Semaglutide to Reduce Myocardial Injury in PATIents With COVID-19

6.1 Background

The current COVID-19 pandemic is rapidly spreading with a global total of ~35 million
cases, with close to 170,000 cases and over 9,500 deaths in Canada alone (as of
10/05/2020). Most affected patients have mild or even no symptoms, however, those
requiring hospitalization have a more severe presentation including pneumonia, acute
respiratory distress syndrome (ARDS), cardiovascular collapse and death. There is
mounting evidence that myocardial injury, occurring in 8-28% of hospitalized patients,
has a major impact on mortality. In a study from Wuhan in China, mortality was 59.6% in
COVID-19 patients with an elevated troponin and only 8.9% in those with a normal troponin
level. ARDS was also more common in troponin-positive patients. The pathophysiology of
myocardial injury following COVID-19 infection is not well understood, but may include
viral myocarditis, cardiomyocyte injury from systemic cytokine storm, reductions in
myocardial blood flow from micro- and macro-vascular thromboses, and severe hypoxemia in
the setting of pre-existing cardiovascular disease (CVD).1 Higher rates of adverse
outcomes with COVID-19 have also been noted in patients with hypertension and diabetes.
Based on these data, approaches to prevent or reduce the vascular consequences of
COVID-19 may be beneficial and should be prioritized for rapid evaluation in controlled
clinical trials.

Currently there is a paucity of approved therapies for COVID-19 infection. Current
interventions are either supportive in nature or experimental anti-viral,
anti-inflammatory, or anti-coagulant in nature. Only dexamethasone has recently been
shown to reduce mortality. To date, there is no proposed treatment directly addressing
the mechanisms of increased cardiovascular risk in this deadly disease. The investigators
have strong rationale and world-leading expertise in this area. This is a prospective,
randomized, controlled, open-label, blinded-evaluation, exploratory (vanguard) study in
hospitalized symptomatic COVID-19 patients age with any two of the following high-risk
features: age >60 years, obesity (BMI> 30), diabetes (by history - with or without
medical treatment), hypertension (on any treatment), cardiovascular disease (by history),
chronic kidney disease (eGFR <60) or elevated biomarkers on admission to hospital
(troponin, d-dimer). Eligible and consented patients will be randomized to one of the
following two treatment regimens in a 1:1 ratio: (1) semaglutide 0.25 mg s.c. immediately
after randomization at baseline, then 0.5 mg s.c. at day 7, day 14, and day 21. The end
of treatment period and primary outcome assessments will occur on day 28. Final secondary
clinical outcome assessment will be at 180 days.

With the results of this study the investigators aim to identify an effective treatment
that will reduce morbidity and mortality of patients with symptomatic COVID-19 infection,
which would in turn reduce the burden on the healthcare system by decreasing the need for
intensive care.

Objectives: The main objective of this research is to determine if once weekly treatment
with the GLP-1 agonist semaglutide for 4 doses will reduce cardiac as well as non-cardiac
complications of COVID-19 infection.

Study Plan: The study design is prospective randomized open-label blinded-evaluation
(PROBE). Eligible patients with symptomatic COVID-19 infection and an enhanced risk
profile as described above, who have been admitted to hospital due to symptoms of
COVID-19 infection but do not as yet require critical care will be approached to
participate in this study. Provided there are no exclusion criteria and the participants
agree by means of documented written informed consent, The participants will be
randomized to receive s.c. semaglutide 0.25 mg s.c. or control immediately after
randomization and then 0.5 mg s.c. at Day 7, Day 14 and Day 21. Blood will be drawn at
Day 7 and Day 14 for the cardiac troponin biomarker and safety parameters. ECG will be
obtained at Day 7±2 and Day 14±2. Primary outcome will be assessed on Day 28.

Primary outcome measure: A composite on Day 28 after randomization of (1) death from any
cause, (2) mechanical ventilation (invasive or non-invasive [bilevel positive airway
pressure or BIPAP])

Major secondary outcome measure:

(1) an elevation to >99th percentile URL upper reference limit (URL) in those with a
baseline cardiac troponin level ≤99th percentile URL; or 3x elevation from baseline in
those with a baseline cardiac troponin >99th percentile URL; measured at Day 7±2 and Day
14±2 post randomization.

Other major secondary outcome measure:

1. A composite on Day 28 after randomization of (1) death from any cause, (2)
mechanical ventilation (invasive or non-invasive [bilevel positive airway pressure]
(3) an elevation to >99th percentile URL in those with a normal baseline troponin
level; or 3x elevation from baseline in those with a baseline troponin; measured at
Day 7±2 and Day 14±2 post randomization.

2. ECG at Day 7±2 and Day 14±2: QRS and ST-T wave changes

3. 28-day organ support-free days

4. A composite of death or intensification of medical therapy in hospitalized
symptomatic patients infected with the COVID-19 virus, that includes the need for
ECLS, mechanical ventilation (invasive or non-invasive [BIPAP]) and/or
vasopressor/inotropic therapy on Day 180 post randomization.

Sample size estimation: The study plan is to enroll 50 patients in an initial feasibility
phase and continue to a total of 400 patients in the complete vanguard study based on the
assumption of a 20% primary event rate in the control group, and a 50% relative risk
reduction in the event rate in the active treatment arm. The rationale for the large
effect size to be tested is the need for a rapid answer for this life-threatening
pandemic. A conditional power analysis will allow the investigators to adjust the study
size as needed. When 70% of the randomized patients have reached the 28-day time-point,
conditional power will be estimated on the primary outcome. If the conditional power is
between 60% and 80%, the sample size will be adjusted to raise the power to 80%.

Planned subgroup analyses: Planned subgroup analyses for the primary endpoint include: 1)
Diabetes vs. no diabetes, 2) baseline troponin >99% percentile URL vs. not, 3) age < 60 y
vs. age ≥ 60 y, 4) eGFR < 60 mL/min vs. eGFR ≥ 60 mL/min, , 6) male vs. female. These
subgroup effects will be explored using a treatment-interaction test.