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AzTrials

Covid19NCT04492501

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

A study testing Therapeutic Plasma exchange, Convalescent Plasma and Tocilizumab in people with Covid19 and Cytokine Release Syndrome, run by UNICEF at 1 site in Pakistan.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 90 years
What is being tested?
Therapeutic Plasma exchange, Convalescent Plasma and Tocilizumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
600 participants
Where
1 sitePakistan
Study dates
1 Apr 2020to 20 Jul 2020
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 90 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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 locations and contacts

1 site in 1 country.

Pakistan1 site

  • Pak Emirates Military Hospital

    Rawalpindi, Punjab Province, 46000

Other trials in Pakistan

About this study

Official title: Role of Investigational Therapies Alone or in Combination to Treat Moderate, Severe and Critical COVID-19

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.

Read the 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
  4. Ferritin >700 mcg/mL and rising in the last 24 hours
  5. LDH > 300 IU (reference 140-250 IU/L) and rising in the last 24 hours
  6. D-Dimer >1000ng/mL (or >1mcg/ml) and rising in the last 24 hours
  7. CRP >70 mg/L (or >10 hsCRP) and rising in the last 24 hours, in absence of bacterial infection
  8. If any 3 of above presents on admission no need to document rise
  9. 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.
Being tested
Therapeutic Plasma exchange, Convalescent Plasma, Tocilizumab, Remdesivir, Mesenchymal stem cell therapy
Keywords
Therapeutic Plasma exchange, tocilizumab, remdesivir, convalescent plasma, mesenchymal stem cell, COVID-19, investigational treatment
Medical subject headings
COVID-19, Cytokine Release Syndrome, Critical Illness

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Therapeutic Plasma exchangeProcedure or surgery

    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 PlasmaBiological

    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

  • TocilizumabDrug

    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

  • RemdesivirDrug

    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 therapyBiological

    Also called MSC

    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 groups in NCT04492501
Study groupRoleWhat they receive
Supportive ArmNo interventionAs 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 armExperimentaladdition 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.
Receives: Procedure: Therapeutic Plasma exchange
TPE in combination with other investigational treatmentsExperimentalDuring 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
Receives: Procedure: Therapeutic Plasma exchange; Biological: Convalescent Plasma; Drug: Tocilizumab; Drug: Remdesivir; Biological: Mesenchymal stem cell therapy
Either alone or combination of MSC, Remdesivir and TocilizumabExperimentalA predefined number of patients will receive either alone Tocilizumab, Remdesivir and Mesenchymal stem cell therapy or their combination
Receives: Procedure: Therapeutic Plasma exchange; Biological: Convalescent Plasma; Drug: Tocilizumab; Drug: Remdesivir; Biological: Mesenchymal stem cell therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. survival

    death or recovery

    Measured: 28 days

Secondary outcomes (4)

  1. duration of hospitalization

    duration in days

    Measured: 28 days

  2. Time to resolution of cytokine release storm

    duration in days to normalize symptoms and laboratory parameters

    Measured: 28 days

  3. Time of viral clearance

    Time in days to turn PCR negative

    Measured: 45 days

  4. Complications

    incidence of Post Covid lung fibrosis

    Measured: 90 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Jul 2020
  2. Study start1 Apr 2020
  3. Primary completion20 Jul 2020
  4. Study completion20 Jul 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Factorial
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)
Enrolment
600 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04492501
Sponsor's protocol ID
Sultan Mehmood Kamran 3
Status last verified
Jul 2020
First submitted
28 Jul 2020
Last updated
30 Jul 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: data can be shared on demand in SPSS sheet

Publications

  • Knaup H, Stahl K, Schmidt BMW, Idowu TO, Busch M, Wiesner O, Welte T, Haller H, Kielstein JT, Hoeper MM, David S. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit Care. 2018 Oct 30;22(1):285. doi: 10.1186/s13054-018-2220-9.

    PubMed 30373638

  • Keith P, Day M, Perkins L, Moyer L, Hewitt K, Wells A. A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19. Crit Care. 2020 Apr 2;24(1):128. doi: 10.1186/s13054-020-2836-4. No abstract available.

    PubMed 32241301

  • Shi H, Zhou C, He P, Huang S, Duan Y, Wang X, Lin K, Zhou C, Zhang X, Zha Y. Successful treatment with plasma exchange followed by intravenous immunoglobulin in a critically ill patient with COVID-19. Int J Antimicrob Agents. 2020 Aug;56(2):105974. doi: 10.1016/j.ijantimicag.2020.105974. Epub 2020 Apr 13.

    PubMed 32298745

  • Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020 Apr;20(4):398-400. doi: 10.1016/S1473-3099(20)30141-9. Epub 2020 Feb 27. No abstract available.

    PubMed 32113510

  • Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, Zhang X, Pan A, Wei H. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020 May 19;117(20):10970-10975. doi: 10.1073/pnas.2005615117. Epub 2020 Apr 29.

    PubMed 32350134

  • Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fatkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764. Epub 2020 Oct 8.

    PubMed 32445440

  • Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, Shan G, Meng F, Du D, Wang S, Fan J, Wang W, Deng L, Shi H, Li H, Hu Z, Zhang F, Gao J, Liu H, Li X, Zhao Y, Yin K, He X, Gao Z, Wang Y, Yang B, Jin R, Stambler I, Lim LW, Su H, Moskalev A, Cano A, Chakrabarti S, Min KJ, Ellison-Hughes G, Caruso C, Jin K, Zhao RC. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging Dis. 2020 Mar 9;11(2):216-228. doi: 10.14336/AD.2020.0228. eCollection 2020 Apr.

    PubMed 32257537

Questions about this trial

What is this clinical trial studying?

A study testing Therapeutic Plasma exchange, Convalescent Plasma and Tocilizumab in people with Covid19 and Cytokine Release Syndrome, run by UNICEF at 1 site in Pakistan.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Pakistan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

survival (time frame: 28 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04492501, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jul 2020.

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