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Stopped by the IP, because the first 6 patients recruited had died and it was unknown if it represented any safety risk or if the sample was insufficient to evaluate the study hypotesis.
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Recent COVID 19 pandemic has overwhelmed health services all around the world, and humanity has yet to find a cure or a vaccine for the treatment of patients, mainly the severe ones, who pose a therapeutic challenge to healthcare professionals given the paucity of information we have regarding SARS-CoV-2 pathogenesis.
Recently, reports mainly from China from patients treated with mesenchymal stem cells have shown promise in accelerating recovery, even in the critically ill and the therapy has sustained an increase in research because of it's powerful immunomodulatory effects, making it and interesting alternative in patients with lung and systemic inflammation.
These effects could help treat a lot of patients and improve their outcomes, reason why phase I/II studies are needed to show their safety and experimental efficacy.
SARS-CoV-2, virus culprit of the COVID 19 that emerged in China, has become now a worldwide problem, with more than three million cases al around the world as reported by the World Health Organization. This situation has put health systems under extreme pressure, being overwhelmed be the amount of patients requiring attention.
Around 5% of patients will require ICU internation, due to severe lung inflammation giving rise to Acute Respiratory Distress Syndrome (ARDS) and a cytokine storm that ultimately affects other organs. In this group, mortality can be as high as 40%.
Mesenchymal stem cells (MSC) have shown great immunomodulatory effects, and are used in other inflammatory conditions as autoimmune diseases, being safe and preliminary effective in improving patients health status. They exert their effect via paracrine and autocrine pathways and have been shown to reduce IL-1, IL-6, Tumor necrosis factor alpha and increase IL-10 in COVID 19 patients. One of the greater advantages of the MSC is that they express no Major Histocompatibility Complex, reducing the risk of host immune reaction.
Given their immunomodulatory effects, research in this topic showing their safety and experimental efficacy are needed, as therapies for severe patients are lacking. Patients, researchers and data analysts will be blinded, and ARDS patients will be randomly allocated in standard therapy plus MSC arm or standard therapy alone to answer these questions.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Mesenchymal stem cell | Experimental | WJ MSC 50*10e6, two doses plus standard treatment with hydroxychloroquine + Lopinavir/Ritonavir or Azithromycin and ventilation support. |
|
| Control group | Active Comparator | Hydroxychloroquine, lopinavir/ritonavir and ventilation support plus placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Wharton's jelly derived Mesenchymal stem cells. | Drug | IV Wharton's jelly derived Mesenchymal stem cells, two doses |
|
| Measure | Description | Time Frame |
|---|---|---|
| Intergroup mortality difference with treatment | Evaluation of efficacy of WJ-MSC defined by mortality at 28 days of application. | 28 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of patients with treatment related adverse events | Safety evaluation of WJ-MSC describing and comparing incidence, type and severity of adverse events in both groups. | 6 months. |
| Difference in days of mechanical ventilation between groups |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in 6 minute walk between groups | Evaluation of the effect of WJ-MSC in pulmonary function measured with 6 minute walk. 6 minute walk is a test that gives information about pulmonary, cardiovascular and musculoskeletal functions. It measures the distance walked in 6 minutes in meters. | 6 months |
| Changes in Pulmonary Computed Tomography Scan between groups |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Alfredo Hernandez-Ruiz, MSc | Clinica Somer | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Somer | Rionegro | Antioquia | Colombia | |||
| BioXcellerator |
Individual data won't be shared.
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Patient code will be stored in sealed, opaque envelops with their respective codification. These envelops will be stored in Clinica Somer's Research Unit and the only person with access permission will be the pharmaceutical chemist in charge. Treatment delivery (MSC or placebo) will also be in charge of the chemist, guaranteeing blinding of patient and healthcare professionals. Data analysis will be done by people blind to the treatment received by each patient.
| Hydroxychloroquine, lopinavir/ritonavir or azithromycin and placebo (standard therapy) | Drug | Standard therapy as per hospital protocol, hydroxychloroquine 400mg + Lopinavir/Ritonavir 400/100 or azithromycin 500mg and Placebo |
|
Evaluation of the effect of WJ-MSC in the time of mechanical ventilation compared between the two groups, as prolonged mechanical ventilation days are associated with higher complication risks as pneumonia, tracheostomy and death.
| From ICU admission to 180 days. |
| Median reduction of days of hospitalization | Evaluation of the effect of WJ-MSC in the time of hospitalization between the two groups as a measure of efficacy. | From hospital admission to 180 days. |
| Median reduction of days of oxygen needs | Evaluation of the effect of WJ-MSC in the time of oxygen needs compared between the two groups as a measure of efficacy. | From hospital admission to 180 days. |
| Difference between "Sequential Organ Failure Assessment" score between groups | "Sequential Organ Failure Assessment" (SOFA) score is a tool used to determine the beginning and evolution of multiorgan failure, ranging from 0 to 24, being 24 the worst scenario. It has been proven useful as an outcome predictor of mortality and ICU stay. The result is the addition of the evaluation of each organ or system. Effect of WJ-MSC in the SOFA score will be compared between the two groups. | Baseline to 7 days |
| Difference between median Murray score between groups | Murray score is a tool used to classify lung injury. 0 = no lung injury, 0.1-2.5, mild to moderate lund injury, >2.5 Acute respiratory distress syndrome. The effect of WJ-MSC in the Murray score will be compared between the two groups. | Baseline and 7 days |
| Difference in APACHE II score between groups | APACHE II is a prognostic score based on 12 different items obtained in the first 24 hours of ICU admission. Its mainly used as a single measure, but some authors have used and described prediction usefulness with repeated measures. It ranges from 0 to 71 points. Higher scores are related to higher ICU mortality. The effect of WJ-MSC in the APACHE II score will compared between the two groups. | Baseline and 7 days |
| Difference in lymphocyte count between groups | Evaluation of the effect of WJ-MSC in lymphocyte count measured in absolute number/mm3. These laboratory measures have been associated with COVID 19 severity. | baseline and 21 days or discharge |
| Changes in C reactive protein concentration between groups | Evaluation of the effect of WJ-MSC in C reactive protein concentration between the two groups, measured in mg/dl. Highest levels have been associated with COVID 19 severity and inflammation. | baseline and 21 days or discharge |
| Changes in D dimer concentration | Evaluation of the effect of WJ-MSC in D dimer between the two groups, measured in micrograms Highest levels have been associated with COVID 19 severity and thromboembolic complications. | baseline and 21 days or discharge |
| Changes in ferritin concentration | Evaluation of the effect of WJ-MSC in ferritin compared between the two groups, measured in nanograms/ml. These laboratory measures have been associated with COVID 19 infection and severity. | baseline and 21 days or discharge |
| Changes in lactate dehydrogenase concentration | Evaluation of the effect of WJ-MSC in LDH compared between the two groups, measured in units/liter. These laboratory measures have been associated with COVID 19 infection and severity. | baseline and 21 days or discharge |
| Impact on interleukin 6 concentrations between groups. | Cytokines are biomarkers of inflammation or inflammatory activity in the human body. Changes in this profile give information about underlying process of inflammation.The effect of WJ-MSC in IL-6 will be compared between the two groups. It will be measured in picograms/ml. | Baseline and 7 days |
| Impact on interleukin 8 concentrations between groups. | Cytokines are biomarkers of inflammation or inflammatory activity in the human body. Changes in this profile give information about underlying process of inflammation. The effect of WJ-MSC in IL 8 will be compared between the two groups. It will be measured in picograms/ml. | Baseline and 7 days |
| Impact on interleukin 10 concentrations between groups. | Cytokines are biomarkers of inflammation or inflammatory activity in the human body. Changes in this profile give information about underlying process of inflammation. The effect of WJ-MSC in IL 10 will be compared between the two groups. It will be measured in picograms/ml. | Baseline and 7 days |
| Impact on tumor necrosis factor alpha concentrations between groups. | Cytokines are biomarkers of inflammation or inflammatory activity in the human body. Changes in this profile give information about underlying process of inflammation. The effect of WJ-MSC in TNF alpha will be compared between the two groups. It will be measured in nanograms/ml. | Baseline to 7 days. |
Evaluation of the effect of WJ-MSC in pulmonary function with thoracic CT scan. CT scan gives information about lung parenchyma, showing acute and chronic changes related to the underlying condition. Radiologic findings will be compared mainly comparing percentage of patients with pulmonary fibrosis. |
| 6 months |
| Changes in Spirometry between groups | Evaluation of the effect of WJ-MSC in pulmonary function measured with spirometry, compared between the two groups. Spirometry gives information about lung volume and mobilization of air. Main parameters to be measured in spirometry are Forced Vital Capacity, Forced Expiratory Volume in 1 second and relation between these two to define if there is obstruction or restriction of airflow. | 6 months |
| Changes in health related quality of life between groups | Evaluation of the effect of WJ-MSC in health related quality of life assessed by 36 Item Short Survey (SF-36). SF 36 is a patient reported tool. Each question is rated from 0 to 100, being 100 the best score possible. The scores are then compared to a population defined median score. Differences in global and specific scoring will be measured between groups. | 6 months |
| Medellín |
| Antioquia-CO |
| 050022 |
| Colombia |
| ID | Term |
|---|---|
| D012128 | Respiratory Distress Syndrome |
| D018352 | Coronavirus Infections |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012120 | Respiration Disorders |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D007239 | Infections |
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| ID | Term |
|---|---|
| D006886 | Hydroxychloroquine |
| D061466 | Lopinavir |
| D019438 | Ritonavir |
| D017963 | Azithromycin |
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D002738 | Chloroquine |
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D001393 | Azoles |
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
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