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PEER REVIEW HISTORY
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ARTICLE DETAILS
TITLE (PROVISIONAL)
AUTHORS
Rationale and Design of Short-Term Exenatide Therapy in Acute
Ischaemic Stroke (STEXAS) - A Randomised, Open-Label, ParallelGroup Study
McGrath, Rachel; Hocking, Samantha; Priglinger, Miriam; Day,
Susan; Herkes, Geoffrey; Krause, Martin; Fulcher, Gregory
VERSION 1 - REVIEW
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Michael d'Emden
Department of Endocrinology and Diabetes
Royal Brisbane and Womens Hospital
Butterfield St
Herston
QLD
Australia
03-Jul-2015
This is a fairly straight forward study design to assess a simple
question – is exenatide as good better than insulin in this study
cohort.
The basic design of the study is sensible, reasonable and rational.
However, it is not clearly enunciated why IV exenatide is to be used.
There is no argument provided as to why IV therapy will be superior
to subcutaneous therapy, the usual mode of administration. There is
no problem administering s/c exenatide to these patients. Exenatide
therapy does not need to be modified quickly, unlike insulin and
there is no issues with absorption. Have they done or is there data to
show that administering iv exenatide in this fashion is superior to s/c
therapy. Is there data to show that 20 ugm exenatide I/V over 24
hours achieves the same plasma levels as 10 ugm bd sub cut ? The
plasma levels may indeed be higher with iv therapy increasing GI
side effects.
Also, there might be an argument that administering the therapy as a
constant infusion will lead quickly to tachyphylaxis and minimise
most of the perceived beneficial effect of exenatide, namely
decreased gastric emptying. One of the potential advantages of s/c
exenatide in these patients would be eliminating the need for an
infusion with its increased demand on nursing time. Exenatide
doesn’t need to be titrated to achieve is therapeutic effect unlike
insulin. It may need to be up-titrated slowly to decrease its side
effects. The study of AIS quoted (25) used s/c exenatide.
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No comment is made about a need to titrate I/V exenatide whereas
this is standard clinical practice with s/c exenatide. Would it be better
to infuse 10 ugm/day for the first 24 hours, then uptitrate to 20 ug if
tolerated ?? I can appreciate that the study has a short time frame
and it is necessary to get to the required dose quickly.
Secondly, the primary aim of the study is unclear. Two primary end
points are to be assessed; I would have thought correct design
would have been one primary end point and make the other one a
secondary end point. The authors state:_ The primary endpoint of
this study is to determine whether exenatide therapy gives rise to
blood glucose levels within the target range of 5 – 10mmol/L within
the first 24 hours after commencing treatment.
They then state that : At the end of the study, the primary endpoint
will be assessed as the percentage of time that the participant’s
blood glucose levels remain within this range, as determined by
continuous glucose monitoring (CGMS).
They then state: In addition, the frequency and duration of
hypoglycaemia in patients receiving exenatide versus insulin therapy
will be determined.
Is this another primary end point ??
IN the box of primary end points, they are listed as:1. Blood glucose levels within target range (5 – 10mmol/L) in the first
24
hours after commencing exenatide treatment.
2. Frequency and duration of hypoglycaemia in patients receiving
exenatide
versus insulin therapy. Hypoglycaemia is defined as a capillary
blood
glucose level/interstitial glucose level < 4mmol/L.
No mention is made of the percentage of time that the participant’s
blood glucose levels remain within this range, as determined by
continuous glucose monitoring. I Believe the primary end point
should be more clearly enunciated. I would image the end point of
most relevance to clinicians would be:- the percentage of time that
the participant’s blood glucose levels remain in range. Secondary
end points would be number of episodes of hypoglycaemia, and
BGLS at 24 hours, or if they titrate the exenatide, perhaps at 48
hours.
REVIEWER
REVIEW RETURNED
GENERAL COMMENTS
Prof. Roberto Federico Villa
University of Pavia
Department of Biology and Biotechnology
Laboratory of Pharmacology and Molecula Medicine of Central
Nervous System
04-Aug-2015
This paper may be of interest, but it is unacceptable for many
reasons. To synthetize I think that, even if this is a pilot study, in any
case the scientific parameters (of any type) should be clearly
indicated. For example, the interval of age was not indicated and >
18 years is wthout of significance; the major problem is that the
laboratory data are not reported, but they must be clearly indicated
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and an appropriate statistical analysis must be discussed; the
gender effect is not discussed, as many other instances (stroke
treatment?); what are the the score of neurological deficits at the
time of
admittance and according to which stroke scale?; it is not clear the
dosage of exenatide as described at page 10, lines 30-43; what is
the dosage of insulin in the insulin-treated group?; Table at page 13
is not clear.
The conclusion is that the discussion is very poor.
VERSION 1 – AUTHOR RESPONSE
Reviewer 1
We wish to thank this Reviewer for their positive comments about our study in their second
paragraph.
1. Please note that there were several reasons as to why we elected to administer exenatide
intravenously, rather than subcutaneously.
a) Due to the short nature of the study treatment period, we felt that the optimum study design would
be IV administration of exenatide, such that the therapeutic dose of circulating exenatide would be
maintained at a steady-state. The peak activity of subcutaneously administered exenatide is 90-120
minutes, however this diminishes within 6-8 hours and another dose is required (Kolterman OG et al.
Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes
mellitus. Am J Health Syst Pharm. 2005 Jan 15;62(2):173-81.) Thus, IV administration of exenatide
should result in peak activity which is maintained throughout the duration of the study treatment
period.
Reference has been made to the rationale behind administering exenatide intravenously by the
addition of the following sentence to the ‘Study Intervention’ section: “The intravenous route was
chosen such that therapeutic exenatide activity will be achieved within a quick timeframe and
maintained over the course of the study treatment period.(29,30)”
b) A recent article by Nauck et al. provided rationale as to why intravenous exenatide may potentially
give rise to less gastrointestinal (GI) side effects than exenatide administered subcutaneously.
Furthermore, several studies in which GLP-1 was administered intravenously reported few instances
of nausea (Lonborg et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation
myocardial infarction; European Healt Journal (2012) 33, 1491-1499; Sourij et al, Efficacy of a
continuous GLP-1 infusion compared with a structured insulin infusion protocol to reach
normoglycaemia in nonfasting type 2 diabetes patients: A clinical pilot trial, Diabetes Care 2009:32; 9
1669-1671). Thus, we felt that intravenous exenatide would result in fewer instances of nausea and
would therefore be better tolerated by study participants.
Reference has been made to the lower frequency of nausea with IV exenatide with the addition of the
following sentence to the “Study Intervention’ section of the manuscript: “Relatively little is known
about the GI side effects of exenatide when administered intravenously however recent evidence
suggests that intravenous administration produces less nausea than subcutaneous
administration.(31)”
2. We agree with the Reviewer that subcutaneous exenatide administration would decrease the
demand on nursing time however as outlined above, we believe that IV administration will give rise to
the optimum treatment for patients in this setting.
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3. The dose of 20µg per day of exenatide for the entirety of the study i.e. for 72 hours was chosen
such that participants would get optimum control of blood glucose levels during the treatment period.
If exenatide was started at 10µg per day and up-titrated to 20µg after 24 hours, there is a risk that
participants would not achieve blood glucose levels within the target range and thus, insulin rescue
therapy would need to be initiated. We have added this rationale to the ‘Study Intervention’ section of
the manuscript: “Furthermore, the dose of exenatide will be not be up-titrated over time (as is the
standard practice with subcutaneous exenatide) to ensure that optimum glycaemic control will be
attained as rapidly as possible.” Finally, the rationale for titration in the context of subcutaneous
administration is to minimise the impact of GI side effects. For the reasons outlined above, it is not
anticipated that this will be an issue with intravenous administration.
4. We have amended the study end points as suggested. The end points have been clarified in the
main body of the manuscript and Table 3 has been updated accordingly.
Reviewer 2
1. We are unsure as to what this Reviewer is referring to with this comment. This study is designed to
test the utility of intravenous exenatide as a glucose regulating therapy in acute ischaemic stroke and
to determine the advantages, if any, over utilising intravenous insulin (standard practice) for this
purpose. The scientific parameters that will be assessed as part of the study include the following:
blood glucose levels within the target range of 5 – 10mmol/L in the exenatide vs. insulin treatment
arms; the incidence of hypoglycaemia in both treatment arms and analysis of circulating inflammatory
markers and metabolic hormone levels in blood samples collected throughout the treatment period.
Upon completion of the study, this information will be disseminated by way of another publication
containing the study results.
2. It is expected that patients recruited to the study will be of older age i.e. > 70 years, however we
have not specified an age range in the study protocol so that all patients presenting to hospital with an
acute ischaemic stroke and a blood glucose level > 10mmol/L (and fitting the other inclusion/exclusion
criteria) may be recruited. Upon study completion, the full age range of participants will be given.
3. We are not aware that there will be an effect of gender on the safety and efficacy of exenatide at
lowering blood glucose levels in this population of patients. After the study has been completed, we
will analyse the data to determine whether there is an effect of gender on any of the outcomes.
4. The stroke treatment to be used throughout the study will be in keeping with current local
guidelines for the management of acute ischaemic stroke. As stated in the study inclusion criteria,
patients presenting with acute ischaemic stroke and a National Institute of Health Stroke Scale
(NIHSS) score of > 20 (indicating a severe stroke) or a Pre Morbid Modified Rankin Score above 3 will
not be eligible for participation in the study.
Thus, we predict that the range of neurological deficits at the time of patients being admitted to the
Acute Stroke ward will range between 0 – 20 for the NIHSS and 0 – 3 for the Pre Morbid Modified
Rankin Score.
5. As outlined in the “Study Intervention” section of the manuscript, “study participants allocated to the
exenatide treatment arm will receive continuous intravenous administration of 20µg per 24 hours of
exenatide (Byetta®; Bristol-Myers Squibb/AstraZeneca, Australia)”. The following sentence has been
further added to this section for clarity: “In total, patients allocated to the exenatide treatment arm will
receive 60µg of exenatide over 3 days i.e. 20µg of exenatide per 24 hours).”
Furthermore, insulin administration will be carried out according to the local hospital protocol.
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Participants will be given a continuous insulin infusion that is titrated to maintain a blood glucose level
within the target range of 5 – 10mmol/L. Thus, there is no specific insulin dose administered.
6. Please note that we have amended this table, such that headings are provided in each of the
columns for clarity.
7. We have not amended the discussion as we believe that our points above address this Reviewer’s
comments sufficiently.
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Rationale and design of Short-Term
EXenatide therapy in Acute ischaemic Stroke
(STEXAS): a randomised, open-label,
parallel-group study
Rachel T McGrath, Samantha L Hocking, Miriam Priglinger, Susan Day,
Geoffrey K Herkes, Martin Krause and Gregory R Fulcher
BMJ Open 2016 6:
doi: 10.1136/bmjopen-2015-008203
Updated information and services can be found at:
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