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| Name | Class |
|---|---|
| Johns Hopkins University | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment | Active Comparator | Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events. |
|
| Placebo | Placebo Comparator | Identically looking capsules containing no active ingredient |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Atorvastatin | Drug | 40-80 mg OD |
| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 2 years of follow-up |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Chicago | Chicago | Illinois | 60637 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41608890 | Derived | Ali B, Shenkar R, Lee J, Alcazar-Felix RJ, Thompson RE, Stadnik A, Sader G, Polster SP, Flemming KD, Liao JK, Sorrentino M, Girard R, Hanley DF, Awad IA. Recurrent Symptomatic Hemorrhage in Cerebral Cavernous Malformations After Discontinuation of Atorvastatin or Placebo. J Am Heart Assoc. 2026 Feb 3;15(3):e46943. doi: 10.1161/JAHA.125.046943. Epub 2026 Jan 29. | |
| 41117517 |
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80 participants were randomized and followed for 2 years and all results are provided only for these participants.
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment 80mg | Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events. Atorvastatin: 40-80 mg OD |
| FG001 | Placebo | Identically looking capsules containing no active ingredient Placebo: inactive |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Baseline characteristics of intention to treat cohort
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| ID | Title | Description |
|---|---|---|
| BG000 | Treatment | Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events. Atorvastatin: 40-80 mg OD |
| BG001 | Placebo | Identically looking capsules containing no active ingredient Placebo: inactive |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Standard Error | absolute value of percent change | 2 years of follow-up |
|
2 years
Subjects were contacted every 3 months to inquire about adverse events, initially by phone and later by protocol mandated self-reporting via the study phone app.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Atorvastatin 80mg | Atorvastatin 80mg OD (optimal dose). Treatment dose will be de-escalated to 40mg based on reported adverse events. Atorvastatin: 80 mg OD |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Elevated creatine kinase (CK) | Musculoskeletal and connective tissue disorders | Systematic Assessment | One subject had elevated creatine kinase on laboratory tests, without overt symptoms. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hepatitis, type unknown | Infections and infestations | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Agnieszka Stadnik | University of Chicago, Medicine and Biological Sciences Division | 773-702-8996 | astadnik@bsd.uchicago.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 18, 2023 | Jun 10, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D020786 | Hemangioma, Cavernous, Central Nervous System |
| ID | Term |
|---|---|
| D006392 | Hemangioma, Cavernous |
| D006391 | Hemangioma |
| D009383 | Neoplasms, Vascular Tissue |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D000069059 | Atorvastatin |
| ID | Term |
|---|---|
| D011758 | Pyrroles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Other |
inactive |
|
| 2 years of follow-up |
| 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. | 1 year of follow-up |
| 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. | 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 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. | 1 year of follow up |
| 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. | 1 year of follow up (from year 1 to year 2) |
| 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 | 2 years of follow-up |
| 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 | 1 year of follow-up |
| 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 | 2 year follow-up |
| Alcazar-Felix RJ, Thompson RE, Stadnik A, Kinkade S, Sader G, Jhaveri A, Lee J, Iqbal J, Polster SP, Shenkar R, Flemming KD, Girard R, Carroll TJ, Hanley DF, Awad IA. Relevance of Lesion Volume as an Outcome in Cerebral Cavernous Malformation Drug Trial: Exploratory Analyses in Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept. Neurosurgery. 2026 Jun 1;98(6):1395-1401. doi: 10.1227/neu.0000000000003814. Epub 2025 Oct 21. |
| 40120614 | Derived | Awad IA, Alcazar-Felix RJ, Stadnik A, Kinkade S, Jhaveri A, Lee J, Hage S, Iqbal J, Polster SP, Shenkar R, Treine K, McBee N, Ostapkovich N, Lane K, Liao JK, Sorrentino M, Lee C, Flemming KD, Girard R, Carroll TJ, Thompson RE, Hanley DF. Safety and efficacy of atorvastatin for rebleeding in cerebral cavernous malformations (AT CASH EPOC): a phase 1/2a, randomised placebo-controlled trial. Lancet Neurol. 2025 Apr;24(4):295-304. doi: 10.1016/S1474-4422(25)00036-5. |
| BG002 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Familial cavernous malformation syndrome | Count of Participants | Participants |
|
| MRI characteristics - number of lesions | Median | Inter-Quartile Range | Lesions |
|
| Location of index CCM lesion with symptomatic hemorrhage | Number | participants |
|
| Time from most recent symptomatic hemorrhage to enrollment, days | Median | Inter-Quartile Range | Days |
|
| Number of symptomatic hemorrhages before enrollment | Median | Inter-Quartile Range | Number of symptomatic hemorrhages |
|
| Modified Rankin Scale score | The mRS (modified Rankin Score) 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. | Number | participants |
|
| European quality of life index Visual Analog Scale | The EQ-VAS (European Quality of Life Visual Analogue Scale) 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 (patients select how they perceive their current health on a 0 to 100 scale). | Mean | Standard Deviation | units on a scale |
|
| MRI characteristics - size of lesion on T2, mm | Median | Inter-Quartile Range | Size on T2, mm |
|
| OG001 |
| Placebo |
Identically looking capsules containing no active ingredient Placebo: inactive |
|
|
| 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. | Posted | Mean | Standard Error | percent change | 2 years of follow-up |
|
|
|
| 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. | Posted | Count of Participants | Participants | 1 year of follow-up |
|
|
|
| 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. | Posted | Count of Participants | Participants | 1 year of follow-up (from year 1 to year 2) |
|
|
|
| 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. | Posted | Mean | Standard Deviation | score on a scale | 1 year of follow up |
|
|
|
| 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. | Posted | Mean | Standard Deviation | score on a scale | 1 year of follow up (from year 1 to year 2) |
|
|
|
| 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 | Posted | Count of Participants | Participants | 2 years of follow-up |
|
|
|
| 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 | Posted | Mean | Standard Deviation | percent change | 1 year of follow-up |
|
|
|
| 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 | Posted | Mean | Standard Deviation | percent change | 2 year follow-up |
|
|
|
| 0 |
| 40 |
| 1 |
| 40 |
| 27 |
| 40 |
| EG001 | Atorvastatin 40mg | Atorvastatin 40mg. Treatment dose was de-escalated to 40mg based on reported adverse events. Atorvastatin: 40 mg | 0 | 1 | 1 | 1 | 1 | 1 |
| EG002 | Placebo | Identically looking capsules containing no active ingredient Placebo: inactive | 0 | 39 | 0 | 39 | 21 | 39 |
|
| Fall | Injury, poisoning and procedural complications | Systematic Assessment | One subject was hospitalized after a fall, determined to have a questionable relationship to the study drug. |
|
| Bladder infection | Infections and infestations | Systematic Assessment |
|
| COVID | Infections and infestations | Systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | Systematic Assessment |
|
| Bruising | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Fecal incontinence | Gastrointestinal disorders | Systematic Assessment |
|
| Gastroesophogeal reflux | Gastrointestinal disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Stomach pain | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Fatigue | General disorders | Systematic Assessment |
|
| Irritability | General disorders | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | Systematic Assessment |
|
| Nystagmus | Nervous system disorders | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Ataxia | Nervous system disorders | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Cardiac disorders, other | Cardiac disorders | Systematic Assessment |
|
| Chest pain - cardiac | Cardiac disorders | Systematic Assessment |
|
| Confusion | Psychiatric disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Dyspareunia | Reproductive system and breast disorders | Systematic Assessment |
|
| Elevated PSA | Renal and urinary disorders | Systematic Assessment |
|
| Eye disorder, other | Eye disorders | Systematic Assessment |
|
| Facial muscle weakness | Nervous system disorders | Systematic Assessment |
|
| Generalized muscle weakness | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
|
| Hypertension | Vascular disorders | Systematic Assessment |
|
| Irregular menstruation | Reproductive system and breast disorders | Systematic Assessment |
|
| Joint range of motion decreased - foot | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Mitral Valve disease | Cardiac disorders | Systematic Assessment |
|
| Muscle weakness lower limb | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Muscle weakness right-sided | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Musculoskeletal and connective tissue disorder - other | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Myositis | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Paresthesia | Nervous system disorders | Systematic Assessment |
|
| Rash maculopapular | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Renal calculi | Renal and urinary disorders | Systematic Assessment |
|
| Seizure | Nervous system disorders | Systematic Assessment |
|
| Shingles | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Skin hyperpigmentation | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Surgical and medical procedures - other | Surgical and medical procedures | Systematic Assessment |
|
| Tremor | Nervous system disorders | Systematic Assessment |
|
| Urine discoloration | Renal and urinary disorders | Systematic Assessment |
|
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| D009369 | Neoplasms |
| D000096826 | Cavernous Sinus Syndromes |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D020785 | Central Nervous System Vascular Malformations |
| D009421 | Nervous System Malformations |
| D054079 | Vascular Malformations |
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D020141 | Hemostatic Disorders |
| D014652 | Vascular Diseases |
| D006474 | Hemorrhagic Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006538 |
| Heptanoic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| mRS 2-3 |
|
| mRS 4 |
|
| mRS 5-6 |
|
| mRS 2-3 |
|
| mRS 4 |
|
| mRS 5-6 |
|