Treatment with exenatide in acute ischemic stroke trial protocol: A prospective, randomized, open label, blinded end-point study of exenatide vs. standard care in post stroke hyperglycemia

So all we need done is get this written up into a stroke protocol and distributed to every stroke hospital in the world. Hospitals not implementing this within a month need to be shut down. Damn it all, we need some action in stroke and that probably requires a lot of hospitals to be closed and stroke professionals fired.  Cleaning house will not be done by the stroke medical world, they are the cause of the problems. We need survivors to take charge.
http://journals.sagepub.com/doi/full/10.1177/1747493018784436?

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Claire Muller, N Wah Cheung, Helen Dewey, ...

First Published July 18, 2018 Product Review

https://doi.org/10.1177/1747493018784436

Article information

Abstract

Rationale

Post-stroke hyperglycemia occurs in up to 50% of patients presenting with acute ischemic stroke. It reduces the efficacy of thrombolysis, increases infarct size, and worsens clinical outcomes. Insulin-based therapies have generally not been beneficial in treating post-stroke hyperglycemia as they are difficult to implement, may cause hypoglycaemia, possibly increase mortality and worsen clinical outcomes. Exenatide may be a safer, simpler, and more effective alternative to insulin in acute ischemic stroke.

Design

TEXAIS is a three year, Phase 2, multi-center, prospective, randomized, open label, blinded end-point trial comparing exenatide to standard of care. It aims to recruit 528 patients with a primary end point of major neurological improvement at 7 days defined as a ≥8-point improvement in NIHSS score, or NIHSS 0–1. Secondary outcomes of hyper- and hypoglycaemia at 5 days and NIHSS and mRS at 90 days will be measured. The treatment arm will receive exenatide 5 µg subcutaneously twice daily. The control arm will receive standard stroke unit care. Continuous glucose monitors will track the dynamic variability of glucose.

Conclusion

TEXAIS aims to show that exenatide is safe and effective in the treatment of post-stroke hyperglycemia. It has been designed to be highly generalizable with an ability to enroll a large percentage of patients with acute ischemic stroke, regardless of admission blood glucose level, diabetes status, or stroke severity, with very low risk of hypoglycemia.
Trial registration: ClinicalTrials.gov/ANZCTR NTA1127

Keywords Acute stroke therapy, incretin, glucagon-like peptide-1 analog, exenatide, hyperglycemia, ischemic stroke, neuroprotection

Background

The prevalence of post-stroke hyperglycemia (PSH) varies between 20 and 60% at admission, particularly in stroke patients with pre-existing diabetes.^1–4 In patients without a previous diagnosis of diabetes, PSH is associated with an up to five-fold increased risk of death.^2,5 Subsequent glucose normalization is associated with improved survival.^2,5,6 Persistent hyperglycemia on serial glucose monitoring is an independent determinant of infarct expansion and is associated with increased short-term and long-term mortality and morbidity.⁷ Despite this, PSH is often poorly recorded, and uncertainty remains regarding appropriate management.⁸ Insulin protocols are difficult to implement, can cause hypoglycemia, and most studies have failed to show that insulin therapy reduces mortality or improves clinical outcomes.^9–12 An Australian multi-centre, stroke care implementation study (n = 1086) using a clearly defined insulin regimen reported that protocol adherence was poor with only 40% of intervention group PSH patients being treated with insulin.⁸
The concept of hyperglycemic “neurotoxicity” has been suggested by both animal models of stroke and clinical trials that report accelerated penumbra-into-infarction conversion, and poor vessel recanalization.^2,5,13,14 Hyperglycemia promotes intracellular lactic acidosis, directly damaging ischemic tissue and increasing blood–brain barrier disruption which in turn augments further inflammation^6,15,16 and predisposes to symptomatic intracerebral hemorrhage.^17,18 PSH is an independent risk factor for reduced tPA recanalization,⁵ reduces fibrinolytic activity,^6,16 and increases oxidative stress and inflammation, all of which culminate in a state of relative hypercoagulation. These deleterious effects of PSH are more pronounced in patients who have early reperfusion,^5,19 highlighting the need for a prompt and early PSH intervention.
Exenatide is a short acting, synthetic, incretin hormone mimetic, i.e. a glucagon-like peptide-1 receptor (GLP-1R) agonist. Following subcutaneous injection, exenatide has a median peak plasma concentration of 2.1 h. It increases insulin secretion in a glucose-dependent manner such that the risk of hypoglycemia is very low.
In acute ischaemic stroke (AIS) animal models, exenatide attenuates oxidative-induced apoptosis, promotes anti-apoptotic proteins, and reduces infarct volume by more than 50%.^20,21 Small clinical trials in ST elevation myocardial infarction patients receiving percutaneous coronary intervention indicate periprocedural exenatide lowered glucose levels and increased myocardial salvage by 30%.²² Following a successful safety and feasibility pilot study,²³ our group undertook a larger randomized study of 17 consecutive patients with AIS comparing subcutaneous exenatide 5 µg twice daily for 5 days with routine standard of care. Exenatide was safe and simple to use, and well tolerated by all patients. The aim of TEXAIS is to confirm these findings, and test efficacy, in a larger Phase 2 study.
More at link.