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CTRI Number  CTRI/2020/06/026196 [Registered on: 28/06/2020] Trial Registered Prospectively
Last Modified On: 17/08/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug
Surgical/Anesthesia
Preventive 
Study Design  Randomized, Parallel Group, Multiple Arm Trial 
Public Title of Study   Prevention of Respiratory Complications In At Surgery in COVID-19 Pandemic 
Scientific Title of Study   Preventing Pulmonary Complications In Surgical Patients At Risk Of COVID-19 
Trial Acronym  PROTECT-Surg 
Secondary IDs if Any  
Secondary ID  Identifier 
2020-001448-24  EudraCT 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dhruva Nath Ghosh 
Designation  Professor 
Affiliation  Christian Medical College Ludhiana 
Address  Christian Medical College Hospital Brown Road

Ludhiana
PUNJAB
141008
India 
Phone  9915198894  
Fax    
Email  dhruvghosh73@gmail.com  
 
Details of Contact Person
Scientific Query
 
Name  Amit Mahajan 
Designation  Professor 
Affiliation  Christian Medical College Ludhiana 
Address  Christian Medical College Hospital Brown Road

Ludhiana
PUNJAB
141008
India 
Phone  9988018700  
Fax    
Email  dr_amitrock@yahoo.co.in  
 
Details of Contact Person
Public Query
 
Name  Amit Mahajan 
Designation  Professor 
Affiliation  Christian Medical College Ludhiana 
Address  Christian Medical College Hospital Brown Road

Ludhiana
PUNJAB
141008
India 
Phone  9915198894  
Fax    
Email  dr_amitrock@yahoo.co.in  
 
Source of Monetary or Material Support  
Christian Medical College Ludhiana 
University Of Birmingham, UK 
 
Primary Sponsor  
Name  University Of Birmingham 
Address  Research Governance Team University of Birmingham Birmingham, B152TT 
Type of Sponsor  Research institution 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     Benin
Ghana
India
Italy
Mexico
Nigeria
Rwanda
South Africa
United Kingdom  
Sites of Study
Modification(s)  
No of Sites = 4  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Madhabananda Kar  All India Institute Of Medical Sciences Bhubaneshwar  Department Of Surgical Oncology
Khordha
ORISSA 
6742476083

madhabananda@gmail.com 
Sanjeev Misra  All India Institute Of Medical Sciences, Jodhpur  Dept Of Surgical Oncology
Jodhpur
RAJASTHAN 
9919140407

misralko@gmail.com 
Amit Mahajan  Christian Medical College   Department Of Surgery Christian Medical College Hospital Brown Road
Ludhiana
PUNJAB 
9988018700

dr_amitrock@yahoo.co.in 
Chandrashekhar Mahakalkar  Datta Meghe Institute Of Medical Sciences, Wardha  Department Of Surgery Jawahar Lal Nehru Medical College & Acharya Vinoba Bhave Rural Hospital
Wardha
MAHARASHTRA 
9822369277

cmahakalkar@rediffmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 4  
Name of Committee  Approval Status 
All India Institute Of Medical Sciences Bhubhaneshwar  Approved 
All India Institute Of Medical Sciences Jodhpur  Approved 
Christian Medical College Ludhiana  Approved 
Datta Meghe Institute Of Medical Sciences Wardha  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  B972||Coronavirus as the cause of diseases classified elsewhere, O||Medical and Surgical,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Control (normal practice; neither trial drug)   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.  
Intervention  Hydroxychloroquine  Hydroxychloroquine is usually used as an antimalarial drug and in auto-immune diseases such as Lupus and Rheumatoid Arthritis. Promising laboratory studies have shown that chloroquine decreases COVID-19 entrance and replication within cells, together with its known anti-inflammatory effect. 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. A subsequent small non-randomised study from France showed reduction of viral load with hydroxychloroquine. 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.  
Intervention  Hydroxychloroquine plus Lopinavir-Ritonavir  Lopinavir 400mg-Ritonavir 100mg by mouth every 12 hours for 10 days or until discharge, whichever occurs first AND Hydroxychloroquine 400mg BD day 1; then 400mg daily day 2-5 or until discharge, whichever occurs first. There are no dual toxicity effects. Patients should undergo perioperative care according to each hospital’s normal practice, the main factors of which will be recorded. Potential interactions will be checked on a case by case basis. Discontinuation rates will be monitored.  
Intervention  Lopinavir-Ritonavir  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. A published series of patients treated with this Lopinavir-Ritonavir showed improved outcomes at 21 days after diagnosis, compared to historical controls. Lopinavir-Ritonavir has previously been shown to improve outcomes in animal models (marmosets) infected with MERS-CoV. 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. 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. 
 
Inclusion Criteria  
Age From  16.00 Year(s)
Age To  80.00 Year(s)
Gender  Both 
Details  1. Patients aged 16 years and over.
2. 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).
3. Asymptomatic of COVID-19, including patients with: those not tested, negative test results, positive test but no symptoms
4. Informed patient consent.
 
 
ExclusionCriteria 
Details  1. Procedures under local anaesthesia.
2. Symptomatic COVID-19 infection (by confirmed COVID-19 test or a clinical diagnosis)
3. Existing regular preoperative treatment with trial drugs.
4. Known history of adverse reaction/contraindication to trial drugs.
5.Pregnancy (including caesarean section).
• Actively breastfeeding.
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
One of the following COVID-19 specific, inpatient, postoperative pulmonary complications: Pneumonia, Acute respiratory distress syndrome, Death
 
All randomised participants will be followed up until death, discharge from hospital, or 30 days post-randomisation (whichever is sooner). Longer-term follow-up (e.g. 5 years) will be sought as appropriate to each participating country’s settings.  
 
Secondary Outcome  
Outcome  TimePoints 
Pneumonia, ARDS, and death will be presented and analysed separately as secondary outcomes.
Unexpected ventilation
Postoperative diagnosis of proven COVID-19 pulmonary complications
Overall SARS-CoV-2 infected rate
Duration of hospital stay (including time spent in intensive care, time ventilated)
Pulmonary function in keeping with the WHO Solidarity Trial outcome scale  
Secondary outcome measures will be recorded on the index hospital admission up to 30 days following surgery 
 
Target Sample Size   Total Sample Size="6400"
Sample Size from India="1100" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3/ Phase 4 
Date of First Enrollment (India)
Modification(s)  
15/08/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  15/08/2020 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="1"
Months="6"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  
Not Yet Recruiting 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   No Publications yet 
Brief Summary  

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 listed to undergo any type of inpatient surgery requiring general or regional anaesthesia (such as vulnerable patients undergoing surgery for a fractured neck of femur). who are asymptomatic of COVID-19 infection (including patients with: those not tested, negative test results, positive test but no symptoms) and are able to give informed consent.

Exclusion: Procedures under local anaesthesia; patients who have symptoms of COVID-19 infection (by confirmed COVID-19 test or a clinical diagnosis); existing regular preoperative treatment with trial drugs; known history of adverse reaction or contraindication to trial drugs; pregnant patients (including caesarean section).

Interventions and randomisation: The trial drugs are Lopinavir-Ritonavir and Hydroxychloroquine. Patients will be randomised 1:1:1:1 to (A) Control (normal practice; neither trial drug), (B) Lopinavir-Ritonavir only, (C) Hydroxychloroquine only, (D) both Lopinavir-Ritonavir and Hydroxychloroquine.

Primary Outcome: Any one of the following COVID-19 specific, inpatient, postoperative pulmonary complications: pneumonia; acute respiratory distress syndrome (ARDS); or death. 

Secondary Outcomes:

·       Unexpected ventilation (unexpected inability to extubate and wean patient from ventilation after general anaesthesia, or reintubation and ventilation by 30 days after surgery)

·       Postoperative diagnosis of proven COVID-19 pulmonary complications

·       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 

Sample size:

The trial uses a Bayesian adaptive platform design, allowing for termination of arms if their superiority to standard care is established, and addition of new treatment arms. The detailed statistical design of the trial will be described in a Statistical Analysis Plan.

The adaptive platform design does not have a fixed sample size. We will set a maximum sample size for each arm of 1600; which is similar to the number needed for a traditional frequentist 2-arm comparison to achieve p<0.05 with 90% power, with event rates of 16% in the control group and 12% in the intervention arm. Interim analyses will be conducted every 200 patients, starting when 250 patients per arm have reached the end of follow-up. All analyses will use Bayesian methods, with weakly informative priors, which will allocate very low probability to unrealistic treatment effects. New treatment arms will be added as more interventions are proposed and they will be compared only with controls recruited contemporaneously. Data from earlier control patients will be used in a more informative prior for the control group in these comparisons. 

 
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