High-dose Simvastatin for Aneurysmal Subarachnoid Haemorrhage
Condition: Subarachnoid Hemorrhage
MeSH terms: Subarachnoid Hemorrhage; Hemorrhage
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Experimental evidences supported the benefit of Simvastatin in subarachnoid haemorrhage.
      Moreover, Simvastatin is a potent agent in achieving low-density lipoprotein (LDL) reduction
      with a proven safety profile. However, there is no clinical data to compare the efficacy of
      different dosage regimens (namely whether high-dose regimen is better) and related
      cost-effectiveness analysis, although biochemical actions and related neuroprotective
      mechanisms were thought to be dosage-related. This gap in knowledge is important, on how to
      implement the use of statin and interpret different trial results. With these in mind, the
      investigators designed the current study.

      Hypothesis:

      Daily Simvastatin 80mg (high dose) treatment given within 96 hours of the ictus over three
      weeks will reduce incidence and duration of delayed ischemic deficits following subarachnoid
      haemorrhage when compared to daily Simvastatin 40mg (normal dose) treatment, leading to
      improvement in clinical outcome, which translates into advantage in terms of
      cost-effectiveness.
    

Detailed description: 
      Title: High-Dose Simvastatin for Aneurysmal Subarachnoid Haemorrhage (HDS-SAH): A multicentre
      randomised controlled double-blinded clinical trial.

      Abstract

      Background: Experimental evidence has indicated the benefit of simvastatin in the treatment
      of subarachnoid haemorrhage. Simvastatin is also a potent agent for reducing low-density
      lipoprotein (LDL). However, no clinical data are available to compare the efficacy of
      different dosage regimens (specifically, whether a high-dose regimen is more effective than a
      normal-dosage regimen) or conduct related cost-effectiveness analyses, even though the
      biochemical actions and related neuroprotective mechanisms are thought to be dosage-related.
      This gap in our knowledge of how to use statins and interpret trial results is very
      important, and motivated the investigators to conduct this study.

      Objective: We hypothesized that eighty milligrams of simvastatin daily (high dose) over three
      weeks initiated within 96 hours of the ictus will reduce the incidence of delayed ischaemic
      deficits following subarachnoid haemorrhage when compared to 40mg of simvastatin daily
      (normal dose), leading to improvements in clinical outcomes and thus cost-effectiveness.

      Methods: The study design is a randomised controlled double-blinded clinical trial
      (ClinicalTrials.gov Identifier: NCT01077206). Two hundred and forty aneurysmal subarachnoid
      haemorrhage patients (presenting within 96 hours of the ictus) from six neurosurgical centres
      are being recruited over three years. Primary outcome measure is Presence of delayed
      ischaemic deficits (DIDs). Secondary outcome measures include Modified Rankin Disability
      Score (mRS) at three months (favourable if 0-2) and Cost-Effectiveness Analysis in terms of
      overall direct cost per patient and incremental cost-effectiveness ratio (ICER).

      Expected outcome: This will be the first study to clarify whether high-dose simvastatin is
      better than normal-dose simvastatin for patients with acute aneurysmal subarachnoid
      haemorrhage in terms of neurological outcomes and cost-effectiveness.

      General Information

      Protocol title: High-dose simvastatin for aneurysmal subarachnoid haemorrhage (HDS-SAH)
      ClinicalTrials.gov Identifier: NCT01077206 (Full protocol available online) Other Study ID
      Number: GW005 Name and address of the funding agency: Health and Health Service Research Fund
      (Reference Number: 07080401), Food and Health Bureau, Hong Kong Government, HKSAR, China
      Study protocol confirmed with grant funding body: 15 September 2009 Ethics approval of the
      study protocol: Joint CUHK-NTEC Clinical Research Ethics Committee, Hong Kong SAR, China

      Study Investigators:

      Steering Committee: Wong GK, Chan MT, Gin T, Siu DY, Leung MC Safety and data monitoring
      committee: Poon WS, Zee B Biostatistics: Zee B

      Site investigators:

      Department of Surgery, Prince of Wales Hospital, Hong Kong, China: Zhu XL, Wong GK;
      Department of Neurosurgery, the 8th Affiliated Hospital of Guangxi Medical University,
      Guangxi, China: M Liang; Department of Neurosurgery, Sichuan Province People's Hospital,
      Sichuan, China: HB Tan; Department of Neurosurgery, Pamela Youde Nethersole Eastern Hospital,
      Hong Kong, China: MW Lee, CK Wong; Department of Neurosurgery, Princess Margaret Hospital,
      Hong Kong China: TK Chan, YC Po; Department of Neurosurgery, Kwong Wah Hospital, Hong Kong
      China: PY Woo, KY Chan

      Rationale and Background Information

      Although aneurysmal subarachnoid haemorrhage (SAH) accounts for only 3-5% of strokes, its
      profound consequences and unique window of intervention justify its classification as a
      separate entity. Early aneurysm occlusion, expert endovascular neurosurgery and microsurgery,
      the use of oral nimodipine and neuro-intensive care are now the standards of care.1-3
      Nevertheless, aneurysmal subarachnoid haemorrhage is still associated with mortality at one
      month for half of all patients, and the other half are left with disability.

      Experimental evidence indicates the benefit of simvastatin in the treatment of subarachnoid
      haemorrhage.4-15 Simvastatin is also potent in reducing LDL, with a proven safety profile.
      Three randomised placebo-controlled pilot trials have supported the use of statins (two with
      80mg of simvastatin and one with 40mg of pravastatin) for the treatment of aneurysmal
      subarachnoid haemorrhage.17-19 A systemic review has suggested that simvastatin may also
      reduce delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage,20 and another
      meta-analysis has recommended the routine use of statins in the care of patients with
      aneurysmal SAH.21 Finally, there is an ongoing multicentre, placebo-controlled phase III
      trial assessing the clinical benefits of treatment with 40mg of simvastatin daily
      [http://www.stashtrial.com/home.html].

      However, no clinical data are available to compare the efficacy of different dosage regimens
      (specifically, whether a high-dose regimen is more effective than a normal-dosage regimen) or
      conduct related cost-effectiveness analyses, even though the biochemical actions and related
      neuroprotective mechanisms are thought to be dosage-related. This gap in our knowledge of how
      to use statins and interpret trial results is very important, and motivated the investigators
      to conduct this study.

      Study Goal and Objective

      The objective of the study is to determine whether a high dose of simvastatin for aneurysmal
      subarachnoid haemorrhage is superior to a normal dose in terms of clinical outcomes and
      cost-effectiveness. We hypothesized that eighty milligrams of simvastatin daily (high dose)
      over three weeks initiated within 96 hours of the ictus will reduce the incidence of delayed
      ischaemic deficits following subarachnoid haemorrhage when compared to 40mg of simvastatin
      daily (normal dose), leading to improvements in clinical outcomes and thus
      cost-effectiveness.

      Study Design

      The study design is a multicentre randomised controlled double-blinded (participants and
      outcome assessors) clinical trial.

      Methodology

      Subjects

      Inclusion criteria:

        1. Patients aged 18-70 years for whom the admitting neurosurgeon has a high index of
           suspicion of a spontaneous aneurysmal subarachnoid haemorrhage with convincing CT scan
           findings.

        2. Any clinical grade, provided there is a reasonable prospect of survival.

        3. The delay from the time of the presenting ictus until randomisation and the initiation
           of trial medication does not exceed 96 hours.

      Exclusion criteria:

        1. Unsalvageable patients: those with fixed and dilated pupils after resuscitation, and/or
           a devastating scan that preludes definitive therapy.

        2. Previous statin therapy.

        3. Current course of Warfarin-type drugs.

        4. Pregnancy.

        5. Known renal or hepatic impairment.

        6. Suspected or known additional disease process that threatens life expectancy (e.g.
           malignancy).

        7. Known or strong suspicion of drug abuse or alcoholism, or the likelihood of being
           amendable to either at the 3-month follow up.

        8. Current course of amiodarone, verapamil or potent CYP3A4 inhibitors.

      Outcome measures and follow-up:

      Primary outcome measures:

        1. Presence of delayed ischaemic deficits (DIDs): a fall of two or more points on the
           modified Glasgow Coma Scale, new focal neurological deficit lasting more than 2 hours,
           new cerebral infarction or CT perfusion evidence of cerebral ischaemia unrelated to
           surgery/embolisation, rebleed, hydrocephalus, infection, electrolyte or metabolic
           disturbance.

           Secondary outcome measures:

        2. Modified Rankin Disability Score (mRS) at three months (favourable if 0-2).

        3. Cost-effective analysis in terms of overall direct cost per patient and incremental
           cost-effectiveness ratio (ICER) of the high-dose group versus normal-dose group, i.e.,
           the cost difference per patient divided by the difference in the percentage of (a)
           favourable outcomes and (b) delayed cerebral ischaemia. Sensitivity analyses for ICER
           will be carried out using the percentages of favourable outcomes and delayed cerebral
           ischaemia.

      Study description

      Ethical approval has been obtained from the respective institutional review boards. The study
      is adhering to the international quality standards provided in the Good Clinical Practice
      guidelines. After informed consent from patients or their next of kin, subjects are being
      randomised to receive 80mg of simvastatin (two tablets of 40mg each) or 40mg of simvastatin
      (one tablet of 40mg and one placebo tablet) per day for 21 days orally or through a
      nasogastric tube.

      Randomisation Once the eligibility criteria have been fulfilled, a permuted-block
      randomisation is carried out using a computer system with an allocation list in random order
      generated by a statistician not related to the project team to protect the blinding and
      integrity of the study. The study drug assignments are concealed within sealed envelopes.
      These envelopes are only opened by site study investigators not involved in the clinical
      management of the recruited patients. The allocation ratio is 1:1. Both the clinical team
      (medical and nursing) and the patients are blinded to the study drug allocation.

      Sample size Assuming that the high-dose group has a 35% delayed cerebral ischaemia risk with
      a 20% absolute reduction in delayed cerebral ischaemia as compared to the standard dose group
      with a 55% delayed cerebral ischaemia, a total of 212 patients will be required (80% power
      and 2-sided alpha=0.05). However, further assuming a 10% loss to follow up, 236 patients will
      need to be recruited. The study was designed with the expectation of 30 patients ¬being
      recruited at each of four centres per year22-23; a total of 240 patients is thus expected to
      be recruited over a 24 month period. Because of delays in starting patient recruitment in
      some centres, two extra centres (a total of six) were initiated for patient recruitment.

      Trial status

      Patient recruitment will be completed in March 2013, and the last recruited patient will be
      due for final outcome assessment in June 2013. Data archiving, data analyses and the
      dissemination of study results will take place in early 2014.

      Safety Considerations

      Drug-related morbidities including rhabdomyolysis and hepatitis have been rare. In the two
      reported pilot studies, only one patient withdrew due to elevated liver parenchymal enzymes,
      which reversed on cessation of medication. Plasma creatinine phosphokinase (CPK), alanine
      aminotransferase (ALT) and aspartate aminotransferase (AST) are being monitored for early
      signs of hepatitis or myositis every 7 days or on clinical suspicion. Administration of the
      study drug ceases if ALT/AST is more than three times the normal level of >180U/L or CPK
      >1,000U/L. Cholesterol levels are also monitored weekly.

      Follow-Up

      In addition to the laboratory tests mentioned above, the patients are followed up daily by
      the clinical team for any adverse events during acute admission and weekly for the first
      three weeks if discharged. A three-month clinical visit is arranged for outcome assessment
      and possible adverse event. A contact number is available for the enrolled patients for
      queries and suspected adverse event report.

      Data Management and Statistical Analysis

      Data are being collected on handwritten forms and archived in a password-protected electronic
      database.

      We aim to perform an intention-to-treat analysis using two-sided probability, with P<0.05
      considered statistically significant. Proportions with (a) DCI and (b) favourable outcomes
      will be compared with chi-square statistics. A sensitivity analysis for ICER will be carried
      out to find the limits of proportions of groups with (a) DCI and (b) favourable outcomes that
      show threshold values.

      Planned exploratory analyses of DCI and favourable outcomes will include multivariate
      logistic regression using presentation SAH grade, age and the presence or absence of
      immediate post-procedural neurological deficits as the key covariates. Additional exploratory
      analyses with similar multivariate logistic regressions are planned, with the extra
      post-randomisation variables of the development of hydrocephalus, timing of hydrocephalus
      treatment and timing of aneurysm treatment.

      Quality Assurance

      The study conforms to the guideline of Good Clinical Practice. Data are managed in a secured
      computer system by a dedicated research assistants supervised by the principal investigator.
      The site investigators are contacted in case of doubt or uncertainty in data forms. The
      safety and data monitoring committee is being led by Professor Wai Sang Poon, Professor of
      Surgery, the Chinese University of Hong Kong. The committee is responsible for issues arising
      from the drugs used in the study, the interpretation of unexpected major adverse events,
      reviewing the study's progress and the submission of related recommendations to the study
      steering committee.

      Expected Outcome of the Study

      This will be the first study to clarify whether high-dose simvastatin is more effective than
      normal-dose simvastatin for patients with acute aneurysmal subarachnoid haemorrhage, in terms
      of neurological outcomes and cost-effectiveness. This gap in our knowledge of how to use
      statins and interpret trial results is very important.

      Duration of Study

      The initially targeted 24-month patient recruitment period has been extended to 30 months,
      with an additional 6 months required to complete the patient follow up and data archive. The
      total study period will thus be 36 months.

      Project Management

      The study steering committee is being led by the principal investigators. The committee is
      responsible for the study design, study implementation, ethics and health authority
      applications, protocol amendments, eventual data interpretation and the dissemination of
      results.

      Statistical design and randomisation are being supervised by Professor Benny Zee, Division of
      Biostatistics, the Jockey Club School of Public Health and Primary Care, the Chinese
      University of Hong Kong.

      The site study investigators are responsible for patient recruitment, reporting adverse
      events and completing the data collection.

      Ethics

      The study protocol was approved by the Joint CUHK-NTEC Clinical Research Ethics Committee,
      Hong Kong SAR, China. Ethical approval was obtained from the institutional review boards of
      the six neurosurgical centres. Written informed consent was obtained from eligible patients
      or next of kin for recruitment into the study.

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Intervention name(s): Simvastatin
Intervention type(s): Drug
Intervention description(s): 80mg daily versus 40mg daily, for 21 days.
Other intervention name(s): Teva
Intervention MeSH terms: Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Aneurysm; statin; subarachnoid hemorrhage