Dantrolene for Vasospasm After Subarachnoid Hemorrhage
Dantrolene for Vasospasm After Subarachnoid Hemorrhage
The University of Massachusetts Medical School (UMMS) institutional review board (IRB) approved this investigator-initiated trial (http://clinicaltrials.gov NCT01024972). Written, informed consent was obtained from all patients or the healthcare proxies prior to the occurrence of cVSP in order to increase the likelihood of patients self-consenting to the study, as required by our IRB. We followed the 2010 CONSORT guidelines for reporting parallel group trials. All patients presenting with aSAH to our institution were screened for study eligibility between October 2009 and October 2012. The main inclusion criteria were aSAH ≥18 years, aneurysm fully secured by coiling or clipping, Hunt & Hess grade <5, modified Fisher Scale >1, alanine transaminase (ALT), aspartate aminotransferase (AST) and AlkPhos <3× upper limit of normal, serum sodium (sNa) ≥135 mmol/L and no mannitol or hypertonic saline administered prior to study drug infusion (details in online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1).
During the infusion period we measured sNa, ALT, AST, AlkPhos and osmolarity daily, and the research study nurse visited participants daily, reviewing flow sheets and speaking to the clinical team to assess for primary and secondary outcomes.
To standardise hyponatremia treatment, we instituted a step-wise protocol (online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1), based on pretrial consensus by our neurointensivists and vascular neurosurgeon. To study the possible effects of IV-D on cVSP, but without increasing risks for patients, all study patients received baseline (before study drug) and daily transcranial Doppler (TCD) for 7 days during the study drug infusion period. One of three trained study TCD examiners performed these TCD, with the same examiner performing all TCD in a participant, when possible (details in online supplement and supplementary figure SI http://jnnp.bmj.com/content/86/9/1029/suppl/DC1). Owing to safety concerns regarding radiation and contrast-dye exposure, repeat angiography was performed only when indicated clinically for suspicion of clinical cVSP (online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1).
All patients with aSAH were treated according to our institutional protocol following published aSAH critical care guidelines, including admission to our closed neuroscience intensive care unit with board-certified neurointensivsts as the primary attending. Details are listed in the online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1.
Eligible patients were randomised 1:1 to IV-D 1.25 mg/kg every 6 h for 7 days or equi-osmolar placebo, consisting of the same solution (free water with 5% mannitol) as IV-D, without active drug, using block randomisation in blocks of four (kept in sealed envelopes in the research pharmacy until patient consent; generated by SAS V.9.2 (PROC PLAN), SAS Institute Inc, Cary, North Carolina, USA; figure 1). We chose this placebo over normal saline as we wanted to specifically explore the safety of dantrolene, and differentiate the effects of dantrolene from those of its solution. The dose was determined by our previous single-dose study in which we explored two doses (1.25 mg/kg and 2.5 mg/kg, both within the maximum FDA approved dose) and found that there was no further vasodilatatory effect with the higher dose. To maintain rigorous double blinding, the research pharmacy covered the entire length of the tubing and infusion bag with a brown plastic bag because of IV-D's bright yellow colour. We administered study drug over a 7-day period, initiated within the first week after the sentinel headache indicating aSAH onset. While funding did not permit a longer administration period, we were confident that IV-D would be administered during the most critical time period for cVSP development.
(Enlarge Image)
Figure 1.
Study design. The baseline TCD and screening labs were performed prior to randomisation to ensure that eligibility criteria were still met. ALT, alanine transaminase; AST, aspartate aminotransferase; AlkPhos, alkaline phosphatase; BP, blood pressure; DCI, delayed cerebral ischaemia; GOS, Glasgow Outcome Scale; ICP, intracranial pressure; IV, intravenous; mRS, modified Rankin Scale; Na, sodium; aSAH, (aneurysmal) subarachnoid hemorrhaege; TCD, transcranial Doppler.
The primary safety outcomes were hyponatremia, liver toxicity, and number of severe adverse events (SAEs) and adverse events (AE); secondary safety outcomes were systemic hypotension, intracranial hypertension, brain oedema and overall tolerability. Detailed outcome definitions and stop rules are listed in online supplementary table SI and the online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1. Efficacy outcomes explored were TCD, angiographic and clinical cVSP, mortality and delayed ischaemic deficits, assessed at discharge. Modified Rankin Scale (mRS), Glasgow Outcome Scale (GOS) and Barthel Index (BI) were assessed at 3 months post-aSAH. Additionally, changes in daily TCD peak systolic (PSV) and mean flow velocities (MVF) for each vessel at prespecified depths, as well as angiographic vessel diameters were quantitatively analysed to explore the effect of IV-D on vessel diameters (online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1).
The FDA granted an IND exemption (IND 106340). All SAEs were reported to our IRB within 24 h. Additionally, a data safety monitoring board (DSMB) reviewed the results of a planned interim analysis after 50% of patients were enrolled, and ruled that the study be continued without need for study protocol modifications. The DSMB additionally asked to analyse daily white cell count, haematocrit and platelets, which were part of clinical routine laboratory measurements, as aplastic anaemia and leukopoenia are rare IV-D side effects.
Based on detecting a clinically important difference in the change in mean sNa from baseline (≥5 mmol/L; details in the online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1), one planned interim analysis, assuming a two-sided α=0.05, and allowing for attrition, we planned to enrol a total n=30 (n=15 per arm) over a 3-year period, providing a power of 93%. After the interim analysis, we increased the sample size to n=32 because two patients withdrew consent from the study for subjective reasons ('nervous about research'). Sample size calculation was performed using EAST (V.5, Cytel Inc, Cambridge, Massachusetts, USA).
We applied intention-to-treat analysis throughout. Categorical data were analysed using Fisher Exact test, while continuous and ordinal data were analysed with Student's t test or Wilcoxon signed-rank test, as appropriate. The odds of AE/SAE were calculated with Generalised Estimation Equation with the patient as the clustering unit. Quantitative TCD and angiogram measurements were analysed using hierarchical linear models, allowing nesting of multiple observations per patient. We calculated the difference between each specific vessel at prespecified locations and each patient's baseline, per previously published methods (details in online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1), and adjusted this difference to each patient's baseline value. Unlike the daily per-protocol TCD assessments, angiograms were only performed when clinically indicated for suspected cVSP, with a small proportion undergoing follow-up angiogram during the infusion period. Therefore, we differentiated angiogram assessments as 'during' the infusion period, from 'after'. Some patients received additional TCD examinations per clinical routine after the 7-day infusion period for suspicion of cVSP. Post hoc we assessed these TCD for 'delayed TCD cVSP', without quantitative analysis, as different examiners, but not our trained study TCD examiners, performed these studies. p Values <0.05 were considered significant. Analyses were performed using SAS V.9.3 (SAS Institute Inc, Cary, North Carolina, USA). Graphs were created using Prism 6.0 (GraphPad Software Inc, La Jolla, California, USA).
Materials and Methods
The University of Massachusetts Medical School (UMMS) institutional review board (IRB) approved this investigator-initiated trial (http://clinicaltrials.gov NCT01024972). Written, informed consent was obtained from all patients or the healthcare proxies prior to the occurrence of cVSP in order to increase the likelihood of patients self-consenting to the study, as required by our IRB. We followed the 2010 CONSORT guidelines for reporting parallel group trials. All patients presenting with aSAH to our institution were screened for study eligibility between October 2009 and October 2012. The main inclusion criteria were aSAH ≥18 years, aneurysm fully secured by coiling or clipping, Hunt & Hess grade <5, modified Fisher Scale >1, alanine transaminase (ALT), aspartate aminotransferase (AST) and AlkPhos <3× upper limit of normal, serum sodium (sNa) ≥135 mmol/L and no mannitol or hypertonic saline administered prior to study drug infusion (details in online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1).
During the infusion period we measured sNa, ALT, AST, AlkPhos and osmolarity daily, and the research study nurse visited participants daily, reviewing flow sheets and speaking to the clinical team to assess for primary and secondary outcomes.
To standardise hyponatremia treatment, we instituted a step-wise protocol (online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1), based on pretrial consensus by our neurointensivists and vascular neurosurgeon. To study the possible effects of IV-D on cVSP, but without increasing risks for patients, all study patients received baseline (before study drug) and daily transcranial Doppler (TCD) for 7 days during the study drug infusion period. One of three trained study TCD examiners performed these TCD, with the same examiner performing all TCD in a participant, when possible (details in online supplement and supplementary figure SI http://jnnp.bmj.com/content/86/9/1029/suppl/DC1). Owing to safety concerns regarding radiation and contrast-dye exposure, repeat angiography was performed only when indicated clinically for suspicion of clinical cVSP (online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1).
Routine Patient Management
All patients with aSAH were treated according to our institutional protocol following published aSAH critical care guidelines, including admission to our closed neuroscience intensive care unit with board-certified neurointensivsts as the primary attending. Details are listed in the online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1.
Randomisation and Intervention
Eligible patients were randomised 1:1 to IV-D 1.25 mg/kg every 6 h for 7 days or equi-osmolar placebo, consisting of the same solution (free water with 5% mannitol) as IV-D, without active drug, using block randomisation in blocks of four (kept in sealed envelopes in the research pharmacy until patient consent; generated by SAS V.9.2 (PROC PLAN), SAS Institute Inc, Cary, North Carolina, USA; figure 1). We chose this placebo over normal saline as we wanted to specifically explore the safety of dantrolene, and differentiate the effects of dantrolene from those of its solution. The dose was determined by our previous single-dose study in which we explored two doses (1.25 mg/kg and 2.5 mg/kg, both within the maximum FDA approved dose) and found that there was no further vasodilatatory effect with the higher dose. To maintain rigorous double blinding, the research pharmacy covered the entire length of the tubing and infusion bag with a brown plastic bag because of IV-D's bright yellow colour. We administered study drug over a 7-day period, initiated within the first week after the sentinel headache indicating aSAH onset. While funding did not permit a longer administration period, we were confident that IV-D would be administered during the most critical time period for cVSP development.
(Enlarge Image)
Figure 1.
Study design. The baseline TCD and screening labs were performed prior to randomisation to ensure that eligibility criteria were still met. ALT, alanine transaminase; AST, aspartate aminotransferase; AlkPhos, alkaline phosphatase; BP, blood pressure; DCI, delayed cerebral ischaemia; GOS, Glasgow Outcome Scale; ICP, intracranial pressure; IV, intravenous; mRS, modified Rankin Scale; Na, sodium; aSAH, (aneurysmal) subarachnoid hemorrhaege; TCD, transcranial Doppler.
Outcome Measures
The primary safety outcomes were hyponatremia, liver toxicity, and number of severe adverse events (SAEs) and adverse events (AE); secondary safety outcomes were systemic hypotension, intracranial hypertension, brain oedema and overall tolerability. Detailed outcome definitions and stop rules are listed in online supplementary table SI and the online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1. Efficacy outcomes explored were TCD, angiographic and clinical cVSP, mortality and delayed ischaemic deficits, assessed at discharge. Modified Rankin Scale (mRS), Glasgow Outcome Scale (GOS) and Barthel Index (BI) were assessed at 3 months post-aSAH. Additionally, changes in daily TCD peak systolic (PSV) and mean flow velocities (MVF) for each vessel at prespecified depths, as well as angiographic vessel diameters were quantitatively analysed to explore the effect of IV-D on vessel diameters (online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1).
Safety Monitoring
The FDA granted an IND exemption (IND 106340). All SAEs were reported to our IRB within 24 h. Additionally, a data safety monitoring board (DSMB) reviewed the results of a planned interim analysis after 50% of patients were enrolled, and ruled that the study be continued without need for study protocol modifications. The DSMB additionally asked to analyse daily white cell count, haematocrit and platelets, which were part of clinical routine laboratory measurements, as aplastic anaemia and leukopoenia are rare IV-D side effects.
Sample Size Calculation
Based on detecting a clinically important difference in the change in mean sNa from baseline (≥5 mmol/L; details in the online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1), one planned interim analysis, assuming a two-sided α=0.05, and allowing for attrition, we planned to enrol a total n=30 (n=15 per arm) over a 3-year period, providing a power of 93%. After the interim analysis, we increased the sample size to n=32 because two patients withdrew consent from the study for subjective reasons ('nervous about research'). Sample size calculation was performed using EAST (V.5, Cytel Inc, Cambridge, Massachusetts, USA).
Statistical Analysis
We applied intention-to-treat analysis throughout. Categorical data were analysed using Fisher Exact test, while continuous and ordinal data were analysed with Student's t test or Wilcoxon signed-rank test, as appropriate. The odds of AE/SAE were calculated with Generalised Estimation Equation with the patient as the clustering unit. Quantitative TCD and angiogram measurements were analysed using hierarchical linear models, allowing nesting of multiple observations per patient. We calculated the difference between each specific vessel at prespecified locations and each patient's baseline, per previously published methods (details in online supplement http://jnnp.bmj.com/content/86/9/1029/suppl/DC1), and adjusted this difference to each patient's baseline value. Unlike the daily per-protocol TCD assessments, angiograms were only performed when clinically indicated for suspected cVSP, with a small proportion undergoing follow-up angiogram during the infusion period. Therefore, we differentiated angiogram assessments as 'during' the infusion period, from 'after'. Some patients received additional TCD examinations per clinical routine after the 7-day infusion period for suspicion of cVSP. Post hoc we assessed these TCD for 'delayed TCD cVSP', without quantitative analysis, as different examiners, but not our trained study TCD examiners, performed these studies. p Values <0.05 were considered significant. Analyses were performed using SAS V.9.3 (SAS Institute Inc, Cary, North Carolina, USA). Graphs were created using Prism 6.0 (GraphPad Software Inc, La Jolla, California, USA).
Source...