Clinical trials

Early Treatment of COVID-19 with
Repurposed Therapies:
The TOGETHER Adaptive Platform Trial
Building Platform Trial Infrastructure for Infectious Diseases

www.togethertrial.com

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Co-Principal Investigators

Dr. Gilmar Reis
Associate Professor
Division of Medicine
Pontificia Universidade Catòlicade Minas Gerais

Dr. Edward Mills
Professor
Health Research Methods,Evidence, and Impact
McMaster University

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Senior Investigators

Dr. Gordon Guyatt

Dr. Lehana Thabane

Dr. Eric Lenze

Dr. Craig Rayner

Dr. Angela Reiersen

Distinguished Professor

Professor

Professor

Associate Professor

Associate Professor

Health Research

Health Research

Department ofMonash University

Department of Psychiatry,Methods, Evidence andMethods, Evidence andPsychiatry, Washington

Washington University in St.

Impact, McMaster

Impact, McMaster

University in St. Louis

President, Integrated
Drug Development

UniversityUniversity
President-elect, Society

for Clinical Trials (SCT)

Certara Inc.

Louis

Clinical trials

Clinical trials in COVID-19 are small,and likely underpowered• Of the 2,908 trials captured in our registry, overhalf (51%) intend to recruit 100 patients or less.

• The median sample size across all trials is100• Despite being small individually, these trials
correspond to over 74,054 participants
collectively.

• Looking at trials investigating HCQ alone (or vs.

standard of care), in a hospitalized setting only,
this corresponds to 4,893 patients – over threetimes the total N of the HCQ arm of theRECOVERY trial.

• Individually, these small trials are not meaningful,but collectively, they represent an extraordinary
untapped source of data.

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What makes useful trials different?
• Remap-Cap• Solidarity• Recovery• Principle• TOGETHERClinical trials

Master Protocols and Platform Trials

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Perpetual trials
Builds trial infrastructure• Creation of trial centers and clinical recruitment sites• Formation of committees and charters (e.g. DSMC, Steering, and Event adjudication)• Trains and retains trial management staff
Trial Design• Adaptive randomization and other adaptive design features• Longitudinal modeling to determine probabilities of success or failure• Shared control patients• No specific sample sizes

TOGETHER Trial Overview

Clinical trials• Randomized adaptive platform trial to investigate the efficacy of repurposed treatments for COVID-19 disease
among high-risk adult outpatients• Received ethics board approval in Brazil (CEP/CONEP#: 41174620.0.1001.5120), and Canada (HiREB#: 13390)• Data and Safety Monitoring Committee provides independent oversight• The trial was initiated on June 2, 2020
• Enrollment into the fluvoxamine arm began on January 15, 2021
• Planned interim analysis of the fluvoxamine arm with the data cut
from August 2nd, 2021

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Trial Setting
Clinical Sites In Minas Gerais:

1. Sete Lagoas
2. Ibirité
3. Brumadinho
4. Governador Valadares
5. Montes Claros
6. Nova Lima
7. Santa Luzia
8. Ouro Preto
9. Belo Horizonte
10. Betim

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Inclusion Criteria
1.
2.

Patients over the age of 18

3.
4.

Positive rapid test for SARS-CoV-2 antigen

Presenting to an outpatient care setting with an acute clinical condition consistent with COVID-19 and symptoms beginning within 7 days of thescreening date

At least one additional criterion for high-risk:•••••••••••

Diabetes mellitus
Systemic arterial hypertensionSymptomatic lung disease
Symptomatic asthma patients
SmokingObesity
Transplant patients

Patient with stage IV chronic kidney disease or on dialysis
immunosuppressed
History of cancer in the last 0.5 years or undergoing current cancer treatment.
Age greater than 50 years

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Exclusion Criteria
9.

Severe psychiatric disorders or major depression

10.

Pregnant or breastfeeding patients

11.

History of severe ventricular cardiac arrhythmia

12.

History of diabetic ketoacidosis or clinical condition that maintains
persistent metabolic acidosis;

5.
Dyspnea secondary to other acute and chronic respiratory causes orinfections

13.

Surgical procedure or use of contrast planned to occur during treatment
or up to 5 days after the last dose of the study medication

6.

14.

Current daily and / or uncontrolled alcoholism

15.

History of seizures in the last month or uncontrolled seizure

16.

History of liver cirrhosis or Child-Pugh C classification

17.

Known severe degenerative neurological diseases and / or severe mental
illness

18.

Inability of the patient or representative to give informed consent oradhere to the procedures proposed in the protocol

19.

Known hypersensitivity and / or intolerance to fluvoxamine, ivermectinor metformin;

20.

Inability to take oral medications

21.

Inability or unwillingness to follow research guidelines and procedures

1.
Diagnostic examination for SARS-CoV2 negative associated with acuteflu-like symptoms
2.
Acute respiratory condition compatible with COVID-19 treated in theprimarycare and requiring hospitalization
3.

Acute respiratory condition due to other causes

4.

Patients who have received vaccination for SARS-CoV2

Acute flu showing at least one of the criteria below:•••

Respiratory Rate > 28 / min;
SaO2 < 90% or < 93% on nasal oxygen therapy at 10 L / min;

PaO2 / FIO2 < 300 mm Hg;

7.

Use of serontonin receptor inhibitors

8.

Use of the following medications in the last 14 days:•••

Monoamine Oxide Inhibitors (phenelzine, tranylcypromine,selegiline, isocarboxazide, moclobemide);
Use of iodinated contrasts during treatment until 05 days after theend;
Use of antiretroviral agents (Treatment of Acquired
Immunodeficiency Syndrome - AIDS);Clinical trialsRandomization• Patients screened for eligibility• Informed consent obtained• Randomized to intervention or placebo• Randomization stratified:• To account for other arms in the trial• Clinical site
• Age (≥50 years vs <50 years)

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Trial Schema

Intervention Timeline
Clinical trials

INF-Lambda
Doxasosin
Fluvoxamine
IVM (low dose)

IVM (high dose)

Metformin

HCQ

LPV/r

Placebo

June 2020

July 2021
March 2021
June 2021
January 2021

October 2020

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Outcomes
Primary Outcomes:• Emergency room visits due to theclinical worsening of COVID-19(defined as participant remaining
under observation for > 6 hours)• Hospitalization due to theprogression of COVID-19 (definedas worsening of viral pneumonia)
and/or complications within 28 daysof randomization.

Secondary Outcomes:• WHO clinical worsening scale• PROMIS global health scale• Mortality defined and all-cause• Cause-specific hospitalization• Viral clearance and viral load
• Respiratory symptoms• Adverse events• Adverse drug reactions• Adherence with medication

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Data Collection• Participants were contacted on Days 1, 2, 3, 4, 5, 7, 10, 14, and 28 via telephone and social media
applications• Participants were contacted at day 60 to assess long-term outcomes• All SAEs were documented and reported as per local regulatory requirements• Data were entered into the trial’s EDC system (IBM Clinical Development)

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Recruitment Over TimeClinical trials

Previous Findings• Hydroxychloroquine or lopinavir/ritonavir vs. placebo• Metformin vs. placebo• Ivermectin vs. placebo

RCT: Effect of Early Treatment with Hydroxychloroquine (HCQ) or Lopinavir/ritonavir (LPV/r) onRisk of Extended Emergency Care or Hospitalization Among Patients with COVID-19
POPULATIONINTERVENTIONFINDINGS

308 Men, 377 Women

685 Patients Randomized

The following had a COVID-19–associatedhospitalization:
8/214 participants from the HCQ group (3.7%);
14/244 participants from the LPV/r group(5.7%);
11/227 participants from the control group(4.8%);

Patients with COVID-19 and
expected hospital stays of ≤ 5days
Median 53 y (18-94 y)

214 HCQ:

244 LPV/r: loading doseloading dose of800 mg at the timeof randomizationand then 400 mg
in daily doses at8:00 AM for 9 daysof 800 mg of lopinavir and200 mg of ritonavir at thefirst 2 intakes, followed by
400 mg of lopinavir and 100
mg of ritonavir every 12hours for the next 9 days.

SETTINGS/LOCATIONS

7 Clinical sites, Minas
Gerais, Brazil

227 Placebo
Oralplacebo talc
tablet

PRIMARY OUTCOMESCOVID-associated hospitalization anddeath measured at day 90

RCT: Effect of Early Treatment with Metformin on Risk of Emergency Care and Hospitalization
Among Patients with COVID-19
POPULATIONINTERVENTION

43% Men, 57% Women

217 Patients

Patients with COVID-19 and expected
hospital stays of ≤ 5 days
Median 52 y (18-90 y)

Metformin 750mg dose
twice daily for 10 days

SETTINGS/LOCATIONS

10 Clinical sites,
Minas Gerais, Brazil

FINDINGS
206 patients

Placebo Oral placebotalc tablet

PRIMARY OUTCOMES
A composite of emergency room visits due toclinical worsening of COVID-19 (requiringobservation for > 6 hours) or hospitalization due
to the progression of COVID-19 within 28 days ofrandomization.

The proportion of patients with extended ER
observation or hospitalization was the 32/217(17.2%) for the metformin group and 27/206(14.5%) in the placebo group

RCT: Effect of Early Treatment with Ivermectin 3-day on Risk of Emergency Care andHospitalization Among Patients with COVID-19
POPULATIONINTERVENTION

43% Men, 56% Women

677 Patients,Patients with COVID-19 and expected
hospital stays of ≤ 5 days
Median 52 y (18-91 y)

SETTINGS/LOCATIONS

10 Clinicalsites, Minas
Gerais, Brazil

Ivermectin 400 mcg/kg
up to 90kg weight every
24 hours for 3 days

FINDINGS678 patients

Placebo Oral placebotalc tablet

PRIMARY OUTCOMES
A composite of emergency room visits due toclinical worsening of COVID-19 (requiringobservation for > 6 hours) or hospitalization
due to the progression of COVID-19 within 28
days of randomization.

The proportion of patients withextended ER observation orhospitalization was the 86/677 for theIVM group and 95/678 in the placebogroup. Relative risk: 0.91 (0.69-1.19).
Mortality relative risk: 0.82 (0.44-1.52)

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Fluvoxamine
Fluvoxamine (742)Placebo (738)Female

407

438

Male

335

300

Age (SD)

47.9 (13.2)

47.8 (13.9)

Multiple co-morbidities

135123Clinical trials

Posterior Probability of Superiority of Fluvoxamine vs.
Placebo on Emergency Room Observation for > 6 Hours or
Hospitalization

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Relative Risk of Emergency Room Observation for > 6Hours or Hospitalization for
Fluvoxamine vs. Placebo

Number ofpatients

Number of events

Relative risk+[95% CrI]

Fluvoxamine

742

74

0.69[0.52;0.91]

Placebo738

107

ReferenceArm+ Calculated in a Bayesian framework

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Posterior Probability of Superiority of Fluvoxamine vs.
Placebo on Emergency Room Observation for > 6 Hours or
Hospitalization
Patients with at least 28 days of Follow-up

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Relative Risk of Emergency Room Observation for > 6Hours or Hospitalization forFluvoxamine vs. Placebo
Patients with at least 28 days of Follow-up
Number ofpatients

Number of events

Relative risk+[95% CrI]

Fluvoxamine

702

74

0.70 [0.53;0.92]

Placebo706

107

Reference

Arm+ Calculated in a Bayesian framework

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Posterior Probability of Superiority of Fluvoxamine vs.
Placebo on Emergency Room Observation for > 6 Hours orHospitalization
Patients with at least 1 day of treatment

Clinical trialsRelative Risk of Emergency Room Observation for > 6
Hours or Hospitalization for
Fluvoxamine vs. Placebo
Patients with at least 1 day of treatment
Number ofpatients

Number of event

Relative risk+[95% CrI]

Fluvoxamine

691

63

0.65[0.48;0.87]

Placebo695

97

Reference

Arm+ Calculated in a Bayesian framework

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Secondary Outcome:Relative Risk of Mortality for
Fluvoxamine vs. Placebo

Number ofpatients

Number of events

Relative risk+[95% CrI]

Fluvoxamine742

170.71 [0.39;1.29]

Placebo738

24

Reference

Arm+ Calculated in a Bayesian framework

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Secondary Outcome:
Viral Suppression at 7 Days
Fluvoxamine vs. Placebo

ArmFluvoxaminePlacebo

Odds Ratio (95% CI)

P-value

0.75 (0.52 – 1.07)
Reference0.12

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Readiness for Dissemination• International COVID-19 Data Alliance (ICODA)• WHO Guidelines Synthesis Group (GRADE)• UK NICE• NIH

Clinical trials

The TOGETHER Team
C0-Principal Investigators:
Edward Mills
Gilmar Reis
Senior Investigators:
Craig Rayner
Eric Lenze
Gordon Guyatt
Lehana Thabane
Angela Reiersen
Data Management:
James Bademian
Kathryne Scholtz
Mindy Wolf
Gerald Smith
Statistics:
Ofir HarariHinda Ruton
Holly Bailey

Data and Safety Monitoring
Committee:
Kristian Thorlund (Chair)
Sonal Singh
William Cameron
James Orbinski
Jonas Haggstrom
Trial Management Group:
Eduardo Silva
Daniela Silva
Jamie Forrest
Cameron Chernecki
Sheila Sprague
Paula McKay
Aline Cruz Milagres
Thiago Santiago Ferraria
Castilho Vitor Quirino dos Santos
Adhemar Dias de Figueirdo Neto
Leonardo Cançado Monteiro Savassi
Maria Izabel Campos Simplicio
Luciene Barra Ribeiro
Rosemary Oliveira

Pharmacist:
Linèria Morais
Communications:
Greg Thomas-ReillyVeronica McGuire
Partner Institutions:
McMaster University
PUC Minas Gerais
University of Ottawa
Platform Life Sciences
MMS Holdings
Cytel Inc
University de Ouro PretoClinical trials

SupportClinical trials

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