Investigational Treatments for COVID-19 in Tertiary Care Hospital of Pakistan

Sponsor
UNICEF
Study ID
NCT04492501
Status
Completed

Conditions

  • ARDS
  • Covid19
  • Critical Illness
  • Cytokine Release Syndrome

Eligibility Criteria

Sex
ALL
Age
18 Years - 90 Years
Healthy Volunteers
Not accepted

Interventions

  • Therapeutic Plasma exchange — PROCEDURE
    1-1.5 plasma volume exchange, 2/3rd plasma should be replacing with FFP to avoid coagulopathy, adequate dieresis to prevent volume overload, 1-5 sessions in total, 1 session daily
  • Convalescent Plasma — BIOLOGICAL
    Convalescent plasma as part of replacement therapy (200-400ml) if reported within 14 days of illness. An IgG titer of \> 1.320 will be considered suitable for use. It will be Collected from person previously infected with Covid-19 and meet following criteria; 1. After 28 day of illness till 3 months 2. Symptom free 2 weeks prior to donation 3. Negative two consecutive PCRs any time between initial positivity and before donation 4. Anti SARS-CoV2 IgG positive, IgM negative 5. Fulfills healthy donor criteria as per WHO/AABB guidelines 6. Volume of plasma to be collected: 900-1200 ml through Apheresis OR plasma separated from phlebotomy donation
  • Tocilizumab — DRUG
    A predefined number of patients having evidence of cytokine release storm with normal procalcitonin level for three consecutive days, a normal blood culture and IL-6 level \> 3 times ULN will be given 1-2 doses of Tocilizumab (80mg IV) . Following contraindications to Tocilizumab will be considered (Allergy to any monoclonal Ab, ANC \< 1000, Platelets \< 50, ALT or AST \> 5 times ULN, Pregnancy and breast feeding, Post TB lung). Some patients will receive it alone in addition to standard treatment whereas in few patients where indicated it will be given in combination with MSC or Remdesivir or both
  • Remdesivir — DRUG
    It will be given to selected patients who have evidence of hypoxemia and presented with in 14 days of illness. For adults requiring invasive mechanical ventilation the dosage of remdesivir is a single loading dose of 200 mg sta on Day 1 followed by once daily maintenance doses of 100 mg IV for 9 days (days 2 through 10). For adults not requiring invasive mechanical ventilation 5 standard doses will be used. However, patients with known hypersensitivity to Remdesivir, multi organ failure, ALT \> 5 times ULN and GFR \< 30ml/minute will not be given Remdesivir. In some patients, where indicated other novel treatments including MSC therapy, Tocilizumab and therapeutic plasma exchange will be given.
  • Mesenchymal stem cell therapy — BIOLOGICAL
    Single Dose of 2 x 106 cells/kg will be administered either alone or in combination with other novel therapies. At Armed Forces Bone Marrow Transplant Centre (AFBMTC), MSCs will be isolated from bone marrow harvested cells. About 50ml bone marrow will be collected from iliac crest using aseptic technique in syringes primed with anticoagulant. The collected sample will be diluted with Phosphate Buffer Saline (PBS) and MSCs will be separated using density gradient centrifugation. After resuspension the cells will be seeded at a fixed concentration of 100,000 cells/cm2 in specially designed flasks and incubated at 37Oc in 5% CO2. Medium will be changed after every third day till harvesting of MSCs from the flasks. Once confluent (approximately day 20) the cells will be harvested with sterile techniques using Trypsin- EDTA solution.

Study Details

Beyond supportive care, there are currently no proven treatment options for coronavirus disease (COVID-19) and related pneumonia, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).Investigators have seen recently from experience in Western countries with best health care systems that pandemics cannot be managed in hospitals. Investigators have seen ICUs crowded to capacity, healthcare workers being exposed and going to quarantine or dying after exposure to large doses of viral inoculums. Investigators recommend that institutions should register for Clinical trials and consider emergency use of TPE. In Pandemics, time is of essence to avoid mortality by intervening early with available evidence, preferably as part of clinical trial.Since the outbreak of corona virus disease (COVID-19), main treatment modalities have been antivirals, interferons, glucocorticoids, anti-coagulants and supportive treatment in addition to traditional Chinese medicine. There are also clinical trials exploring hydroxyquinoline / chloroquine sulphate, azithromycin, immunoglobulins, Vitamin-C, washed microbiota, nebulized interferon, teicoplanin as well as Mesenchymal stem cells. However, most of these trials were small and remain in the experimental phase with currently no effective / specific antiviral with robust scientific evidence as regards the mortality reduction in COVID-19.In an attempt to treat COVID-19, investigator will use different investigational treatment either alone or in combination to see mortality and morbidity benefit on the basis of limitted evidence available so far. These investigational modalities include Therapeutic plasma exchange (TPE), Convalescent Plasma (CP), Remdesivir, Tocilizumab and Mesenchymal stem cell (MSC) therapy in addition to standard supportive treatment.

Key Dates

Start date
Apr 1, 2020
Status verified
Jul 2020
Primary completion
Jul 20, 2020
Completion
Jul 20, 2020

Study Design

Enrollment
600 participants (actual)
Allocation
NON_RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT

Arms

  • No Intervention: Supportive Arm
    As per Institutional COVID-19 Management Guidelines all patients of moderate, severe and critical COVID-19 received standard protocol of aspirin, anticoagulation, ulcer prophylaxis, awake Proning (if PaO2 \< 80mmHg) and corticosteroids. All patients of Cytokine release storm (CRS) received either Methylprednisolone 1 mg/kg or Dexamethasone 6-12mg/day irrespective of disease severity.
  • Experimental: TPE arm
    addition to standard care TPE will be performed once daily using COBE Spectra Apheresis machine version 7 (Manufacturer TERUMO BCT, Lakewood, CO, USA INC) having continuous flow centrifugation. Venous access will be achieved using an ultrasound guided double lumen catheter (Arrow - 12 FR) via femoral vein. Patient's total blood volume will be calculated as per Nadler's formula. Anticoagulant acid dextrose ratio will be 1:10 and flow rate 30-40 ml/minutes (Adjusted as per hemodynamic status). Patients' blood pressure, pulse, oxygen saturation will be monitored throughout procedure. Duration of procedure varied from 2-4 hours and 1-1.5 times total plasma volume will be removed during each procedure. Replacement fluid will be fresh frozen plasma (FFP) and normal saline in 2:1 respectively. All procedures will be performed in intensive care or high dependency unit by Apheresis Department of PEMH. TPE will be continued till recovery.
  • Experimental: TPE in combination with other investigational treatments
    During TPE, Replacement fluid will be fresh frozen plasma (FFP) and normal saline in 2:1 respectively plus 200-400 ml of convalescent plasma. A predefined number of patients will also receive mesenchymal stem cell therapy and/or Remdesivir
  • Experimental: Either alone or combination of MSC, Remdesivir and Tocilizumab
    A predefined number of patients will receive either alone Tocilizumab, Remdesivir and Mesenchymal stem cell therapy or their combination

Primary Outcome Measure

survival [ Time Frame: 28 days ]

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