ATOCH-II is a multicentre, prospective, double-blind, placebo-controlled, randomised trial involving 240 patients with CSDH to be recruited from 14 neurosurgery centres in China who are collaborative partners in the Oriental Neurosurgical Evidence-based Study Team (ONET).23 ONET is the first neurosurgical professional organization devoted to evidence-based medicine in China (Chair, Department of Neurosurgery, Tianjin Medical University General Hospital) with the mission to establish clinical research thinking, train clinical researchers, conduct randomised trials, and promote the development of evidence-based medicine in neurosurgery.
Patient inclusion and exclusion criteria
The study population will be drawn from consecutive patients with CSDH admitted to ONET neurosurgical centres. Patients are eligible who meet all of the following inclusion criteria: age ≥18 and ≤90 years; diagnosis of supratentorial (unilateral or bilateral) CSDH confirmed on CT imaging within 72 hours after admission; a single unilateral hematoma ≥10 mL; pre-morbid functional independence, estimated according to scores 1 (no symptoms), 2 (symptoms), or 3 (some disability but independent in function) on the modified Rankin scale (mRS); the attending physician’s judgment that cerebral herniation and/or surgical evacuation are unlikely to occur; and the provision of informed consent, or by an appropriate proxy according to local requirements.
Exclusion criteria include: known allergy to a statin (<4 weeks), glucocorticoid or their ingredients; considered to have a high likelihood of cerebral trauma or cerebral herniation and/or requirement surgical evacuation or decompression; structural lesions including tumor, haematologic diseases, tuberculous, arachnoid cyst, vascular malformation, ventricular peritoneal shunt or other severe co-morbidity; abnormal liver function, hepatitis or uncontrolled liver disease, as well as other disease that has an influence of prognosis or the ability to assess the study outcomes; uncontrolled diabetes mellitus, with blood glucose levels consistently >10 mmol/L; history of femoral head necrosis; recent (<4 weeks) corticosteroid or anticoagulation use, or abnormal coagulation function (<4 weeks); likelihood of pregnancy or breastfeeding during the course of the study; participation in another clinical trial (<4 weeks); high likelihood of poor adherence to the treatment or follow-up schedule; and any other reason according to the opinion of the attending clinician researcher.
Randomisation and blinding
Eligible patients are centrally randomised in a 1:1 allocation ratio to intervention (atorvastatin combined with low-dose dexamethasone) and control (atorvastatin combined with matching placebo) groups using a blocked randomization method via a data acquisition system for electronic data capture (DAS for EDC, Version 5.0) developed by Stemexcel Technology Co. Ltd., Beijing. DAS for Interactive Web Response System (IWRS) is used to assign the randomization number to the treatment allocation and drug distribution, and each center will compete to recruit subjects.
All patients are to take oral 20 mg atorvastatin (one tablet) daily for 4 weeks as a standard of care. Those patients allocated to the intervention group will receive extra dexamethasone with the dose of 0.75mg per once for three times daily during the first 14 days, and thereafter the dose will be reduced to twice daily for 7 days, and then once a day for another 7 days. Thus, a total of 560 mg atorvastatin and 47.25mg dexamethasone will be taken 28 days. Patients assigned to the control group will receive the same open atorvastatin regimen but also placebo dexamethasone in the same schedule over 28 days.
Study medication is provided free of charge to participants: atorvastatin by Pfizer Inc. and dexamethasone by Tianjin Pacific Pharmaceutical Co. Ltd. (Tianjin, China). The placebo dexamethasone, which is composed of dextrin and with the same weight and appearance as dexamethasone, is made by Tianjin Pacific Pharmaceutical Co. Ltd. (Tianjin, China), which has a certification of good manufacturing practice for pharmaceutical products (GMP) issued by the State Food and Drug Administration of China. Study medication is packed identically and labeled ‘for clinical study use only’ with a packaging number, verification code, dosage, specifications, storage, batch number, duration of usage, and manufacturer.
A statistician and staff independent of the study research team oversee packaging of the study medication, with use of a package number and drug verification code on the tag. Each participant is allocated a unique number to be applied to a drug package number for dispensing and consistency in the database.
Baseline demographic and clinical features, including medical history, severity and type of neurological deficit, and physical and biochemical results, are collected at the time of enrollment in the study. Treatment should be initiated immediately after randomisation (Table). All background care should follow standard guideline recommendations for the management of CSDH in China which includes the withholding of anticoagulation and use of antiplatelet agents; and prescribing prophylactic antiepileptic drugs and regular use analgesics. The Study Flow chart illustrates key steps in the trial (Figure).
Each patient receives an in-person clinical assessment at an outpatient clinic by two attending neurosurgeons who are kept blind to the treatment allocation, every two weeks during the 28-day treatment duration, and then each month thereafter until 180 days post-randomization. If a participant develops any form of neurological deterioration (e.g. altered level of consciousness) that is suggestive of expansion of the haematoma, they may be admitted to hospital for assessment and treatment until their symptoms are relieved or resolve. If surgery is undertaken for a deteriorating patient, the randomised oral study medication is to be resumed as soon as possible after the operation until the end of the planned 28-day treatment period.
Treatment compliance is monitored through pill counts and regular contact with participants, with instructions to adjust medication dosage at weekly outpatient clinic visits. The use of other medications is recorded, including their name, dose, and duration of treatment. Any change in haematological and biochemical markers, such as liver function tests, and side-effects such as myalgia, constipation, and other possible drug-related symptoms, will be recorded.
At the end of the 28-day treatment period, haematoma volume will be re-evaluated on repeat CT scans and the following treatment regimens considered: (i) if the haematoma has resolved or present in a very small amount, the investigator can stop study treatment and only conduct follow-up observations until 180 days; (ii) if the haematoma appears reduced but still present, the investigator can decide either to consider ceasing medication and observing considering early surgery; (iii) if there is no obvious change in the haematoma, two researchers can jointly determine whether to continue conservative management or undertake surgery; and (iv) if the amount of haematoma is increased, the patient may undergo surgery. All details of any treatment during the 180 days study period are recorded.
The primary outcome is a composite of ‘good outcome’, including any reduction in subdural haematoma volume from baseline and free of surgery and death within 28 days of the treatment. The haematoma volume is measured centrally using the Tada formula of maximal length (L) × maximal width (W) × maximal thickness (H), divided by 2,24 on the acquired CT images by 3 independent neuroradiologists blind to treatment location. Details of the location, density, and compartment of the haematoma are also recorded.
Secondary outcomes include: functional outcome according to a ‘shift’ in the distribution of the full range of scores on mRS at 28 days; function on the modified Barthel Index measure of actives of daily living (ADL-BI) at 28 days; surgical intervention at 28, 90 and 180 days; and reduction in haematoma volume at 14, 28 and 90 days.
Details of all the adverse events will be recorded in hospital and via outpatient clinic follow-up visits as well as via telephone checks until 180 days. Those reporting an adverse event will have a comprehensive physical examination to document vital signs (body temperature, heart rate, respiratory rate and blood pressure) and general items for any positive signs (coverage of the skin, eye, ear, nose, throat, lung, heart, stomach, skeletal muscle, limbs and nervous system); and laboratory tests of haematology, biochemistry and renal function, lipid profile, and coagulation, and myoglobin and creatine kinases in patients with suspected rhabdomyolysis; and electrocardiography.
A serious adverse event (SAE) is defined as an event with causing or with potential to cause, significant harm or requiring medical intervention, whether or not it is considered related to the study treatment. A non-serious adverse event is defined as any undesirable medical experience occurring to a patient, including abnormal laboratory values without clinical consequences.
All SAEs are to be reported within 24 hours of the site investigator becoming aware, and a full report is to be filled to the sponsor and the state food and drug administration (SFDA). The ethics committee of pharmaceutical affairs of ONET will conduct an investigation to confirm the causes of an SAE, decide whether the participant can continue with study medication and deal with the related participants complications and adverse events. All patients are to be follow-up according to the intention-to-treat (ITT) principle.
We estimate a sample size of 240 patients will provide 90% power to detect a treatment effect of 20% absolute improvement in the primary composite good outcome, after considering a 5% loss-to-follow-up at 4 weeks, then 240 patients in total with 120 per group is needed to be recruited for this study and good outcome in the single atorvastatin control group of 62.6% being consistent with the single atorvastatin group of the ATOCH trial(48 of 81),15 a pilot trial showing 20 of 30 patients had a good outcome in a single atorvastatin group,24 and medical record data showing 9 of 12 patients had a good outcome at a single center in 2017.17 The combined drug treatment effect was assumed to be consistent with the percentage of good outcome found in 29 of 30 patients in a pilot clinical trial24 and 95 of 108 patients medical record from our single center showing with a good outcome.
Data management and quality control
Data management will be performed by the Stemexcel Technology company, Beijing, China23 using specially designed case report forms (CRF) on a DAS for EDC system. All CRFs are first examined and verified by 2 investigators at each study site, before a data manager undertakes further central checks and confirmation or correction of any errors or inconsistencies via a clinical monitor before finalization of the data. The CRF will be inspected by an assigned person at regular intervals throughout the trial in order to verify adherence to the protocol. Data lock occurs when all subjects have completed their follow-up and there are no outstanding data queries.
The primary analysis will be performed according to the modified ITT principle, comprising all randomized participants. A per-protocol analysis will also be undertaken for all participants who have taken at least one dose of the trial medication and complete at least one follow-up assessment. The description of indicators will be by number of cases (and percentages) for categorical variables, and mean (standard deviation) or median (interquartile range) for continuous variables. The Chi-square test and logistic regression with adjustment for site, age, sex, and baseline haematoma volume will be adopted for the comparison of the primary outcome between treatment groups. For secondary outcomes, the Student’s t-test or non-parametric Wilcoxon tests will be performed for continuous outcomes and the Chi-square test for dichotomous outcomes, respectively. Ordinal logistic regression will be used for analysis of the shift in the full range of scores on the mRS. All statistical tests are two-sided, with a p-value <0.05 indicating statistical significance. All analysis will be conducted using SAS 9.4 (SAS Institute Inc. US).
Ethics and dissemination
All ethical and legal requirements are required to be met before any subject is enrolled in the trial. The study protocol, participant information sheet and consent form are to be approved according to local and national regulations, centrally by the ethics committee of Tianjin Medical University General Hospital and at ethics committees of each participating site. Participants are to be made aware of the investigational nature of the study. The study will be conducted according to the Declaration of Helsinki (2008) and the results reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.