Corona Virus Disease 2019(COVID-19)
Conditions
Brief summary
COVID-19 caused clusters of severe respiratory illness and was associated with 2% mortality. No specific anti-viral treatment exists. The mainstay of clinical management is largely symptomatic treatment, with organ support in intensive care for seriously ill patients. Cellular therapy, using mesenchymal stem cells has been shown to reduce nonproductive inflammation and affect tissue regeneration and is being evaluated in patients with ARDS. This clinical trial is to inspect the safety and efficiency of mesenchymal stem cells (MSCs) therapy for severe COVID-19.
Detailed description
The Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection has unprecedentedly spread in the worldwide and been declared as a pandemic by the world health organization. COVID-19 is characterized by sustained cytokines production and hyper-inflammation, can cause clusters of severe respiratory illness with a fatality rate around 2-5%. There are currently no prophylactic vaccine and no specific antiviral treatment agents available recommended for COVID-19. Therefore, it is urgent to find a safe and effective therapeutic approach to COVID-19. During the last decade, the promising features of mesenchymal stem cells (MSCs), including their regenerative properties and ability to differentiate into diverse cell lineages, have generated great interest among researchers whose work has offered intriguing perspectives on cell-based therapies for various diseases. These findings seem to highlight that the beneficial effect of MSC-based treatment could be principally due by the immunomodulation and regenerative potential of these cells. MSCs could significantly reduce the pathological changes of lung and inhibit the cell-mediated immune inflammatory response induced by influenza virus in animal model . MSCs has been shown to reduce nonproductive inflammation and affect tissue regeneration and is being evaluated in patients with ARDS. Our phase I preliminary data of parallel assignment study(NCT04252118) showed that three doses of MSCs was safe in patients with COVID-19. Randomized control trial is needed to assess efficacy and safety. The investigators will do a prospective, double-blind, multicentre, randomised trial to assess treatment with three intravenous doses of MSCs compared with placebo. 90 severe COVID-19 patients will be recruited in China. 60 patients will receive i.v. transfusion 3 times of MSCs (4.0\*10E7 cells per time) and the standard of care as the treated group. In addition, the 30 patients will receive placebo and standard of care as control group. Change in lesion proportion (%) of full lung volume from baseline to day 10, day28 and 90, change in consolidation/ ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90, time to clinical improvement in 28 days, mMRC (Modified Medical Research Council) dyspnea scale, 6-minute walk test, maximum vital capacity (VCmax), Diffusing Capacity (DLCO), oxygen saturation, oxygenation index, duration of oxygen therapy, side effects, immunological characteristics (immune cells, inflammatory factors, etc.) will be evaluated during the 90 days follow up.
Interventions
BIOLOGICALUC-MSCs
3 does of UC-MSCs(4.0\*10E7 cells per time) intravenously at Day 0, Day 3, Day 6.
3 does of placebo（intravenously at Day 0, Day 3, Day 6）
Sponsors
Huoshenshan Hospital
Maternal and Child Health Hospital of Hubei Province
The General Hospital of Central Theater Command
Vcanbio Cell and Gene Engineering Corp., Ltd.
Beijing 302 Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, double-blind, placebo-controlled study
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged at 18 years (including) -75 years old 2. Hospitalized 3. Laboratory confirmation of SARS-CoV-2 infection by reverse-transcription polymerase chain reaction (RT-PCR) from any diagnostic sampling source 4. Pneumonia that is judged by computed tomography 5. In accordance with any one of the following : 1)dyspnea (RR ≥ 30 times / min), 2)finger oxygen saturation ≤ 93% in resting state, 3)arterial oxygen partial pressure (PaO2) / oxygen absorption concentration (FiO2) ≤ 300MMHG, 4)pulmonary imaging shows that the focus progress \> 50% in 24-48 hours 6. Interstitial lung damage is judged by computed tomography.
Exclusion criteria
1. Pregnancy, lactation and those who are not pregnant but do not take effective contraceptives measures; 2. Patients with malignant tumor, other serious systemic diseases and psychosis; 3. Patients who are participating in other clinical trials; 4. Inability to provide informed consent or to comply with test requirements. 5. Co-Infection of HIV, tuberculosis, influenza virus, adenovirus and other respiratory infection virus. 6. Invasive ventilation 7. Shock 8. Combined with other organ failure( need organ support) 9. Interstitial lung damage caused by other reasons ( in 2 weeks) 10. The pulmonary imaging revealed the interstitial damage of lungs before the COVID-19 confirmed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in lesion proportion (%) of full lung volume from baseline to day 28. | Day 28 | Evaluation of Pneumonia Improvement |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in consolidation lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90. | Day 10, Day 28, Day 90 | Evaluation of Pneumonia Improvement |
| Change in ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90. | Day 10, Day 28, Day 90 | Evaluation of Pneumonia Improvement |
| Pulmonary fibrosis - related morphological features in CT scan at day 90 a. cord-like shadow b. honeycomb-like shadows c. interlobular septal thickening d. intralobular interstitial thickening e. pleural thickening | Day 90 | Evaluation of Pneumonia Improvement |
| Lung densitometry: Change in total voxel 'weight' in lesion area voxel 'weight'=voxel density (in HU) × voxel volume (in voxel) | Day 10, Day 28, Day 90 | Evaluation of Pneumonia Improvement |
| Lung densitometry: volumes histogram of lung density distribution (<-750, -750~-300, -300~50, >50) at day 10, 28 and 90. | Day 10, Day 28, Day 90 | Evaluation of Pneumonia Improvement |
| Time to clinical improvement in 28 days. | Day 28 | Clinical improvement defined as a one-point deduction from baseline in a 6 ordinal scale: 1. Not hospitalized; 2. Hospitalized, not requiring supplemental oxygen; 3. Hospitalized, requiring supplemental oxygen; 4. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5. Hospitalized, on invasive mechanical ventilation or ECMO; 6. Death. |
| Oxygenation index( PaO2/FiO2) | Day 6, Day 10, Day 28 | Evaluation of Pneumonia Improvement |
| Duration of oxygen therapy(days) | Day 28, Day 90 | Evaluation of Pneumonia Improvement |
| Blood oxygen saturation | Day 6, Day 10, Day 28 | Evaluation of Pneumonia Improvement |
| Change in lesion proportion (%) of full lung volume from baseline to day 10 and 90 | Day 10, Day 90 | Evaluation of Pneumonia Improvement |
| Maximum vital capacity (VCmax) | Baseline, Day 10, Day 14, Day 21, Day 28, Day 90 | Evaluation of Pneumonia Improvement |
| Diffusing Capacity (DLCO) | Baseline, Day 10, Day 14, Day 21, Day 28, Day 90 | Evaluation of Pneumonia Improvement |
| mMRC (Modified Medical Research Council) dyspnea scale | Day 28, Day 90 | Evaluation of Pneumonia Improvement No limitation of activities, discharged from hospital =Score 1; Hospitalized, no oxygen therapy=Score 2; Oxygen by mask or nasal prongs-Score 3; Non-invasive ventilation or high-flow oxygen=Score 4; Mechanical ventilation or ECMO=Score 5; Death=Score 6. |
| Changes of absolute lymphocyte counts and subsets from baseline to day 6, 10, 28 and 90. | Day 6, Day 10, Day 28, Day 90 | Marker of Immunological function |
| Changes of cytokine/chemokine levels from baseline to day 6, 10, 28 and 90. | Day 6, Day 10, Day 28, Day 90 | Marker of Immunological function |
| Adverse events | Day 0 through Day 90 | Safety endpoints |
| Serious adverse events | Day 0 through Day 90 | Safety endpoints |
| All-cause mortality | Day 0 through Day 90 | Safety endpoints |
| 6-minute walk test | Day 28, Day 90 | Evaluation of Pneumonia Improvement |
Countries
China
Outcome results
None listed