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: pactr.samrc.ac.za
Trial no.: PACTR202004893013257 Date of Approval: 23/04/2020
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Preventing Pulmonary Complications in Surgical Patients at Risk of COVID-19
Official scientific title PROTECT-Surg
Brief summary describing the background and objectives of the trial Background: Surgical patients represent a highly vulnerable patient group, who are at particular risk of COVID-19 exposure and complications whilst in hospital for essential surgical treatment. They are vulnerable because of their underlying comorbidity and also because they will be subjected to artificial ventilation at the time of surgery. There are currently no interventional trials looking to prevent or mitigate the pulmonary complications associated with concurrent COVID-19 infection acquired either just before surgery or during the postoperative stay in hospital. Primary objectives: To provide reliable estimates of the effect of study treatments on postoperative pulmonary complications during the COVID-19 pandemic. Secondary objectives: To assess the effects of study treatments on: • Post-operative proven COVID-19 pulmonary complications • Overall SARS-CoV-2 infected rate • Duration of intensive care and total hospital stay • Pulmonary function in keeping with WHO Solidarity Trial outcome scale (detailed in Appendix 2) • Safety and tolerability of study treatments Design: Adaptive platform design, multi-centre, open-label, randomised controlled trial. The interim trial results will be monitored by an independent Data Monitoring Committee (DMC), who will periodically assess whether the randomised comparisons in the study have provided evidence on postoperative pulmonary complications that is strong enough to influence global treatment guidelines. Trial arms will be amended on recommendation from the DMC and new arms can be added if a new drug or vaccine is released during the study that requires evaluation. Centre eligibility: Any hospital performing elective or emergency adult surgery that has recorded at least one case of COVID-19. Participants Inclusion: Adults (aged 16 years and over in the UK - this criteria MUST be made country-specific) listed to undergo any type of inpatient surgery requiring general or regional anaesthesia (such
Type of trial RCT
Acronym (If the trial has an acronym then please provide) PROTECT Sur
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied COVID-19
Purpose of the trial Prevention
Anticipated trial start date 25/04/2020
Actual trial start date 25/05/2020
Anticipated date of last follow up 25/05/2021
Actual Last follow-up date 25/04/2021
Anticipated target sample size (number of participants) 6400
Actual target sample size (number of participants) 6400
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
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
Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously Randomised Simple randomization using a randomization table created by a computer software program Central randomisation by phone/fax Masking/blinding used Outcome Assessors,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Hydroxychloroquine 400mg BD Hydroxychloroquine- 2-5 days or until patient is discharged Hydroxychloroquine is usually used as an antimalarial drug and in auto-immune diseases such as Lupus and Rheumatoid Arthritis[9]. Promising laboratory studies have shown that chloroquine decreases COVID-19 entrance and replication within cells, together with its known anti-inflammatory effect [10-12]. From small early phase clinical trials in China that included more than 100 patients being treated for COVID-19 pneumonia, chloroquine was associated with a shorter course of disease and less pneumonia exacerbation [13, 14]. A subsequent small non-randomised study from France showed reduction of viral load with hydroxychloroquine.[15] It has been used widely for many years without any major safety concerns. The Summary of Product Characteristics (SPC) lists all the reported adverse effects (section 4.8) but does not identify any commonly occurring adverse events which are specifically problems for surgical patients. 1600
Experimental Group Lopinavir Ritonavir Lopinavir 400mg-Ritonavir 100mg 12 hourly 10 days or until patient is discharged Lopinavir is a HIV-1 (Human Immunodeficiency Virus 1) protease inhibitor, normally used as part of combined drug therapy for HIV. Ritonavir is added to Lopinavir to enhance efficacy by increasing serum availability [3]. In-vitro experiments show viral susceptibility to the drug[4, 5]. A published series of patients treated with this Lopinavir-Ritonavir showed improved outcomes at 21 days after diagnosis, compared to historical controls [6]. Lopinavir-Ritonavir has previously been shown to improve outcomes in animal models (marmosets) infected with MERS-CoV [7]. A trial including 194 patients with advanced COVID-19 infection showed a small difference in time to clinical improvement, suggesting the need for further trials evaluating this drug [8]. Though early studies have not shown any difference in post treatment viral load, some centres are using this drug combination off-label to treat COVID-19 patients. No work has yet looked at the impact of these drugs on pre-infection or pre-symptomatic treatment (or in vulnerable patients). Robust evidence is needed to prove or exclude the benefit of Lopinavir-Ritonavir use to prevent pulmonary complications in patients undergoing surgery 1600
Experimental Group Hydroxychloroquine plus Lopinavir Ritonavir Lopinavir 400mg-Ritonavir 100mg by mouth every 12 hours Hydroxychloroquine 400mg 10 days or until patient is discharged The small French non-randomised study suggested that hydroxychloroquine’s effect may be reinforced by adding an antiretroviral[15]. The clinical benefit of this strategy for COVID-19 patients has not yet been established and requires late phase testing, especially in vulnerable patients.[16] The clinical benefit of this strategy for COVID-19 patients has not been established yet. A synergic effect might arise from combination with other drugs such as hydroxychloroquine, which has a complementary mechanism of action[17, 18]. 1600
Control Group normal practice neither trial drug duration of hospital stay Treatment without the trial drugs. Patients will be treated as per hospital routine practice without receiving any of the drugs given in the intervention arms. The control arm may change over the course of the trial and will be monitored by the TMG and DMC. 1600 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
• Patients aged 16 years and over in Ghana. (This criteria MUST be made country-specific) • Planned to undergo any type of elective or emergency inpatient surgery requiring general or regional anaesthesia (such as vulnerable patients undergoing surgery for a fractured neck of femur). • Asymptomatic of COVID-19, including patients with: those not tested, negative test results, positive test but no symptoms • Informed patient consent. • Procedures under local anaesthesia. • Symptomatic COVID-19 infection (by confirmed COVID-19 test or a clinical diagnosis); these patients will be eligible for the RECOVERY trial. • Existing regular preoperative treatment with trial drugs. • Known history of adverse reaction/contraindication to trial drugs. • Pregnancy (including caesarean section). • Actively breastfeeding. 80 and over: 80+ Year,Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s) 16 Year(s) 90 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 20/04/2020 NIHR Ethics committee
Ethics Committee Address
Street address City Postal code Country
Newcastle upon Tyre Newcastle 0044 United Kingdom
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome • Pneumonia • Acute respiratory distress syndrome (ARDS) • Death 30 days
Secondary Outcome • Pneumonia, ARDS, and death will be presented and analysed separately as secondary outcomes as well as within the composite primary outcome measure. • Unexpected ventilation (unexpected inability to extubate and wean patient from ventilation after general anaesthesia, or reintubation and ventilation up to 30 days after surgery) • Postoperative diagnosis of proven COVID-19 pulmonary complications (the method of diagnosis will be collected, i.e. infection based on microbiological testing or clinical features) • Overall SARS-CoV-2 infected rate (symptomatic and/or asymptomatic). • Duration of hospital stay (including time spent in intensive care, time ventilated) • Pulmonary function in keeping with the WHO Solidarity Trial outcome scale (will be detailed in Appendix 2) 30years
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Ghana Hub Tamale Teaching Hosipital Hospital Tamale 00233 Ghana
FUNDING SOURCES
Name of source Street address City Postal code Country
National Institute of Health Research Main Office London 0044 United Kingdom
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Dr Birgit Whitman Main Office Birmingham United Kingdom University
COLLABORATORS
Name Street address City Postal code Country
University for Development Studies School of Medicine and Health Sciences Tamale Teaching Hospital Hospital road Tamale 00233 Ghana
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Stephen Tabiri stabiri@UDS.edu.gh +233542968262 Hospital
City Postal code Country Position/Affiliation
Tamale 00233 Ghana Hub lead
Role Name Email Phone Street address
Principal Investigator Aneel Bhangu a.a.bhangu@bham.ac.uk +447789770619 Main Office
City Postal code Country Position/Affiliation
Birmingham 0044 United Kingdom Chief Investigator
Role Name Email Phone Street address
Public Enquiries Sohini Chakrabortee s.chakrabortee@bham.ac.uk +441213718121 Edgbaston
City Postal code Country Position/Affiliation
Birmingham 0044 United Kingdom NIHR Global Health Research Unit on Global Surgery
Role Name Email Phone Street address
Scientific Enquiries Dion Morton Dion.Morton@uhb.nhs.uk +44121371200 Edgbaston
City Postal code Country Position/Affiliation
Birmingham 0044 United Kingdom Barling Chair of Surgery and Director NIHR Global Health Research Unit on Global Surgery
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes The security of the trial database is governed by the policies of the University of Birmingham. Data management and data security within BCTU will abide by the requirements of the General Data Protection Regulations and any subsequent amendments. The trial will be conducted at collaborating sites in accordance with the country-specific data protection requirements. Data will be acquired and stored on the REDCap platform. At BCTU and at participating hospitals, access to data will be restricted and will require a login username and password. No study data will be held in handheld media, laptops, personal computers, or other similar media. Individual participant information obtained as a result of this study is considered confidential. All data will be analysed and reported in summary format. No individual will be identifiable. Informed Consent Form,Study Protocol Research staff will utilise a web-based database to record participant data in accordance with the protocol. Trial-specific data may either be entered directly onto the database, or alternatively paper CRFs may be completed by local research staff, and data entered on the database at a later date as necessary. Site teams must enter data on the trial database as soon after each assessment as possible; continuation of trial arms will be dependent on interim analyses and consequently maintaining a high level of data completeness and accuracy must be prioritised. Data will be acquired and stored on the REDCap platform. At BCTU and at participating hospitals, access to data will be restricted and will require a login username and password. No study data will be held in handheld media, laptops, personal computers, or other similar media
URL Results Available Results Summary Result Posting Date First Journal Publication Date
under construction 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