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

NCT04492501 | Completed DMC

• 1 other identifier: Sultan Mehmood Kamran 3
• Study Type: interventional
• Target: 600
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Covid19; Cytokine Release Syndrome; Critical Illness; ARDS

Keywords

Therapeutic Plasma exchange; tocilizumab; remdesivir; convalescent plasma; mesenchymal stem cell; COVID-19; investigational treatment

Outcome Measures

Primary Outcomes (1)

• survival

  death or recovery

  28 days

Secondary Outcomes (4)

• duration of hospitalization

  28 days

• Time to resolution of cytokine release storm

  28 days

• Time of viral clearance

  45 days

• Complications

  90 days

Study Arms (4)

Supportive Arm

NO INTERVENTION

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

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.

Procedure: Therapeutic Plasma exchange

TPE in combination with other investigational treatments

EXPERIMENTAL

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

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

Either alone or combination of MSC, Remdesivir and Tocilizumab

EXPERIMENTAL

A predefined number of patients will receive either alone Tocilizumab, Remdesivir and Mesenchymal stem cell therapy or their combination

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

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

Either alone or combination of MSC, Remdesivir and Tocilizumab; TPE arm; TPE in combination with other investigational treatments

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

Either alone or combination of MSC, Remdesivir and Tocilizumab; TPE in combination with other investigational treatments

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

Either alone or combination of MSC, Remdesivir and Tocilizumab; TPE in combination with other investigational treatments

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.

Either alone or combination of MSC, Remdesivir and Tocilizumab; TPE in combination with other investigational treatments

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.

Also known as: MSC

Either alone or combination of MSC, Remdesivir and Tocilizumab; TPE in combination with other investigational treatments

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• UNICEF: lead
• Pak Emirates Military Hospital Rawalpindi: collaborator

Study Sites (1)

Pak Emirates Military Hospital

Rawalpindi, Punjab Province, 46000, Pakistan

Location

Related Publications (7)

• 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.

  PMID: 30373638 BACKGROUND

• 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.

  PMID: 32241301 BACKGROUND

• 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.

  PMID: 32298745 BACKGROUND

• 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.

  PMID: 32113510 BACKGROUND

• 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.

  PMID: 32350134 BACKGROUND

• 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.

  PMID: 32445440 BACKGROUND

• 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.

  PMID: 32257537 BACKGROUND

MeSH Terms

Conditions

COVID-19; Cytokine Release Syndrome; Critical Illness

Interventions

Plasma Exchange; tocilizumab; remdesivir

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Disease Attributes

Intervention Hierarchy (Ancestors)

Blood Transfusion; Biological Therapy; Therapeutics; Plasmapheresis; Blood Component Removal; Sorption Detoxification; Extracorporeal Circulation; Surgical Procedures, Operative

Study Officials

• Sumaira Irum, MIT

  UNICEF

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Classified Medical specialist

Model Details: 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.

Study Record Dates

• First Submitted: July 28, 2020
• First Posted: July 30, 2020
• Study Start: April 1, 2020
• Primary Completion: July 20, 2020
• Study Completion: July 20, 2020
• Last Updated: July 30, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: 6 months from completion of study
• Access Criteria: email

Locations

PA (1)