- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04492501
Investigational Treatments for COVID-19 in Tertiary Care Hospital of Pakistan
Role of Investigational Therapies Alone or in Combination to Treat Moderate, Severe and Critical COVID-19
Study Overview
Status
Conditions
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
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.
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).
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
- 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
- Ferritin >1000 mcg/L and rising in last 24 hours
- Ferritin >2000 mcg/L in patient requiring high flow oxygen or ventilation
Lymphopenia < 800 cells/ul or lymphocyte percentage <20% and two of the following
- Ferritin >700 mcg/mL and rising in the last 24 hours
- LDH > 300 IU (reference 140-250 IU/L) and rising in the last 24 hours
- D-Dimer >1000ng/mL (or >1mcg/ml) and rising in the last 24 hours
- CRP >70 mg/L (or >10 hsCRP) and rising in the last 24 hours, in absence of bacterial infection
- 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.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Punjab
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Rawalpindi, Punjab, Pakistan, 46000
- Pak Emirates military hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NON_RANDOMIZED
- Interventional Model: FACTORIAL
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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.
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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.
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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
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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
|
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;
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 Names:
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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
|
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;
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 Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
survival
Time Frame: 28 days
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death or recovery
|
28 days
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
duration of hospitalization
Time Frame: 28 days
|
duration in days
|
28 days
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Time to resolution of cytokine release storm
Time Frame: 28 days
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duration in days to normalize symptoms and laboratory parameters
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28 days
|
Time of viral clearance
Time Frame: 45 days
|
Time in days to turn PCR negative
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45 days
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Complications
Time Frame: 90 days
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incidence of Post Covid lung fibrosis
|
90 days
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: Sumaira Irum, MIT, UNICEF
Publications and helpful links
General 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Coronavirus Infections
- Coronaviridae Infections
- Nidovirales Infections
- RNA Virus Infections
- Virus Diseases
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Pneumonia, Viral
- Pneumonia
- Lung Diseases
- Systemic Inflammatory Response Syndrome
- Inflammation
- Disease Attributes
- Shock
- COVID-19
- Critical Illness
- Cytokine Release Syndrome
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Antimetabolites
- Remdesivir
Other Study ID Numbers
- Sultan Mehmood Kamran 3
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ICF
- ANALYTIC_CODE
- CSR
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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