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

U

United Nations Children's Fund (UNICEF)

Status

Completed

Conditions

Cytokine Release Syndrome
Critical Illness
Covid19
ARDS

Treatments

Biological: Mesenchymal stem cell therapy
Drug: Remdesivir
Drug: Tocilizumab
Biological: Convalescent Plasma
Procedure: Therapeutic Plasma exchange

Study type

Interventional

Funder types

Other

Identifiers

NCT04492501
Sultan Mehmood Kamran 3

Details and patient eligibility

About

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.

Full 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
  4. 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.

Enrollment

600 patients

Sex

All

Ages

18 to 90 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

  • PCR positive confirmed COVID-19
  • Admitted in hospital
  • willing patients to participate in trial
  • Day of illness less than 14 days
  • no contraindications to invasive procedure or novel therapies

Exclusion criteria

  • co morbidities with life expectancy less than 6 months
  • Multi organ failure
  • Septic shock before initiation of treatment
  • Congestive cardiac failure (EF<20%) (4)
  • Those receiving immunotherapy, Anti-thymocyte globulin or hematopoietic stem cell transplant in recent past
  • Patients of hematological or solid organ malignancies

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Factorial Assignment

Masking

None (Open label)

600 participants in 4 patient groups

Supportive Arm
No Intervention group
Description:
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.
TPE arm
Experimental group
Description:
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.
Treatment:
Procedure: Therapeutic Plasma exchange
TPE in combination with other investigational treatments
Experimental group
Description:
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
Treatment:
Procedure: Therapeutic Plasma exchange
Biological: Convalescent Plasma
Drug: Remdesivir
Biological: Mesenchymal stem cell therapy
Drug: Tocilizumab
Either alone or combination of MSC, Remdesivir and Tocilizumab
Experimental group
Description:
A predefined number of patients will receive either alone Tocilizumab, Remdesivir and Mesenchymal stem cell therapy or their combination
Treatment:
Procedure: Therapeutic Plasma exchange
Biological: Convalescent Plasma
Drug: Remdesivir
Biological: Mesenchymal stem cell therapy
Drug: Tocilizumab

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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