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 Table of Contents  
STUDY PROTOCOL
Year : 2016  |  Volume : 1  |  Issue : 2  |  Page : 62-68

Atorvastatin for treating spontaneous subarachnoid hemorrhage: study protocol for a randomized double-blind placebo-controlled trial


Department of Neurosurgery, Clinical Medical School of Anhui Medical University, 101st Hospital of PLA (Wuxi Taihu Hospital), Wuxi, Jiangsu Province, China

Date of Web Publication29-Apr-2016

Correspondence Address:
Jun-hui Chen
Department of Neurosurgery, Clinical Medical School of Anhui Medical University, 101st Hospital of PLA (Wuxi Taihu Hospital), Wuxi, Jiangsu Province
China
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Source of Support: This study was supported by the Army Scientific Research Foundation of Nanjing Military Region of Chinese PLA; the Foundation of the 101 Hospital of Chinese PLA., Conflict of Interest: None


DOI: 10.4103/2468-5577.181236

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  Abstract 

Background: Animal studies have confirmed that statins have neuroprotective effects during and following a subarachnoid hemorrhage; however, the therapeutic effect of statins in humans remains controversial. The interpretation of data currently available on the clinical application of statins to spontaneous subarachnoid hemorrhage is limited by the small sample sizes used in the studies, making it difficult to draw valid conclusions regarding the multiple neuroprotective effects of statins. Thus, we propose to perform a randomized double-blind placebo-controlled parallel-group clinical trial to determine the effects of atorvastatin on spontaneous subarachnoid hemorrhage, apoptosis-related factors, and serum inflammatory factors in cerebrospinal fluid and to observe its neuroprotective effect mediated by relieving vasospasm.
Methods/Design: This is a randomized parallel-group placebo-controlled double-blind clinical trial. This trial will recruit 300 patients with spontaneous subarachnoid hemorrhage from the Department of Neurosurgery, 101 st Hospital of PLA (Wuxi Taihu Hospital). These patients will be equally and randomly assigned to atorvastatin (40 mg/day) and placebo control groups. Outcomes will be evaluated at baseline, 3, 5, and 14 days after hemorrhage, and 6 months after discharge. The primary outcomes will be the results of computed tomography (CT) angiography combined with CT perfusion imaging and conventional CT. The secondary outcomes will be cerebrospinal fluid analysis, blood testing (tumor necrosis factor α, vascular endothelial growth factor, interleukin-6, and C-reactive protein levels), and the Hunt-Hess classification, the results of transcranial Doppler ultrasonography, and the scores on the Glasgow Coma Scale, the Glasgow Outcome Scale, and the National Institutes of Health Stroke Scale.
Discussion: The results of this trial will provide data on the clinical application and neuroregenerative effect of atorvastatin in the acute stage of spontaneous subarachnoid hemorrhage.
Trial registration: This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005395) on 18 May 2014.

Keywords: clinical trial; atorvastatin; spontaneous subarachnoid hemorrhage; statins; randomized controlled trial


How to cite this article:
Chen Jh, Wang Yh. Atorvastatin for treating spontaneous subarachnoid hemorrhage: study protocol for a randomized double-blind placebo-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2016;1:62-8

How to cite this URL:
Chen Jh, Wang Yh. Atorvastatin for treating spontaneous subarachnoid hemorrhage: study protocol for a randomized double-blind placebo-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2016 [cited 2018 Dec 19];1:62-8. Available from: http://www.actnjournal.com/text.asp?2016/1/2/62/181236


  Introduction Top


Subarachnoid hemorrhage mainly refers to when a traumatic or non-traumatic intracranial hemorrhage, caused by a variety of reasons, induces blood to flow into the subarachnoid space (Welty and Horner, 1990; King and Martin, 1994). Non-traumatic subarachnoid hemorrhage is also known as spontaneous subarachnoid hemorrhage. Blood gathered in the subarachnoid space can cause severe inflammation as well as an increase in nitric oxide, endothelin, oxyhemoglobin, and proinflammatory cytokine levels. The collected blood may also lead to vascular spasm, stenosis, and ischemic brain damage, resulting in early brain injury and cerebral vasospasm. Early brain injury and cerebral vasospasm are the main causes of neurological dysfunction and death after subarachnoid hemorrhage (Sobey and Faraci, 1998; Tseng et al., 2005; Rabinstein, 2011). The delayed neurological dysfunction caused by spontaneous subarachnoid hemorrhage is not primarily caused by vascular spasm, but is possibly due to early vascular dysfunction, indicating that early administration of drugs for endothelial protection may be beneficial to the prognosis of patients. Cerda et al. (2015) verified that in addition to lowering lipid, statins improve endothelial function by reducing oxygen free radical production and increasing nitric oxide synthesis in endothelial cells. Statins resist platelet aggregation (Kato et al., 2004; Antoniades et al., 2011; Luzak et al., 2012) and antagonize coagulation factor VII activity (Ural and Avcu, 2006; Dietzen et al., 2007) by elevating nitric oxide synthase activity. Statins also improve overall fibrinolytic activity, reduce the inflammatory response, maintain the integrity of the blood-brain barrier, and ease cerebral vasospasm to mitigate subarachnoid hemorrhage (Cheng et al., 2009).

Many animal studies have shown that statins have neuroprotective effects on subarachnoid hemorrhage (Tseng et al., 2005; Chou et al., 2008; McGirt et al., 2009; Vergouwen et al., 2009; Garg et al., 2013; Kirkpatrick et al., 2014; Yoshimura et al., 2014), but its clinical therapeutic effects remain controversial. Garg et al. (2013) confirmed that simvastatin may relieve cerebral vasospasm after subarachnoid hemorrhage, but cannot improve patient outcome. At present, there are few data concerning clinical application of statins in patients with spontaneous subarachnoid hemorrhage, and those studies that do exist have small sample sizes. To reach a convincing conclusion, the results of a large-sample, double-blind, randomized, placebo-controlled trial are needed. Thus, the present proposed randomized, parallel-group, placebo-controlled, double-blind clinical trial has been designed to determine the effects of atorvastatin on spontaneous subarachnoid hemorrhage, apoptosis-related factors, and serum inflammatory factors in cerebrospinal fluid.


  Methods/Design Top


Study design

This randomized, parallel-group, placebo-controlled, double-blind clinical trial will be conducted in the Department of Neurosurgery at 101 st Hospital of PLA (Wuxi Taihu Hospital).

Ethical considerations and informed consent

An investigator or investigator-authorized personnel will explain the benefits and risks of participation to the study to each patient, family member, and guardian and obtain written informed consent. This project has obtained the written approval of the Medical Ethics Committee of 101 st Hospital of PLA (Wuxi Taihu Hospital) (approval No. 2014-YXLL-001) and is in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association.

Study participants

Patients with spontaneous subarachnoid hemorrhage hospitalized in the Department of Neurosurgery at 101 st Hospital of PLA (Wuxi Taihu Hospital) will be recruited to participate in this study.

Inclusion criteria

  • Patients meeting all of the following criteria will be considered for admission to the trial:
  • Aged 20-80 years; both sexes
  • Sudden severe headache, vomiting, and meningeal irritation (Suarez, 2015)
  • Abnormal computed tomography (CT) scans of the brain or a lumbar puncture showing that the cerebrospinal fluid is bloody and under increased pressure (Smith et al., 2013; Suarez, 2015)
  • First onset of symptoms
  • Time of atorvastatin administration is within 72 hours after hemorrhage
  • Informed consent of patients or their family members


Exclusion criteria

Patients presenting with one of the following criteria will be excluded from the trial:

  • Traumatic subarachnoid hemorrhage
  • Hyperlipidemia combined with diabetes mellitus
  • Abnormal liver enzymes, myopathy, and rhabdomyolysis
  • History of mental illness or epilepsy
  • Serious heart and lung disease or multiple organ dysfunction
  • Recent chemotherapy and radiotherapy
  • Currently participating in other clinical trials


Randomization

The 300 participants will be numbered according to their time of admission by a statistician using a table of random numbers. The participants will be equally assigned to either the atorvastatin group or a placebo control group. Doctors, patients, and assessors will be blinded regarding patient group assignments to avoid measurement bias.

Blinding and emergency unblinding

The treatment program for each participant will be generated using a random allocation sequence and placed in ordered, sealed, opaque envelopes. The blinded codes will be preserved by the drug administrator. If a patient has a serious adverse event and it is necessary to immediately determine the drug administered, a principal investigator of the research unit will open that patient's envelope. Once the data are unmasked, the patient will be discontinued from the trial. The clinical research associate will be informed of the result. Researchers will record the reason and date of the unmasking and sign the case report form.

Interventions

Patients in both groups will receive conventional treatments, such as sedation, absolute bed rest, fluid balance, and hemostasis.

Atorvastatin group: in addition to the conventional treatments, patients will be orally administered atorvastatin (trade name: Lipitor; approval No. GYZZ H2005140; Pfizer Dalian Pharmaceutical Plant, Dalian, China), 20 mg twice each day for a daily total of 40 mg.

Placebo control group: in addition to the conventional treatments, patients will be orally administered placebo (starch tablets with the same appearance as atorvastatin). The dosage will be consistent with that for atorvastatin.

A flow chart for this clinical trial is shown in [Figure 1].
Figure 1: Flow chart of the trial.

Click here to view


Outcome measures

Primary outcomes


  • CT angiography combined with CT perfusion imaging will be used to measure cerebral vasospasm and cerebral microcirculation at 3, 14 days after hemorrhage and 6 months after discharge. The tested measurements will include mean transit time, time to peak, relative cerebral blood volume, and relative cerebral blood flow
  • Conventional CT will be utilized to detect cerebral infarction at 3, 5 days after hemorrhage, and 6 months after discharge


Secondary outcomes

  • Cerebrospinal fluid will be examined for nuclear factor κB and caspase-3 levels
  • Blood tests will be conducted for tumor necrosis factor-α, vascular endothelial growth factor, interleukin-6, and C-reactive protein levels
  • The Hunt-Hess classification (Nina et al., 2001) will be applied to assess clinical status and prognosis
  • Transcranial Doppler ultrasonography (Ehrlich et al., 2016) will be employed to detect vasospasm. The measurements will include cerebral blood flow velocity, pulsatility index, and resistance index
  • The Glasgow Coma Scale (Okamura, 2014) will be used to assess the degree of coma
  • The Glasgow Outcome Scale (Wilson et al., 1998) will be utilized to evaluate prognosis
  • The National Institutes of Health Stroke Scale (Gocan and Fisher, 2008) will be applied to assess neurological function


The key outcomes are listed in [Table 1].
Table 1 Outcome measures and measurement points


Click here to view


Follow-up

The participants will be followed up 6 months after discharge. The patients will be requested by telephone to return to the hospital for examinations that will include CT angiography plus CT perfusion imaging, conventional CT, blood testing, cerebrospinal fluid analysis, transcranial Doppler ultrasonography, and neurological scale assessments. If a patient is lost to follow-up, the last values assessed will be considered the values for the 6-month follow-up.

Safety

Adverse reactions may include gastrointestinal dysfunction, immune system dysfunction, insomnia, forgetfulness, nervous system dysfunction, pruritus, myalgia, arthralgia, and serum transaminase and phosphocreatine kinase abnormalities.

To facilitate truthful reporting by patients of the changes in their conditions after drug use, the doctors will avoid asking patients leading questions. Adverse events or unanticipated side effects (symptoms, signs, and laboratory tests) will be recorded in addition to the curative effects.

If severe adverse events occur, researchers will immediately take appropriate therapeutic measures. The drug will be withdrawn. Drug withdrawal time, adverse events, symptoms, occurrence time, duration, treatment, and outcome will be recorded. The investigators will report all severe adverse events to the responsible unit, reporting units, the ethics committee, the Drug Supervision and Administration Department, and the relevant administrative departments within 24 hours. The investigators will sign and date the report.

Data management

The medical records will be electronically saved on a computer. The accuracy of data recorded on the case data form will be verified. Any changes or corrections will retain a clear record of the original. The investigator will record the date of changes or corrections, sign his or her name, and explain the reasons for the change (if necessary). The medical records along with any changes, deletions, or additions will be electronically saved on a computer. The audit trail will be set so that it is protected by the system and will not be able to be modified or edited by anyone. The clinical data management system will have authority management such that only authorized personnel will be allowed to operate it. The use of an electronic signature is a common means of managing electronic management systems. Only authorized personnel can log onto the system for data entry or modification or to view the data, preventing unauthorized logins and access to any clinical data so that it remains secure and confidential. In accordance with the China Drug Clinical Trial Management Specification, all records will be preserved for at least 5 years after completion of the trial.

Statistical analysis

The data will be analyzed using SPSS 20.0 software. Measurement data will be expressed as the mean ± SD. The evaluation at different time points after treatment of the results of CT angiography plus CT perfusion imaging, conventional CT, blood testing, cerebrospinal fluid analysis, transcranial Doppler ultrasonography, and neurological scale assessments will be compared using paired t-tests. The evaluation of CT angiography plus CT perfusion imaging, conventional CT, blood test, cerebrospinal fluid analysis, transcranial Doppler sonography, and neurological scale assessment results between the two groups will be compared using two-sample t-tests. A value of P < 0.05 will be considered statistically significant.

An intention-to-treat analysis will be used for all patients who have been assigned random numbers by the randomization procedure. If any measurements in the medical records or outcome measures are found to be incomplete during the statistical analysis, the final data obtained will be considered the final result for the purpose of the statistical analysis.

Trial quality assurance and control

JHC, one of the authors, will be responsible for quality assurance and control. A clinical research associate assigned by the sponsor will visit the hospital regularly to ensure that the protocol has been strictly followed and that all data are correctly recorded. The researchers will implement standard operating procedures for clinical trials before, during, and after the trial. During the trial, inspectors will monitor the correctness and integrity of the data using case registration forms. Researchers will be provided with training to enable uniform recording methods and judgment standards. Researchers will carefully record all information on case report forms to ensure that the data are correct and reliable. The investigators will use normal reference ranges as standards to determine abnormal laboratory test results. All observations and findings will be checked to ensure data reliability and to ensure that the conclusions come from the original data. In the clinical trials and data processing stage, there will be corresponding data management measures. Active measures will be taken to control the dropout rate to within 20%.


  Discussion Top


Sedation, absolute bed rest, fluid balance, and hemostasis are for the symptomatic treatment of patients with spontaneous subarachnoid hemorrhage. Such conventional treatments cannot effectively restore the patient's neurological condition. Thus, the goal of this study is to confirm the multiple neuroprotective effects of atorvastatin, including reducing inflammation, relieving vasospasm, improving endothelial cell function, and confronting blood coagulation activity in the treatment of spontaneous subarachnoid hemorrhage through this clinical trial. It remains poorly understood whether the addition of atorvastatin to the treatment protocol will improve outcome in the recovery of neurological function. The most common adverse reaction of atorvastatin is myopathy, which resolves after drug withdrawal because it occurs with atorvastatin administration in a dose-dependent manner (Hermann et al., 2006; Soininen et al., 2006; Abdelbaset et al., 2014). The effect of atorvastatin on liver function is limited (Gershovich and Lyman, 2004; Tikkanen et al., 2013; Kalantari and Naghipour, 2014). Therefore, atorvastatin is expected to become a relatively safe method for the treatment of spontaneous subarachnoid hemorrhage. If this large sample size, randomized, parallel-group, placebo-controlled, double-blind clinical trial verifies the effectiveness of atorvastatin, this drug will be considered effective for the treatment of spontaneous subarachnoid hemorrhage.



Trial status


Ongoing and recruiting at the time of submission.

Conflicts of interest

None declared.

Author contributions

JHC and YHW conceived and designed the trial procedure, wrote the paper, and approved the final version of the paper for publication.

Plagiarism check

This paper was screened twice using CrossCheck to verify origi-nality before publication.

Peer review

This paper was double-blinded and stringently reviewed by international expert reviewers.[31]

 
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