM Change Score) | QSM change score by assigned treatment; year 2 minus year 1 | 15.18 absolute value of percent change | Standard Error 10.8 |
| Treatment | Percent Change in Mean Lesional QSM (QSM Change Score) | QSM change score by assigned treatment; year 1 minus baseline | 7.35 absolute value of percent change | Standard Error 9.77 |
| Placebo | Percent Change in Mean Lesional QSM (QSM Change Score) | QSM change score by assigned treatment; year 2 minus year 1 | 26.80 absolute value of percent change | Standard Error 11.22 |
| Placebo | Percent Change in Mean Lesional QSM (QSM Change Score) | QSM change score by assigned treatment; year 1 minus baseline | 0.24 absolute value of percent change | Standard Error 10.08 |
Secondary
Compare Rate of Drug Compliance in Atorvastatin vs Placebo Group
Compare number of subjects with 90% or greater protocol compliance throughout the 2 year follow-up period
Time frame: 2 years of follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment | Compare Rate of Drug Compliance in Atorvastatin vs Placebo Group | 33 Participants |
| Placebo | Compare Rate of Drug Compliance in Atorvastatin vs Placebo Group | 31 Participants |
Secondary
Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit
Compare the changes in modified Rankin Score between atorvastatin and placebo groups at the year 1 follow-up visit. The mRS is a simple global measure of functional disability. Scores range from 0 (no symptoms) to 6 (death). An mRS score of 0 to 1 is considered a minimal clinical disability, and 0 to 2 is independent.
Time frame: 1 year of follow-up
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 5-6 | 0 Participants |
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 0 | 2 Participants |
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 1 | 25 Participants |
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 2-3 | 8 Participants |
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 4 | 0 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 4 | 0 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 2-3 | 8 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 0 | 8 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 5-6 | 0 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 1 Follow-up Visit | mRS 1 | 20 Participants |
Secondary
Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit.
Compare the changes in modified Rankin Score between atorvastatin and placebo groups at the year 2 follow-up visit (change between mRS score at year 1 follow up visit and year 2 follow up visit). The mRS is a simple global measure of functional disability. Scores range from 0 (no symptoms) to 6 (death). An mRS score of 0 to 1 is considered a minimal clinical disability, and 0 to 2 is independent.
Time frame: 1 year of follow-up (from year 1 to year 2)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 1 | 17 Participants |
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 4 | 1 Participants |
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 2-3 | 7 Participants |
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 5-6 | 0 Participants |
| Treatment | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 0 | 6 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 5-6 | 0 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 0 | 12 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 1 | 12 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 2-3 | 7 Participants |
| Placebo | Compare the Changes in Modified Rankin Score Between Atorvastatin and Placebo Groups at the Year 2 Follow-up Visit. | mRS 4 | 0 Participants |
Secondary
Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 1
Compare the mean percent change in peripheral blood leukocyte ROCK activity between atorvastatin and placebo groups from baseline to year 1
Time frame: 1 year of follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 1 | 32.68 percent change | Standard Deviation 75.72 |
| Placebo | Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 1 | 22.73 percent change | Standard Deviation 80.21 |
Secondary
Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 2
Compare the mean percent change in peripheral blood leukocyte ROCK activity between atorvastatin and placebo groups from baseline to year 2
Time frame: 2 year follow-up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 2 | 68.17 percent change | Standard Deviation 101.2 |
| Placebo | Mean Percent Change in Rho-associated Protein Kinase (ROCK) Activity in Peripheral Blood Leukocytes From Baseline to Year 2 | 55.62 percent change | Standard Deviation 95.22 |
Secondary
Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 1 Follow-up Visit.
Mean score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the year 1 follow-up visit The EQ-VAS is a vertical visual analogue scale that takes values between 100 (best imaginable health) and 0 (worst imaginable health), on which patients provide a global assessment of their health.
Time frame: 1 year of follow up
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 1 Follow-up Visit. | 78.3 score on a scale | Standard Deviation 17.5 |
| Placebo | Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 1 Follow-up Visit. | 78.1 score on a scale | Standard Deviation 17.1 |
Secondary
Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 2 Follow-up Visit
Mean score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the year 2 follow-up visit The EQ-VAS is a vertical visual analogue scale that takes values between 100 (best imaginable health) and 0 (worst imaginable health), on which patients provide a global assessment of their health.
Time frame: 1 year of follow up (from year 1 to year 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment | Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 2 Follow-up Visit | 80.1 score on a scale | Standard Deviation 16 |
| Placebo | Mean Score of European Quality of Life Visual Analogue Scale (EQ-VAS) at the Year 2 Follow-up Visit | 80.5 score on a scale | Standard Deviation 12 |
Secondary
Percent Change in Dynamic Contrast-enhanced Quantitative Perfusion (DCEQP) Value (Vascular Permeability) in Index Lesion (Lesional DCEQP Change Score)
DCEQP change score is the absolute value of the Percent Change in DCEQP value of the index lesion, presented as a mean value across all participants from baseline to year 1 and year 1 to year 2 follow-up MRIs DCEQP measures vascular permeability and perfusion, in this case as measured in the index lesion. A higher DCEQP value reflects higher permeability in the lesion.
Time frame: 2 years of follow-up
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment | Percent Change in Dynamic Contrast-enhanced Quantitative Perfusion (DCEQP) Value (Vascular Permeability) in Index Lesion (Lesional DCEQP Change Score) | Mean lesional DCEQP percent change by assigned treatment; year one minus baseline | 103.40 percent change | Standard Error 40.64 |
| Treatment | Percent Change in Dynamic Contrast-enhanced Quantitative Perfusion (DCEQP) Value (Vascular Permeability) in Index Lesion (Lesional DCEQP Change Score) | Mean lesional DCEQP percent change by assigned treatment; year two minus year one | 124.52 percent change | Standard Error 85.15 |
| Placebo | Percent Change in Dynamic Contrast-enhanced Quantitative Perfusion (DCEQP) Value (Vascular Permeability) in Index Lesion (Lesional DCEQP Change Score) | Mean lesional DCEQP percent change by assigned treatment; year one minus baseline | 35.69 percent change | Standard Error 50.59 |
| Placebo | Percent Change in Dynamic Contrast-enhanced Quantitative Perfusion (DCEQP) Value (Vascular Permeability) in Index Lesion (Lesional DCEQP Change Score) | Mean lesional DCEQP percent change by assigned treatment; year two minus year one | 124.82 percent change | Standard Error 88.92 |