Investigational Treatments for COVID-19 in Tertiary Care Hospital of Pakistan
Condition: Covid19; Cytokine Release Syndrome; Critical Illness; ARDS
MeSH terms: COVID-19; Critical Illness; Cytokine Release Syndrome
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      Long title: Role of different investigational treatments alone or in combination to treat
      moderate, severe and critical COVID-19 in addition to standard treatment; An Open label,
      Phase 2 Study Clinical Phase: multi arm, Phase 2 Open Label Conducted by: Department of
      Pulmonology and Critical Care; Pak Emirates Military Hospital. Sample Size: 600 Study
      Population: Hospitalized COVID-19 patients aged ≥18 years to 80 years of with Moderate-
      severe-critical disease Study Duration: 1st April, 2020 to 31st July 2020 Study Design: This
      open label phase 2 trial will assess the efficacy and safety of following treatment options
      1. Standard treatment including steroids 2. Therapeutic plasma exchange in addition to
      standard treatment 3. Therapeutic Plasma exchange in combination with Convalescent Plasma in
      addition to standard treatment 4. Tocilizumab in addition to standard treatment 5. Remdesivir
      alone or in combination with Therapeutic plasma exchange in addition to standard treatment 6.
      Mesenchymal stem cell therapy in combination with other investigational treatments in
      addition to standard treatment Operational Definitions

        1. Moderate disease:

           COVID-19 positive case with lung infiltrates < 50% of total lung fields on Chest X-ray /
           peripheral ground glass opacities (GGOs) on High Resolution Computerized Tomography
           (HRCT)chest but no evidence of hypoxemia.

        2. Severe disease:

           COVID-19 pneumonia with evidence of hypoxemia (RR > 30/minute or PaO2 on ABGs < 80mmHg
           or PaO2/FiO2 (PF ratio) < 300 or lung infiltrates > 50% of the lung field).

        3. Critical illness:

           COVID-19 pneumonia with evidence of either respiratory failure (PaO2 < 60mmHg) or
           multiorgan dysfunction syndrome (MODS) measured by Sequential Organ Failure assessment
           (SOFA score) > 10 or septic shock (Systolic BP less than 90 or less than 40mm Hg of
           baseline in hypertensive or Urine output < 0.5 ml/kg/hour).Age, sex, comorbidities, date
           of symptoms, source of infection, type of admission SOFA score, Clinical status, vital
           signs including temperature, respiratory rate, oxygen saturation, oxygen requirement,
           Complete Blood counts (CBC) with neutrophil counts, lymphocytes count, C-reactive
           Proteins (CRP), chest imaging (CT or X-ray), location and status in hospital

        4. Cytokine release storm (CRS):

      Diagnostic criteria of Cytokine release syndrome (CRS) CRS is defined as fever of equal to or
      more than 100 F persisting > 48 hours in absence of documented bacterial infection and ANY of
      the following in the presence of moderate, severe or critical disease

        1. Ferritin >1000 mcg/L and rising in last 24 hours

        2. Ferritin >2000 mcg/L in patient requiring high flow oxygen or ventilation

        3. Lymphopenia < 800 cells/ul or lymphocyte percentage <20% and two of the following

             1. Ferritin >700 mcg/mL and rising in the last 24 hours

             2. LDH > 300 IU (reference 140-250 IU/L) and rising in the last 24 hours

             3. D-Dimer >1000ng/mL (or >1mcg/ml) and rising in the last 24 hours

             4. CRP >70 mg/L (or >10 hsCRP) and rising in the last 24 hours, in absence of
                bacterial infection

             5. If any 3 of above presents on admission no need to document rise

      5. Standard treatment: 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 CRS received Methylprednisolone 1 mg/kg irrespective of disease severity. 6.
      Therapeutic Plasma exchange (TPE) Therapeutic plasma exchange: 1-1.5 plasma exchange daily
      (1-5 sessions) with replacement fluid Fresh frozen Plasma (FFP) (whole volume) to 70 willing
      patients of moderate, severe and critical disease with evidence of CRS after explaining the
      investigational role of this therapy. TPE will be given in addition to standard treatment to
      70 patients randomly. TPE related complications to be documented 7. Recovery Recovery to be
      defined by de-escalation of patients condition from severe to moderate, or from moderate to
      mild, plus at least 2 of the following; serum Ferritin < 1000 ug/ml (and decreasing trend on
      two consecutive days), serum LDH normalization, C-reactive protein > 50% fold reduction (and
      decreasing trend in on two consecutive days),), ALC > 1000 and PT/APTT normalization.
    

Intervention name(s): Therapeutic Plasma exchange; Convalescent Plasma; Tocilizumab; Remdesivir; Mesenchymal stem cell therapy
Intervention type(s): Procedure; Biological; Drug; Drug; Biological
Intervention description(s): 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 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;
After 28 day of illness till 3 months
Symptom free 2 weeks prior to donation
Negative two consecutive PCRs any time between initial positivity and before donation
Anti SARS-CoV2 IgG positive, IgM negative
Fulfills healthy donor criteria as per WHO/AABB guidelines
Volume of plasma to be collected: 900-1200 ml through Apheresis OR plasma separated from phlebotomy donation; 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; 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.; 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.
Other intervention name(s): MSC
Intervention MeSH terms: Remdesivir
Allocation: Non-Randomized
Intervention model: Factorial Assignment
Intervention model description: It will be an interventional retrospective case control, single centre based cohort study in Pak Emirates Military Hospital Rawalpindi (PEMH), Pakistan from 1st April to 31st July 2020. This study will be carried out at the Department of Pulmonology and Critical care. PEMH is the largest Covid-19 designated hospital in the country. Data of all hospitalized patients is maintained by PEMH Covid-19 Research and evaluation cell. The study was approved by Institutional Review Board.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Therapeutic Plasma exchange; tocilizumab; remdesivir; convalescent plasma; mesenchymal stem cell; COVID-19; investigational treatment