<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04492501</url>
  </required_header>
  <id_info>
    <org_study_id>Sultan Mehmood Kamran 3</org_study_id>
    <nct_id>NCT04492501</nct_id>
  </id_info>
  <brief_title>Investigational Treatments for COVID-19 in Tertiary Care Hospital of Pakistan</brief_title>
  <official_title>Role of Investigational Therapies Alone or in Combination to Treat Moderate, Severe and Critical COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UNICEF</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pak Emirates Military Hospital Rawalpindi</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>UNICEF</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Beyond supportive care, there are currently no proven treatment options for coronavirus&#xD;
      disease (COVID-19) and related pneumonia, caused by Severe Acute Respiratory Syndrome&#xD;
      Coronavirus 2 (SARS-CoV-2).Investigators have seen recently from experience in Western&#xD;
      countries with best health care systems that pandemics cannot be managed in hospitals.&#xD;
      Investigators have seen ICUs crowded to capacity, healthcare workers being exposed and going&#xD;
      to quarantine or dying after exposure to large doses of viral inoculums. Investigators&#xD;
      recommend that institutions should register for Clinical trials and consider emergency use of&#xD;
      TPE. In Pandemics, time is of essence to avoid mortality by intervening early with available&#xD;
      evidence, preferably as part of clinical trial.Since the outbreak of corona virus disease&#xD;
      (COVID-19), main treatment modalities have been antivirals, interferons, glucocorticoids,&#xD;
      anti-coagulants and supportive treatment in addition to traditional Chinese medicine. There&#xD;
      are also clinical trials exploring hydroxyquinoline / chloroquine sulphate, azithromycin,&#xD;
      immunoglobulins, Vitamin-C, washed microbiota, nebulized interferon, teicoplanin as well as&#xD;
      Mesenchymal stem cells. However, most of these trials were small and remain in the&#xD;
      experimental phase with currently no effective / speciﬁc antiviral with robust scientific&#xD;
      evidence as regards the mortality reduction in COVID-19.In an attempt to treat COVID-19,&#xD;
      investigator will use different investigational treatment either alone or in combination to&#xD;
      see mortality and morbidity benefit on the basis of limitted evidence available so far. These&#xD;
      investigational modalities include Therapeutic plasma exchange (TPE), Convalescent Plasma&#xD;
      (CP), Remdesivir, Tocilizumab and Mesenchymal stem cell (MSC) therapy in addition to standard&#xD;
      supportive treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Long title: Role of different investigational treatments alone or in combination to treat&#xD;
      moderate, severe and critical COVID-19 in addition to standard treatment; An Open label,&#xD;
      Phase 2 Study Clinical Phase: multi arm, Phase 2 Open Label Conducted by: Department of&#xD;
      Pulmonology and Critical Care; Pak Emirates Military Hospital. Sample Size: 600 Study&#xD;
      Population: Hospitalized COVID-19 patients aged ≥18 years to 80 years of with Moderate-&#xD;
      severe-critical disease Study Duration: 1st April, 2020 to 31st July 2020 Study Design: This&#xD;
      open label phase 2 trial will assess the efficacy and safety of following treatment options&#xD;
      1. Standard treatment including steroids 2. Therapeutic plasma exchange in addition to&#xD;
      standard treatment 3. Therapeutic Plasma exchange in combination with Convalescent Plasma in&#xD;
      addition to standard treatment 4. Tocilizumab in addition to standard treatment 5. Remdesivir&#xD;
      alone or in combination with Therapeutic plasma exchange in addition to standard treatment 6.&#xD;
      Mesenchymal stem cell therapy in combination with other investigational treatments in&#xD;
      addition to standard treatment Operational Definitions&#xD;
&#xD;
        1. Moderate disease:&#xD;
&#xD;
           COVID-19 positive case with lung infiltrates &lt; 50% of total lung fields on Chest X-ray /&#xD;
           peripheral ground glass opacities (GGOs) on High Resolution Computerized Tomography&#xD;
           (HRCT)chest but no evidence of hypoxemia.&#xD;
&#xD;
        2. Severe disease:&#xD;
&#xD;
           COVID-19 pneumonia with evidence of hypoxemia (RR &gt; 30/minute or PaO2 on ABGs &lt; 80mmHg&#xD;
           or PaO2/FiO2 (PF ratio) &lt; 300 or lung infiltrates &gt; 50% of the lung field).&#xD;
&#xD;
        3. Critical illness:&#xD;
&#xD;
           COVID-19 pneumonia with evidence of either respiratory failure (PaO2 &lt; 60mmHg) or&#xD;
           multiorgan dysfunction syndrome (MODS) measured by Sequential Organ Failure assessment&#xD;
           (SOFA score) &gt; 10 or septic shock (Systolic BP less than 90 or less than 40mm Hg of&#xD;
           baseline in hypertensive or Urine output &lt; 0.5 ml/kg/hour).Age, sex, comorbidities, date&#xD;
           of symptoms, source of infection, type of admission SOFA score, Clinical status, vital&#xD;
           signs including temperature, respiratory rate, oxygen saturation, oxygen requirement,&#xD;
           Complete Blood counts (CBC) with neutrophil counts, lymphocytes count, C-reactive&#xD;
           Proteins (CRP), chest imaging (CT or X-ray), location and status in hospital&#xD;
&#xD;
        4. Cytokine release storm (CRS):&#xD;
&#xD;
      Diagnostic criteria of Cytokine release syndrome (CRS) CRS is defined as fever of equal to or&#xD;
      more than 100 F persisting &gt; 48 hours in absence of documented bacterial infection and ANY of&#xD;
      the following in the presence of moderate, severe or critical disease&#xD;
&#xD;
        1. Ferritin &gt;1000 mcg/L and rising in last 24 hours&#xD;
&#xD;
        2. Ferritin &gt;2000 mcg/L in patient requiring high flow oxygen or ventilation&#xD;
&#xD;
        3. Lymphopenia &lt; 800 cells/ul or lymphocyte percentage &lt;20% and two of the following&#xD;
&#xD;
             1. Ferritin &gt;700 mcg/mL and rising in the last 24 hours&#xD;
&#xD;
             2. LDH &gt; 300 IU (reference 140-250 IU/L) and rising in the last 24 hours&#xD;
&#xD;
             3. D-Dimer &gt;1000ng/mL (or &gt;1mcg/ml) and rising in the last 24 hours&#xD;
&#xD;
             4. CRP &gt;70 mg/L (or &gt;10 hsCRP) and rising in the last 24 hours, in absence of&#xD;
                bacterial infection&#xD;
&#xD;
             5. If any 3 of above presents on admission no need to document rise&#xD;
&#xD;
      5. Standard treatment: As per Institutional COVID-19 Management Guidelines all patients of&#xD;
      moderate, severe and critical COVID-19 received standard protocol of aspirin,&#xD;
      anticoagulation, ulcer prophylaxis, awake Proning (if PaO2 &lt; 80mmHg) and corticosteroids. All&#xD;
      patients of CRS received Methylprednisolone 1 mg/kg irrespective of disease severity. 6.&#xD;
      Therapeutic Plasma exchange (TPE) Therapeutic plasma exchange: 1-1.5 plasma exchange daily&#xD;
      (1-5 sessions) with replacement fluid Fresh frozen Plasma (FFP) (whole volume) to 70 willing&#xD;
      patients of moderate, severe and critical disease with evidence of CRS after explaining the&#xD;
      investigational role of this therapy. TPE will be given in addition to standard treatment to&#xD;
      70 patients randomly. TPE related complications to be documented 7. Recovery Recovery to be&#xD;
      defined by de-escalation of patients condition from severe to moderate, or from moderate to&#xD;
      mild, plus at least 2 of the following; serum Ferritin &lt; 1000 ug/ml (and decreasing trend on&#xD;
      two consecutive days), serum LDH normalization, C-reactive protein &gt; 50% fold reduction (and&#xD;
      decreasing trend in on two consecutive days),), ALC &gt; 1000 and PT/APTT normalization.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 1, 2020</start_date>
  <completion_date type="Actual">July 20, 2020</completion_date>
  <primary_completion_date type="Actual">July 20, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <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.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>survival</measure>
    <time_frame>28 days</time_frame>
    <description>death or recovery</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>duration of hospitalization</measure>
    <time_frame>28 days</time_frame>
    <description>duration in days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to resolution of cytokine release storm</measure>
    <time_frame>28 days</time_frame>
    <description>duration in days to normalize symptoms and laboratory parameters</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time of viral clearance</measure>
    <time_frame>45 days</time_frame>
    <description>Time in days to turn PCR negative</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complications</measure>
    <time_frame>90 days</time_frame>
    <description>incidence of Post Covid lung fibrosis</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">600</enrollment>
  <condition>Covid19</condition>
  <condition>Cytokine Release Syndrome</condition>
  <condition>Critical Illness</condition>
  <condition>ARDS</condition>
  <arm_group>
    <arm_group_label>Supportive Arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <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 &lt; 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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TPE arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TPE in combination with other investigational treatments</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Either alone or combination of MSC, Remdesivir and Tocilizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A predefined number of patients will receive either alone Tocilizumab, Remdesivir and Mesenchymal stem cell therapy or their combination</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Therapeutic Plasma exchange</intervention_name>
    <description>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</description>
    <arm_group_label>Either alone or combination of MSC, Remdesivir and Tocilizumab</arm_group_label>
    <arm_group_label>TPE arm</arm_group_label>
    <arm_group_label>TPE in combination with other investigational treatments</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Convalescent Plasma</intervention_name>
    <description>Convalescent plasma as part of replacement therapy (200-400ml) if reported within 14 days of illness. An IgG titer of &gt; 1.320 will be considered suitable for use. It will be Collected from person previously infected with Covid-19 and meet following criteria;&#xD;
After 28 day of illness till 3 months&#xD;
Symptom free 2 weeks prior to donation&#xD;
Negative two consecutive PCRs any time between initial positivity and before donation&#xD;
Anti SARS-CoV2 IgG positive, IgM negative&#xD;
Fulfills healthy donor criteria as per WHO/AABB guidelines&#xD;
Volume of plasma to be collected: 900-1200 ml through Apheresis OR plasma separated from phlebotomy donation</description>
    <arm_group_label>Either alone or combination of MSC, Remdesivir and Tocilizumab</arm_group_label>
    <arm_group_label>TPE in combination with other investigational treatments</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>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 &gt; 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 &lt; 1000, Platelets &lt; 50, ALT or AST &gt; 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</description>
    <arm_group_label>Either alone or combination of MSC, Remdesivir and Tocilizumab</arm_group_label>
    <arm_group_label>TPE in combination with other investigational treatments</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Remdesivir</intervention_name>
    <description>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 &gt; 5 times ULN and GFR &lt; 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.</description>
    <arm_group_label>Either alone or combination of MSC, Remdesivir and Tocilizumab</arm_group_label>
    <arm_group_label>TPE in combination with other investigational treatments</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Mesenchymal stem cell therapy</intervention_name>
    <description>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.</description>
    <arm_group_label>Either alone or combination of MSC, Remdesivir and Tocilizumab</arm_group_label>
    <arm_group_label>TPE in combination with other investigational treatments</arm_group_label>
    <other_name>MSC</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  PCR positive confirmed COVID-19&#xD;
&#xD;
          -  Admitted in hospital&#xD;
&#xD;
          -  willing patients to participate in trial&#xD;
&#xD;
          -  Day of illness less than 14 days&#xD;
&#xD;
          -  no contraindications to invasive procedure or novel therapies&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  co morbidities with life expectancy less than 6 months&#xD;
&#xD;
          -  Multi organ failure&#xD;
&#xD;
          -  Septic shock before initiation of treatment&#xD;
&#xD;
          -  Congestive cardiac failure (EF&lt;20%) (4)&#xD;
&#xD;
          -  Those receiving immunotherapy, Anti-thymocyte globulin or hematopoietic stem cell&#xD;
             transplant in recent past&#xD;
&#xD;
          -  Patients of hematological or solid organ malignancies&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sumaira Irum, MIT</last_name>
    <role>Study Director</role>
    <affiliation>UNICEF</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Pak Emirates Military Hospital</name>
      <address>
        <city>Rawalpindi</city>
        <state>Punjab</state>
        <zip>46000</zip>
        <country>Pakistan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Pakistan</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>30373638</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>32241301</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>32298745</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>32113510</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>32350134</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>32445440</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>32257537</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 28, 2020</study_first_submitted>
  <study_first_submitted_qc>July 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 30, 2020</study_first_posted>
  <last_update_submitted>July 28, 2020</last_update_submitted>
  <last_update_submitted_qc>July 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 30, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>UNICEF</investigator_affiliation>
    <investigator_full_name>sultan mehmood kamran</investigator_full_name>
    <investigator_title>Classified Medical specialist</investigator_title>
  </responsible_party>
  <keyword>Therapeutic Plasma exchange</keyword>
  <keyword>tocilizumab</keyword>
  <keyword>remdesivir</keyword>
  <keyword>convalescent plasma</keyword>
  <keyword>mesenchymal stem cell</keyword>
  <keyword>COVID-19</keyword>
  <keyword>investigational treatment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Critical Illness</mesh_term>
    <mesh_term>Cytokine Release Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Remdesivir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>data can be shared on demand in SPSS sheet</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>6 months from completion of study</ipd_time_frame>
    <ipd_access_criteria>email</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04492501
org study id: Sultan Mehmood Kamran 3
nct id: NCT04492501
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
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.
primary purpose: Treatment
masking: None (Open Label)
measure: survival
time frame: 28 days
description: death or recovery
measure: duration of hospitalization
time frame: 28 days
description: duration in days
measure: Time to resolution of cytokine release storm
time frame: 28 days
description: duration in days to normalize symptoms and laboratory parameters
measure: Time of viral clearance
time frame: 45 days
description: Time in days to turn PCR negative
measure: Complications
time frame: 90 days
description: incidence of Post Covid lung fibrosis
arm group label: Supportive Arm
arm group type: No Intervention
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.
arm group label: TPE arm
arm group type: Experimental
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.
arm group label: TPE in combination with other investigational treatments
arm group type: Experimental
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
arm group label: Either alone or combination of MSC, Remdesivir and Tocilizumab
arm group type: Experimental
description: A predefined number of patients will receive either alone Tocilizumab, Remdesivir and Mesenchymal stem cell therapy or their combination
intervention type: Procedure
intervention name: Therapeutic Plasma exchange
description: 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
arm group label: Either alone or combination of MSC, Remdesivir and Tocilizumab
arm group label: TPE arm
arm group label: TPE in combination with other investigational treatments
intervention type: Biological
intervention name: Convalescent Plasma
description: 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
arm group label: Either alone or combination of MSC, Remdesivir and Tocilizumab
arm group label: TPE in combination with other investigational treatments
intervention type: Drug
intervention name: Tocilizumab
description: 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
arm group label: Either alone or combination of MSC, Remdesivir and Tocilizumab
arm group label: TPE in combination with other investigational treatments
intervention type: Drug
intervention name: Remdesivir
description: 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.
arm group label: Either alone or combination of MSC, Remdesivir and Tocilizumab
arm group label: TPE in combination with other investigational treatments
intervention type: Biological
intervention name: Mesenchymal stem cell therapy
description: 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.
arm group label: Either alone or combination of MSC, Remdesivir and Tocilizumab
arm group label: TPE in combination with other investigational treatments
other name: MSC
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Sumaira Irum, MIT
role: Study Director
affiliation: UNICEF
facility: 
country: Pakistan
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
citation: 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
responsible party type: Principal Investigator
investigator affiliation: UNICEF
investigator full name: sultan mehmood kamran
investigator title: Classified Medical specialist
mesh term: COVID-19
mesh term: Critical Illness
mesh term: Cytokine Release Syndrome
mesh term: Remdesivir
sharing ipd: Yes
ipd description: data can be shared on demand in SPSS sheet
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: 6 months from completion of study
ipd access criteria: email