Effect of ATorvastatin On Chronic subdural Hematoma (ATOCH): a study protocol for a randomized controlled trial

Background Chronic subdural hematoma (CSDH) is a common disease that is more prevalent in older people. Surgical intervention is a safe treatment of choice. However, the recurrence rate is relatively high and the outcome is not always satisfactory among surgically treated patients. It is believed that aberrant angiogenesis and intracapsular inflammation contribute to the development of CSDH. Atorvastatin is reported to promote angiogenesis and suppress inflammation. We have recently shown that atorvastatin is effective to non-surgically reduce and eliminate CSDH with minimal side effects. Here, we report a clinical research trial protocol that is designed to evaluate the therapeutic effects of atorvastatin on CSDH. Methods/Design We have designed a multi-center, randomized, placebo-controlled, double blind clinical trial for evaluating the efficacy of oral atorvastatin in reducing CSDH. We have so far recruited 96 patients with CT-confirmed or MRI-confirmed CSDHs from 16 medical centers in China. These patients were originally recruited for the Oriental Neurosurgical Evidence-based Study Team (ONET) study. After informed consent is provided, patients are randomized to receive either atorvastatin (oral 20 mg/night for 8 weeks) or placebo (dextrin for 8 weeks); and followed for 16 weeks after the treatment. The primary outcome is the change in hematoma volume at the end of 8-week treatment. Secondary outcomes include: changes in 1) the hematoma volume at the 4th, 12th, and 24th weeks; 2) Markwalder’s Grading Scale and Glasgow Coma Scale (MGS-GCS); 3) Glasgow Outcome Score (GOS) and 4) Activities of Daily Life – the Barthel Index scale (ADL-BI). Safety will be assessed during the study by monitoring adverse events, laboratory tests, electrocardiography (ECG), measurements of vital signs (temperature, pulse, and blood pressure) and body weight. Discussion Results of this trial will provide critical information regarding whether atorvastatin is an effective and safe alternative to surgical treatment of CSDH. Trial registration ClinicalTrials.gov Identifier – NCT02024373 The date of trial registration: 7 August 2013 Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-1045-y) contains supplementary material, which is available to authorized users.


Background
Chronic subdural hematoma (CSDH) is a common type of encephalic hematoma with an incidence of 5/10,000 in the general population and 58/10,000 in people who are 70 years or older [1]. Head trauma is the most common risk factor for CSDH [2], along with age. CSDH occurs in up to 26.5 % of patients who are 65 years or older. Older patients also have a significantly higher recurrence rate as compared to the general population [3]. Incidences of CSDH and recurrent CSDH are expected to raise worldwide with an aging population. In addition, the increasing use of anticoagulant/antiplatelet therapies is also a common risk factor for CSDH in patients without a history of trauma [4] and poses a challenge for the surgical treatment of CSDH. Unlike subacute subdural hematoma (SSDH), spontaneous reabsorption is rare in CSDH and surgery has traditionally been the treatment of choice [5]. However, the rate of recurrent CSDH is high (approximately 25 %) in surgically treated patients [6], leading to a mortality of 11.1-13.5 % [7]. The surgical outcome is particularly poor for patients of 90 years or older [8].
Because of unsatisfactory outcomes of surgery, several adjuvant or conservative therapies have been clinically tested, including corticosteroids, as complementary therapies [1]. Dexamethasone is reported to effectively reduce the volume of CSDH after surgery [9][10][11][12]. It is also reported that perindopril (angiotensin converting enzyme inhibitor, ACEI) reduces the recrudescence of CSDH after surgery [13]. We have recently reported the effect of atorvastatin on reducing CSDH in 23 patients [14].
The pathogenesis of CSDH and mechanisms of above adjuvant therapies remain poorly understood. It has been reported that a CSDH hematoma contains a large number of erythrocytes from continuous blood leakage due to primitively formed blood vessels in the hematoma wall. Vascular endothelial growth factor (VEGF) is detected at a significantly high level in hematoma and in the serum of CSDH patients. [15]. VEGF promotes angiogenesis, but, at a persistent high level, also inhibits the maturation of new vessels [16]. We have previously demonstrated the presence of a pseudo envelope around a subdural hematoma that contains immature and abnormal vessels [17]. In addition, a hematoma is also enriched in proinflammatory cytokines [18][19][20]. We and other have shown that statins (hydroxy-methylglutaryl-CoA reductase inhibitors) mobilize circulating endothelial progenitor cells (EPCs) to enhance angiogenesis [21][22][23][24][25]. Atorvastatin also inhibits VEGF and reduces the inflammatory reaction [26,27] as well as up-regulating Notch1/Jagged1 signal, which is critical for VEGF-induced vessel formation and maturation. These reports led us to hypothesize that atorvastatin modulates VEGF expression and the level of inflammation in hematoma, resulting in the shrinkage of CSDH. This protocol was designed to test this hypothesis.

Study objective
The primary objective of this trial is to evaluate the efficacy of atorvastatin in reducing or eliminating CSDHs after 2 months without surgery.
The secondary objectives are to evaluate changes in hematoma volume (non-enhanced computerized tomography (CT) scan) at the 4 th week during the treatment; and at the 12 th and 24 th weeks during the follow-up period; and to measure the effect of atorvastatin on improving neurological function in patients with CSDH as assayed by the MGS-GCS, GOS, and ADL-BI at 4 weeks, 8 weeks and 6 months after atorvastatin therapy is initiated.

Trial design
The trial is designed as a multi-center, phase II, prospective, double blind, randomized, placebo-controlled study. Eligible patients are randomized in a 1:1 allocation ratio to one of the two treatment arms: 20 mg daily of atorvastatin (treatment) and placebo drug (control). The treatment will continue for 8 weeks followed by 16 weeks of follow-up.
Patients will be recruited from 16 neurosurgery centers in China that are participants in the Oriental Neurosurgical Evidence-based Study Team (ONET) ( Table 1, additional ethics documentations in Additional file 1). ONET is chaired by the Department of Neurosurgery, Tianjin Medical University General Hospital. Before the enrollment, patients or their family guardians will be fully informed about the trial, its potential outcomes and adverse events; and provide informed consent. The informed consent forms are in Chinese and English. The study will be conducted according to the Declaration of Helsinki. The ethics boards of Tianjin Medical University General Hospital and other participating hospitals have approved this study.

Inclusion criteria
The inclusion criteria are CSDH patients who: (1) are ≥ 18 and < 90 years old of either gender; (2) have evidence of supratentorial, unilateral or bilateral CSDH by CT scan (magnetic resonance imaging (MRI) scan is warranted if diagnosis is difficult); (3) have MGS-GCS < Grade 3 (Additional file 2); (4) have no cerebral herniation and immediate needs for surgery (as determined by 2 attending physicians); (5) have had no previous surgery on CSDH; and (6) fully understand the nature of this trial and provide informed consent.

Exclusion criteria
The exclusion criteria are: (1) allergic to statins or their ingredients; (2) cerebral herniation; (3) subdural hematoma caused by tumors, hematologic diseases or other known severe comorbidities such as multiple organ failure, uncontrolled diabetes mellitus and heart failure; (4) abnormal liver function or liver diseases including uncontrolled hepatitis; (5) other diseases that may interfere with the study as determined by 2 attending neurosurgeons; (6) patients on oral statin medication for more than 1 week before randomization or who are expected to take statins in the next 6 months; (7) patients on oral steroids for more than 1 week before randomization or who are expected to take such medications in the next 6 months; (8) a participant in clinical trials in the past 4 weeks; (9) pregnancy or breastfeeding; (10) failure to complete the trial by poor compliance; (11) other conditions that render a patient unsuitable for the trial as determined by the study investigators.

Medication and placebo
The 10-mg tablet of atorvastatin is provided by Pfizer, Inc. and taken orally at 20 mg daily before bed. The placebo drug matching oral atorvastatin is made of dextrin with the same weight and appearance and made by Shandong ARURA Pharmaceutical Research & Development. Co., Ltd. with the certification of good manufacturing practice (GMP) for pharmaceutical products issued by the China Food and Drug Administration (CFDA).
Atorvastatin and placebo are packed identically and labeled with packaging number, verification code, dosage, specifications, storage, batch number, the duration of usage, and manufacturer. The package will be labeled: "for clinical study use only."

Randomization
Eligible subjects are assigned randomly to either statin or placebo group through the Central Randomization System. The Data Acquisition System for Electronic Data Capture (DAS for EDC) 5.0 (Beijing Stemexcel Technology Co., Ltd., Beijing, China) will be used to produce random numbers. An EDC system is a computerized system designed for the collection of clinical data in electronic format for use mainly in human clinical trials. The ratio of experimental and control group is calculated, by a biostatistician independent of the study data management and statistical analysis, to be 1:1.
After initial screening, an investigator will log onto the Central Randomization System to enter demographic information of an enrolled patient to produce a random number application. A designated individual will then apply for a drug package number and dispense the drug when the package number is consistent with the one recorded in the database.

Treatment and intervention
Atorvastatin: oral intake of a 20 mg Atorvastatin tablet daily for 8 weeks.
Placebo: oral intake of a placebo tablet daily for 8 weeks.
At the end of the 8-week treatment, the volume of hematoma will be evaluated by CT scan for the following outcomes: 1. A hematoma disappears or is significantly reduced from the size measured before the treatment. Regardless of whether a smaller hematoma remains, the patient will enter into the follow-up period and should not be continuously treated with atorvastatin. 2. A hematoma does not change significantly or increases by CT scan at the end of 8 weeks of treatment (this can occur in patients who receive placebo). At the end of atorvastatin treatment, attending surgeons can decide if these patients need to receive surgery. The detailed medication and treatment during the process will be continuously recorded for 24 weeks. 3. For any patients whose hematoma increases as determined by CT scan and/or neurological deficits progress during the follow-up period, he or she may undergo surgery. The detailed medication and treatments during the process will be recorded for 24 weeks.

Timeline schedule
Protocol-mandated assessments will be performed according to the schedule ( Table 2). The study flow chart illustrates key steps of the trial (Fig. 1).

Concomitant care
All patients in the study will receive routine laboratory assessments, including complete blood count (CBC), coagulation (international normalized ratio, INR), liver and renal function, blood lipids and urinalysis. Head CT images will be recorded in Digital Imaging and Communication in Medicine (DICOM) format and evaluated centrally in a triple-blinded manner. Blood samples will be analyzed in a local laboratory and saved in a Case Report Form (CRF) format. The 4 regular follow-up visits are scheduled at the 4 th , 8 th , 12 th and 24 th weeks after the initiation of atorvastatin treatment.
The ACEIs (such as perindopril, captopril, enalapril) are reported to eliminate CSDH [9,28] and are thus their use is not allowed during the course of atorvastatin treatment. Anticoagulants (warfarin or new oral anticoagulants), antiplatelet drugs (aspirin, clopidogrel) or Xuesaitong (traditional Chinese medicine for activating blood circulation) can potentially interfere with hematoma absorption and are not recommended during the treatment. However, these patients will not be exclusively excluded from the trial participation. The following drugs may potentially interact with statins and/or cause adverse events [29] and will not be recommended during the treatment: red yeast rice, erythromycin, fibrates, cyclosporin, macrolide antibacterials, azole antifungals, tacrolimus, gemfibrozil, troglitazone, and itraconazole. The use of any medications will be recorded if they are used concomitantly during atorvastatin treatment in CRF, including name, dosing and duration of these medications.
Most participants are treated as outpatients receiving conventional and standard cares such as rest and pain relief. Family members are responsible for monitoring patients for progress in neurological symptoms such as worsening headache. If a patient is reported to have worsening symptoms, he or she will be further evaluated by two attending physicians for neurological deficits. These patients may be admitted during the trial for treatment of progressing neurological deficits and discharged when their symptoms are relieved significantly. Whether these patients remain on the trial as inpatients will be determined on a case-by-case basis by two participating investigators/surgeons.

Outcomes
The primary outcome is the change of hematoma volume 8 weeks after atorvastatin treatment on nonenhanced CT scan.
Secondary outcomes are changes of hematoma volume at the 4 th , 12 th , and 24 th weeks; MGS-GCS, GOS and ADL-BI scores; and improvements in neurological symptoms and signs and laboratory tests.

Sample size
We have previous shown, in a pilot study of a small patient cohort, that a significant reduction in hematoma volume was found in 95.7 % of CSDH patients treated with atorvastatin. This result provides a base for the power calculation of this trial where we assume that 80 % of patients in the treatment group achieve reduction in hematoma volume and neurological deficits as compared to 50 % reduction in placebo control patients. When the test power (1 − β) is 80 %, we will need to recruit 52 patients in each treatment group based on a 2size data comparison to reach statistical significance. When a 20 % drop-out rate is taken into the consideration, the sample size is expanded to 126 patients. However, we propose to recruit 200 patients, with 50 % randomly assigned to the atorvastatin treatment group, to meet the requirement of the CFDA for drug registration that the number of cases in treatment group shall not be less than 100 in a phase II clinical trial.

Data analysis
A 2-tailed test will be performed and a p value of less than or equal to 0.05 is considered to be statistically significant. Statistical analysis will be performed by SAS 9.3 (SAS Institute Inc., Cary, NC, USA). The quantitative parameters include group means, standard deviation, median, minimum value and maximum value. A secondary descriptive analysis will summarize improvements of neurological symptoms. For the secondary outcome measures, neurological symptoms and clinical signs of patients in each group are first to be described. Both MGS-GCS and ADL-BI as measured at admission, 3 and 6 months are statistically compared using analysis of covariance (ANCOVA) with the treatment group as a fixed effect and using MGS-GCS and ADL-BI baseline values as covariates.

Data monitoring
Data monitoring and management will be performed by Stemexcel Technology Company (Beijing Stemexcel Technology Co., Ltd., Beijing, China).
The trial data are recorded in the electronic data management system (DAS for EDC). The CRF is designed according to the protocol in order to collect trial data and to define trial procedures. The form is finalized after sponsors' approval. CRF data from each participant will be examined and verified by two investigators at a given study site. The entered data will be systematically checked by medically trained personnel. Errors will be Week 3 ± 1D Week 4 ± 1D Week 8 ± 3D (treatment end) Week 12 ± 3D 4 Week 24 ± 7D 4

Informed consent √
History collection The remaining drugs need to be recovered 4 At weeks 12 and 24, CT should be performed; other laboratory examinations will be selected when needed corrected by medically trained personnel and communicated to the site investigators. The CRF will be inspected by an assigned person at regular intervals throughout the trial in order to verify the protocol compliance. The entered data should be complete, consistent and accurate.

SAEs
Severe adverse drug reaction/events (SAEs) refer to the following conditions: death, life-threatening or permanent or significant disability, permanent functional injury to the organs, hospitalization for emergencies or prolonged hospitalization. Once a SAE is confirmed in a patient, this patient will be removed from the trial and a report should be filled within 24 hours. A full report regarding SAEs should be filled to the sponsor and SFDA. The ethics committee of pharmaceutical affairs of ONET will conduct an investigation to identify causes of SAEs and decide whether the trial will be terminated. The severity of SAE, its relationship with the trial medication, and treatments should be recorded in the CRF. The above conditions are delivered to the ethics committee of all participating hospitals.

Interim analysis
Interim analysis will not be conducted.

Auditing
Before the trial is ended, a serial quality control audit of the database will be conducted.

Methodology
The ATOCH study is designed based on our previous experience in treating CSDH with atorvastatin, showing that 22 out of 23 patients achieved complete hematoma elimination during the follow-up period after atorvastatin treatment. We, therefore, expect a significant volume reduction in the hematomas of patients on atorvastatin. However, since this is a conservative treatment trial of a clinical condition that is traditionally treated surgically, we limit our recruitment to patients who have a small-medium volume of CSDH and whose MGS-GCS is less than 3. To reduce adverse risks, especially patients on placebo, all patients will be closely monitored for acute neurological deterioration. If neurological symptoms deteriorate during the trial, patients will receive an emergency head CT scanning and necessary surgery. Such patients will be removed from the trial.
Except for rhabdomyolysis and impact on liver function, atorvastatin is considered to be generally very safe. Thus, we do not plan to waive SAE for this trial protocol. If a patient develops any suspected related side effects, he or she will be immediately excluded. If atorvastatin-related side effects are confirmed, treatment will be terminated and affected patients will be followed for 6 months.

Discussion
ATOCH is an atorvastatin-based clinical trial for CSDH. To our knowledge, it is the first complete conservative treatment trial for CSDH, undertaken in order to exclude the influence of surgery as compared to previous trials focusing on reducing the relapse of CSDH after surgery. This trial is based on our previous data [14] and on known effects of statins on modulating inflammation and enhancing angiogenesis [30,31] as reported for chronic obstructive pneumonic disease (COPD) [32] and acute respiratory distress syndrome (ARDS) [33]. We propose to test atorvastatin, but not other statins, based on our published report on treating CSDH with atorvastatin.
We believe that this trial is necessary because options for conservative treatment of CSDH are very limited [34][35][36] . While cortisones were found effective in some reports [1,[9][10][11][37][38][39] by primarily blocking inflammation and regulating angiogenesis, they often result in a high incidence of complications at high dose. These complications include digestive tract ulceration, increase in plasma glucose, and deterioration in diabetes [40]. The long-term application of dexamethasone also induces osteoporosis and decreases insulin sensitivity [41]. Perindopril is reported to reduce the relapse rate of CSDH after surgery, but it has not been reported to treat CSDH alone [13]. In contrast, we have shown that atorvastatin is an effective alternative to surgery for CSDH because of its high efficacy and minimal side effects [14]. The most frequent side effect of atorvastatin is myopathy, which is believed to be dose-dependent and spontaneously resolves when atorvastatin is discontinued [42]. The impairment of liver function by atorvastatin is now believed to be very limited [43,44]. Thus, atorvastatin is expected to be safer than currently available conservative therapies for CSDH. If atorvastatin is proven to be effective through the ATOCH trial, we believe that it can become the therapeutic choice complementary to traditional surgical therapy with or without medical intervention.

Trial status
The trial started in February 2014 and 96 patients have now been enrolled.