Pan African Clinical Trials Registry

South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: www.pactr.org
Trial no.: PACTR202007700757139 Date of Approval: 14/07/2020
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title TOGETHER 3 Trial. COVID-19
Official scientific title TOGETHER 3 Trial: An Adaptive Randomized Platform Trial to Investigate the Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults. COVID-19
Brief summary describing the background and objectives of the trial This protocol is for an adaptive platform trial for the treatment of high-risk adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection not requiring hospital admission. This proposal builds on an US-based adaptive platform trial for high-risk SARS-CoV-2 adult outpatients (TOGETHER 1) as well as Brazil (TOGETHER 2). The primary research question is to the efficacy of experimental interventions to prevent lower respiratory tract infections (LRTI) among persons with SARS-CoV2 infection who are at high risk of progression. The primary outcomes of trial will include progression to LRTI, defined by SpO2<93% or 6% decrease in Sp02 from baseline; and presence of viral shedding from nasal swabs at day 10 of treatment. Other agents are rapidly being screened and developed for SARS-CoV-2 infection and could be incorporated into this protocol as additional arms. The flexible platform trial design will allow additional agents to be added and tested with standardized eligibility criteria, outcomes, and measurements. If an intervention is shown to be effective, this design would allow replacement of the placebo group with the effective intervention as the comparator.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) TOGETHER 3
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied COVID-19
Purpose of the trial Treatment: Drugs
Anticipated trial start date 13/07/2020
Actual trial start date
Anticipated date of last follow up 31/05/2021
Actual Last follow-up date 31/07/2021
Anticipated target sample size (number of participants) 420
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
20200410 South African Health Products Regulatory Authority
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Allocation was determined by the holder of the sequence who is situated off site Masking/blinding used Care giver/Provider,Outcome Assessors,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Ascorbic acid Ascorbic acid 1000 mg orally twice daily for 1 day then 500 mg orally twice daily for 9 days 10 days Ascorbic acid 165 Active-Treatment of Control Group
Experimental Group Lopinavir ritonavir 800mg-200mg orally twice daily x 1 day, then 400mg-100mg twice daily for an additional 9 days 10 days Lopinavir/ritonavir 800mg/200mg orally twice daily x 1 day, then 400mg/100mg twice daily for an additional 9 days 165
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
Participants are eligible to be included in the study only if all of the following criteria apply: High-risk cohort: 1. Men or women 18-80 years, inclusive, at the time of signing the informed consent 2. Willing and able to provide informed consent 3. Laboratory confirmed SARS-CoV-2 infection, with test results within past 72 hours 4. At increased risk of developing severe COVID-19 disease (at least one of the following) • Age ≥60 • Presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, emphysema, or tuberculosis on treatment • Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment • Hypertension, requiring at least 1 antihypertensive oral medication for treatment • Coronary artery disease with history of graft or stent • Cardiac failure, Class 2 or greater using New York Heart Association functional class • History of organ or stem cell transplant • Immunocompromised status due to disease (e.g., those living with human immunodeficiency virus, confirmed malignancy) • Immunocompromised status due to medication (e.g., persons taking 20 mg or more of prednisone equivalents a day, anti-inflammatory monoclonal antibody therapies, or cancer therapies) • Body mass index ≥ 30 kg/m2 Participants are excluded from the study if any of the following criteria apply: 1. Known hypersensitivity to any of the study drugs 2. Currently hospitalized 3. Signs of respiratory distress prior to randomization, including respiratory rate >24 per minute and/or SpO2 < 93% 4. Chronic kidney disease (Stage IV or receiving dialysis) 5. Known liver disease or cirrhosis 6. Known personal or family history of long QT syndrome 7. Taking chronic medications associated with prolonged QT and may induce Torsades de Pointes as per CredibleMeds.org, including certain antipsychotic medications or antidepressants (e.g., citalopram, venlafaxine, and bupropion) and unable to stop during the trial 8. Baseline QTc interval of > 470 ms in males, and > 480 ms in females if indicated by the safety profile of the investigational product 9. Potentially clinically significant pharmacokinetic and pharmacodynamic drug interactions as determined by the study clinical pharmacologist* 10. Currently participating in a clinical trial currently or within 30 days of randomization. 80 and over: 80+ Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 80 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 06/07/2020 Stellenbosch University Health Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Francie van Zijl Drive Cape Town 7505 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome LRTI, defined by SpO2<93% or decline from baseline of 6% in 2 measurements at least 2 hours apart. Study end
Primary Outcome Time to clearance of nasal SARS-CoV-2, defined as 1 negative swab. Study end
Secondary Outcome Serious adverse events (including death, hospitalization) and adverse events resulting in treatment discontinuation Study end
Secondary Outcome Hospitalisation Study end
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Family Centre for Research with Ubuntu Francie van Zijl Drive, Tygerberg Hospital Cape Town 7505 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
University of Washington 1410 NE Campus Parkway Seattle 98195 United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Cytel Inc 802-777 West Broadway Vancouver Canada Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
University of Cape Town Woolsack Drive Cape Town 7701 South Africa
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Mark Cotton mcot@sun.ac.za +27219384302 Francie van Zil Drive
City Postal code Country Position/Affiliation
Cape Town South Africa Director of the Family Centre for Research with Ubuntu FAMCRU
Role Name Email Phone Street address
Public Enquiries Caroldine Neal neal@sun.ac.za +27219384228 Francie van Zijl Drive
City Postal code Country Position/Affiliation
Cape Town 8001 South Africa Study Coordinator
Role Name Email Phone Street address
Scientific Enquiries Eric Decloedt ericdecloedt@sun.ac.za +27219389340 Francie van Zijl Drive
City Postal code Country Position/Affiliation
Cape Town 8001 South Africa Study Lead and co PI
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes All of the individual participant data during this COVID-19 trial will be shared after deidentification. Analytic Code,Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol As soon as possible after study completion, but at least within 12 months after study completion. Data will be available for sharing up to 5 years after study completion. The raw study data will be made available to individuals or organisations who make legitimate and appropriate requests, provided that permission from the international PI and his institution, funder and the Stellenbosch University Health Research Ethics Committee have been obtained.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information
Section Name Field Name Date Reason Old Value Updated Value
Eligibility Age group 14/07/2020 Edit to include the full age range Adult: 19 Year-44 Year Adult: 19 Year-44 Year, Middle Aged: 45 Year(s)-64 Year(s), Aged: 65+ Year(s), 80 and over: 80+ Year
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Public title 14/07/2020 edit TOGETHER 3 Trial TOGETHER 3 Trial. COVID-19
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Official scientific title 14/07/2020 edit TOGETHER 3 Trial: An Adaptive Randomized Platform Trial to Investigate the Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults TOGETHER 3 Trial: An Adaptive Randomized Platform Trial to Investigate the Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults. COVID-19
Section Name Field Name Date Reason Old Value Updated Value
Reporting Plan to share IPD 14/07/2020 Mandatory IPD sharing statement. Undecided Yes
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD description 14/07/2020 Mandatory IPD sharing statement. All of the individual participant data during this COVID-19 trial will be shared after deidentification.
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD-Sharing time frame 14/07/2020 Mandatory IPD sharing statement. As soon as possible after study completion, but at least within 12 months after study completion. Data will be available for sharing up to 5 years after study completion.
Section Name Field Name Date Reason Old Value Updated Value
Reporting Key access criteria 14/07/2020 Mandatory IPD sharing statement. The raw study data will be made available to individuals or organisations who make legitimate and appropriate requests, provided that permission from the international PI and his institution, funder and the Stellenbosch University Health Research Ethics Committee have been obtained.
Section Name Field Name Date Reason Old Value Updated Value
Reporting Study protocol document 14/07/2020 Document that will be shared. Study Protocol, Statistical Analysis Plan, Informed Consent Form, Clinical Study Report, Analytic Code