Clinical trial NCT04615871: Semaglutide to Reduce Myocardial Injury in PATIents With COVID-19
Official title: Semaglutide to Reduce Myocardial Injury in PATIents With COVID-19 Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Covid19
Myocardial Injury
Keywords: Covid-19
myocardial injury
GLP-1 agonist
semaglutide
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Unity Health Toronto
name: Canadian Institutes of Health Research (CIHR)
name: University of Toronto
First posted: 2020-11-04
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized to receive active treatment - s.c. semaglutide for 4 weekly doses in addition to standard of care or control - standard of care only
Primary purpose: TREATMENT

Brief summary: 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 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±2 and Day 14±2 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 of (1) death from any cause or (2) mechanical ventilation (invasive or non-invasive) at 28 days.

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 1 week (7-days) post randomization.

Other major secondary outcome measure:

A composite of

1. Death from any cause, mechanical ventilation or vasopressor or ECLS support at 28 days
2. 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 1 and 2 weeks (7±2 and 14±2 days) post randomization.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

Symptomatic\* COVID-2 infection confirmed by a positive COVID-19 test requiring hospitalization \[or equivalent health care setting\] with any two of the following high-risk features:

* age ≥ 60 years
* obesity (BMI \>30)
* diabetes mellitus
* hypertension (on treatment or recently diagnosed)h
* coronary artery, cerebrovascular or peripheral vascular disease∫
* chronic kidney disease (CKD) \[eGFR \<60 mL/min/1.73m2 using the CKD Epidemiology Collaboration equation
* admission troponin \>99% of ULN
* admission d-dimer \> 1µg/ml
* O2 saturation ≤93% e on room air or need for any O2 therapy

Exclusion Criteria:

* Age \<18 years
* History of pancreatitis
* History of multiple endocrine neoplasia or medullary thyroid cancer
* Current use of a GLP-1 receptor agonist \[use of a DPP-4 inhibitor is allowed\]
* Positive beta-HCG (pregnancy test is mandated with baseline bloodwork for all female subjects ≤50 years of age
* Breastfeeding, if they intend to continue breastfeeding
* Elevation of serum lipase, direct (conjugated) bilirubin, or alkaline phosphatase (ALP) more than 3X the upper limit of normal on baseline bloodwork
* history of decompensated heart failure with reduced ejection fraction (\<35%) within 90 days, or known stable NYHA class IV heart failure prior to their COVID-19 illness
* imminent mechanical ventilation or death
* O2 therapy with high flow nasal cannula at FiO2 \>50% or already on mechanical ventilation
* Any marker of hemodynamic instability at baseline defined as persistent SBP \<90 mmHg after rehydration, or \> 220 mmHg after receiving routine antihypertensive therapy, or HR \<50 bpm or \> 140 bpm after rehydration.
* inability to provide informed consent from patient or Substitute Decision Maker (SDM)

Primary outcomes:
measure: Composite of death or mechanical ventilation
timeFrame: 28 days after randomization
Secondary outcomes:
measure: cardiac troponin level
timeFrame: 7±2 days after randomization
measure: cardiac troponin level
timeFrame: 14±2 days after randomization
measure: ECG
timeFrame: Day 7±2 and Day 14±2
measure: 28-day organ support-free days
timeFrame: 28 days
measure: A composite of death or intensification of medical therapy
timeFrame: 180 days
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: Instituto Prevent Senior
city: São Paulo
country: Brazil
facility: State University of Campinas
city: Mississauga
country: Canada
facility: Trillium Health Partners
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Peter Munk Cardiac Centre
state: Ontario
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Mexico City
country: Mexico
facility: Hospital de Infectologia
city: Mexico City
country: Mexico
facility: Hospital General Regional
city: Querétaro
country: Mexico
facility: Hospital Regional 2
city: Birmingham
country: United Kingdom
facility: Sandwell and West Birmingham NHS Trust
Study officials:
affiliation: University Health Network, Toronto
name: Vladimir Dzavik, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network, Toronto
name: Mansoor Husain, MD
role: PRINCIPAL_INVESTIGATOR
References: