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Glibenclamide in aneurysmatic subarachnoid hemorrhage (GASH): study protocol for a randomized controlled trial

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Year of Publication: 2019

Authors: Bruno Braga Sisnando da Costa, Isabela Costola Windlin, Edwin Koterba, ..., Eberval Gadelha Figueiredo

Journal: Trials

Citation: Trials (2019) 20:413

Link: https://doi.org/10.1186/s13063-019-3517-y

PDF: https://d-nb.info/1200198239/34

Clinical Question

Does glibenclamide improve clinical outcomes, reduce mortality, and improve quality of life and cognitive performance in patients with aneurysmal subarachnoid hemorrhage?

Bottom Line

This is a study protocol (no results yet). The trial is designed to test whether glibenclamide 5 mg daily for 21 days improves functional outcomes at 6 months in patients with aneurysmal SAH. Based on experimental evidence showing glibenclamide blocks Sur1-Trpm4 channels, reducing edema, inflammation, and neuronal death, positive outcomes are expected particularly in language and memory preservation. Trial began recruitment July 2018 with 36 patients enrolled as of protocol publication.

        Major Points
        Study protocol for randomized, double-blind, placebo-controlled trial (no results available)
Target enrollment: 80 patients with aneurysmal SAH
Intervention: glibenclamide 5 mg daily orally or via NG tube for 21 days
Primary outcome: mRS at 6 months (favorable 0-2 vs unfavorable 3-6)
Secondary outcomes: cognitive status (SF-36, MoCA), death, delayed cerebral ischemia, adverse events
Mechanism: glibenclamide inhibits Sur1-Trpm4 channel, reducing edema and neuronal death
Experimental data show reduced mortality (5% vs 67%), less brain swelling, improved neurological outcomes
In SAH models: reduced ZO-1 abnormalities, less edema, reduced inflammation, reduced hippocampal apoptosis
Phase IIa trial in ischemic stroke (RP-1127) showed only 20% malignant edema vs 88% expected
Retrospective studies suggest sulfonylureas improve outcomes in diabetic patients with ischemic stroke
No clinical trials of glibenclamide in SAH prior to this protocol
All patients receive nimodipine 60 mg every 4 hours for 21 days as standard care
Aneurysm treatment (surgery or coiling) performed ASAP per standard of care
Recruitment: Hospital das Clínicas, University of São Paulo, Brazil
Trial began July 2018, had 36 patients enrolled as of May 2019 protocol publication
Expected completion: recruitment by August 2019, final follow-up December 2019
Interim analysis planned at 50% enrollment (40 patients)
Independent Data Monitoring Committee oversees safety

      

Design

Study Type: Randomized, double-blind, placebo-controlled trial (protocol)

Randomization: 1

Blinding: Double-blind. Computer-generated randomization by blocks of 10 (5 glibenclamide, 5 placebo). Coded bottles prepared and stored by pharmacy staff member not involved in enrollment. All participants (patients, investigators, neuropsychologists, medical/nursing staff) blinded except one investigator monitoring adverse effects. Patients can withdraw and learn allocation at any time

Enrollment Period: 2018-2019 (began July 2018)

Follow-up Duration: 6 months

Centers: 1

Countries: Brazil

Sample Size: 80

Analysis: Intention-to-treat analysis including patients who died during first 21 days. Results presented as adjusted common OR with 95% CI (OR <1 favors glibenclamide, p<0.05 significant). Logistic regression with conventional dichotomy favorable mRS (0-2) vs unfavorable (3-6). Mann-Whitney U test, χ² test, or two-sample t-tests as appropriate. Analysis blinded to group allocations. SPSS Statistics v24.0. Sample size calculation: 80 patients for 90% power at 5% significance (two-sided) to detect 7% absolute increase in favorable outcomes, assuming proportional odds model

Inclusion Criteria

Radiological confirmatory evidence of aneurysmal subarachnoid hemorrhage (by DSA, CTA, or MRA)
Age 18-70 years
Presentation less than 96 hours from ictus
Written informed consent from patient or legal representative

Exclusion Criteria

Patients taking glibenclamide therapy at presentation
Pregnancy
No reasonable prospect of survival (Hunt and Hess grade V)
Known renal or hepatic impairment
Patient not fully independent before bleed
Strong suspicion of drug or alcohol misuse
Patient taking warfarin-type drugs
Suspected additional life-threatening disease

Baseline Characteristics

Note: Protocol only - no baseline characteristics available yet. Trial ongoing with 36 patients enrolled as of May 2019

Arms

Field	Control	Glibenclamide 5 mg daily
Intervention	Coded bottles containing 21 similar tablets of placebo assigned a number. One tablet daily given orally or via nasogastric tube starting ASAP within 96 hours of ictus, continuing until day 21 after bleed. Aneurysm treatment (microsurgery or embolization) performed ASAP per standard of care. Nimodipine 60 mg every 4 hours started on admission and continued until day 21 after ictus (standard care). No patient discharged during treatment period for proper adverse effect monitoring. Capillary glucose checked every 4 hours during 21-day treatment. Demographics, medical history, investigation results collected. Severity assessed by WFNS grading scale and modified Fischer scale. mRS assessed at 6 months by physician blinded to allocation. Neuropsychologists evaluate quality of life (SF-36) and cognitive performance (MoCA) at 6 months, blinded to allocation	Coded bottles containing 21 tablets of glibenclamide 5 mg assigned a number. One tablet daily given orally or via nasogastric tube starting ASAP within 96 hours of ictus, continuing until day 21 after bleed. Aneurysm treatment (microsurgery or embolization) performed ASAP per standard of care. Nimodipine 60 mg every 4 hours started on admission and continued until day 21 after ictus (standard care). No patient discharged during treatment period for proper adverse effect monitoring. Capillary glucose checked every 4 hours during 21-day treatment. Demographics, medical history, investigation results collected. Severity assessed by WFNS grading scale and modified Fischer scale. mRS assessed at 6 months by physician blinded to allocation. Neuropsychologists evaluate quality of life (SF-36) and cognitive performance (MoCA) at 6 months, blinded to allocation
Duration	21 days treatment, 6 months follow-up	21 days treatment, 6 months follow-up

Outcomes

Outcome	Type	Control	Intervention
Modified Rankin Scale (mRS) score at 6 months, dichotomized as favorable (mRS 0-2) vs unfavorable (mRS 3-6)	Primary	Not yet available (protocol only)	Not yet available (protocol only)
Cognitive assessment at 6 months - Montreal Cognitive Assessment (MoCA) by ten domains grade punctuation (0-100)	Secondary	Not yet available	Not yet available
Quality of life at 6 months - Short-Form Health Survey Questionnaire (SF-36)	Secondary	Not yet available	Not yet available
Death at 6 months	Secondary	Not yet available	Not yet available
Delayed cerebral ischemia (focal neurological impairment or ≥2 point decrease in GCS lasting ≥1 hour, not apparent immediately after aneurysm occlusion, cannot be attributed to other causes)	Secondary	Not yet available	Not yet available
Occurrence of serious adverse events attributed to study medication	Secondary	Not yet available	Not yet available
Note	Adverse		Protocol specifies monitoring for hypoglycemia (capillary glucose every 4 hours during 21-day treatment). Trial will be interrupted if refractory hypoglycemia (glucose persistently <70 mg/dL) exceeds 40% of treated patients. One investigator unblinded to monitor adverse effects. Independent DMC reviews safety data. Interim analysis at 50% enrollment (40 patients)

Subgroup Analysis

Not specified in protocol. Potential confounding factors include baseline clinical conditions and aneurysm treatment method (clipping vs coiling), but randomization expected to match groups

Criticisms

Protocol only - no results available yet
Single center study limits generalizability
Sample size of 80 may be insufficient for detecting smaller treatment effects
Unblinded outcome assessment could introduce bias (one investigator has access to allocations for safety monitoring)
Potential confounding from different aneurysm treatment methods (clipping vs coiling)
Baseline clinical condition variability could affect outcomes
Glibenclamide dose (5 mg) lower than some experimental studies suggesting higher doses may be more effective
No placebo run-in period to assess compliance
Treatment window up to 96 hours may be too wide - earlier intervention might be more effective
No stratification by SAH severity (WFNS grade) in randomization
Hypoglycemia monitoring by unblinded investigator could introduce bias
6-month follow-up may be insufficient to detect long-term cognitive benefits
Primary outcome (mRS) relatively insensitive to subtle cognitive changes
No assessment of angiographic vasospasm as outcome
Trial stopped if hypoglycemia >40% may be too conservative
No dose-ranging - only testing single 5 mg dose
Patients not discharged during 21-day treatment may not reflect real-world practice

Funding

No direct funding received. Medical care, interventional drugs, data collection and analysis provided by Faculdade de Medicina da Universidade de São Paulo

Based on: GASH (Trials, 2019)

Authors: Bruno Braga Sisnando da Costa, Isabela Costola Windlin, Edwin Koterba, ..., Eberval Gadelha Figueiredo

Citation: Trials (2019) 20:413

Content summarized and formatted by NeuroTrials.ai.

GASH

(2019)

Objective

To evaluate the role of glibenclamide on clinical outcome, mortality, quality of life, and cognitive performance in patients with aneurysmal subarachnoid hemorrhage

Study Summary

• Protocol for randomized, double-blind, placebo-controlled trial
• 80 patients to receive glibenclamide 5 mg daily or placebo for 21 days
• Primary outcome: mRS at 6 months (favorable 0-2 vs unfavorable 3-6)
• Secondary outcomes: cognitive status (SF-36, MoCA), death, delayed cerebral ischemia, adverse events
• Based on experimental evidence showing glibenclamide reduces edema, inflammation, and neuronal death via Sur1-Trpm4 channel inhibition

Intervention

Glibenclamide 5 mg daily orally or via nasogastric tube for 21 days vs placebo

Inclusion Criteria

Radiological confirmation of aneurysmal SAH, age 18-70 years, presentation <96 hours from ictus

Study Design

Arms: Glibenclamide 5 mg daily vs Placebo

Patients per Arm: 40 per arm (estimated 80 total)

Outcome

Protocol only - no results yet. Trial began recruitment July 2018, had 36 patients enrolled as of protocol publication

Bottom Line

Major Points

Study protocol for randomized, double-blind, placebo-controlled trial (no results available)
Target enrollment: 80 patients with aneurysmal SAH
Intervention: glibenclamide 5 mg daily orally or via NG tube for 21 days
Primary outcome: mRS at 6 months (favorable 0-2 vs unfavorable 3-6)
Secondary outcomes: cognitive status (SF-36, MoCA), death, delayed cerebral ischemia, adverse events
Mechanism: glibenclamide inhibits Sur1-Trpm4 channel, reducing edema and neuronal death
Experimental data show reduced mortality (5% vs 67%), less brain swelling, improved neurological outcomes
In SAH models: reduced ZO-1 abnormalities, less edema, reduced inflammation, reduced hippocampal apoptosis
Phase IIa trial in ischemic stroke (RP-1127) showed only 20% malignant edema vs 88% expected
Retrospective studies suggest sulfonylureas improve outcomes in diabetic patients with ischemic stroke
No clinical trials of glibenclamide in SAH prior to this protocol
All patients receive nimodipine 60 mg every 4 hours for 21 days as standard care
Aneurysm treatment (surgery or coiling) performed ASAP per standard of care
Recruitment: Hospital das Clínicas, University of São Paulo, Brazil
Trial began July 2018, had 36 patients enrolled as of May 2019 protocol publication
Expected completion: recruitment by August 2019, final follow-up December 2019
Interim analysis planned at 50% enrollment (40 patients)
Independent Data Monitoring Committee oversees safety

Study Design

Study Type: Randomized, double-blind, placebo-controlled trial (protocol)
Randomization: Yes
Blinding: Double-blind. Computer-generated randomization by blocks of 10 (5 glibenclamide, 5 placebo). Coded bottles prepared and stored by pharmacy staff member not involved in enrollment. All participants (patients, investigators, neuropsychologists, medical/nursing staff) blinded except one investigator monitoring adverse effects. Patients can withdraw and learn allocation at any time
Sample Size: 80
Follow-up: 6 months
Centers: 1
Countries: Brazil

Primary Outcome

Definition: Modified Rankin Scale (mRS) score at 6 months, dichotomized as favorable (mRS 0-2) vs unfavorable (mRS 3-6)

Control	Intervention	HR/OR	P-value
Not yet available (protocol only)	Not yet available (protocol only)	-	-

Limitations & Criticisms

Protocol only - no results available yet
Single center study limits generalizability
Sample size of 80 may be insufficient for detecting smaller treatment effects
Unblinded outcome assessment could introduce bias (one investigator has access to allocations for safety monitoring)
Potential confounding from different aneurysm treatment methods (clipping vs coiling)
Baseline clinical condition variability could affect outcomes
Glibenclamide dose (5 mg) lower than some experimental studies suggesting higher doses may be more effective
No placebo run-in period to assess compliance
Treatment window up to 96 hours may be too wide - earlier intervention might be more effective
No stratification by SAH severity (WFNS grade) in randomization
Hypoglycemia monitoring by unblinded investigator could introduce bias
6-month follow-up may be insufficient to detect long-term cognitive benefits
Primary outcome (mRS) relatively insensitive to subtle cognitive changes
No assessment of angiographic vasospasm as outcome
Trial stopped if hypoglycemia >40% may be too conservative
No dose-ranging - only testing single 5 mg dose
Patients not discharged during 21-day treatment may not reflect real-world practice

Citation

Trials (2019) 20:413

View Original Publication →

GASH

Glibenclamide in aneurysmatic subarachnoid hemorrhage (GASH): study protocol for a randomized controlled trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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