Clinical trial NCT04288102: Treatment With Human Umbilical Cord-derived Mesenchymal Stem Cells for Severe Corona Virus Disease 2019 (COVID-19)
Official title: A Phase II, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Human Umbilical Cord-derived Mesenchymal Stem Cells in the Treatment of Severe COVID-19 Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Corona Virus Disease 2019(COVID-19)
Lead sponsor: Beijing 302 Hospital
Sponsor class: OTHER
Collaborators: name: Huoshenshan Hospital
name: Maternal and Child Health Hospital of Hubei Province
name: The General Hospital of Central Theater Command
name: Vcanbio Cell and Gene Engineering Corp., Ltd.
First posted: 2020-02-28
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, placebo-controlled study
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in lesion proportion (%) of full lung volume from baseline to day 28.
timeFrame: Day 28
Secondary outcomes:
measure: Change in lesion proportion (%) of full lung volume from baseline to day 10 and 90
timeFrame: Day 10, Day 90
measure: Change in consolidation lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90.
timeFrame: Day 10, Day 28, Day 90
measure: Change in ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90.
timeFrame: Day 10, Day 28, Day 90
measure: 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
timeFrame: Day 90
measure: Lung densitometry: Change in total voxel 'weight' in lesion area voxel 'weight'=voxel density (in HU) × voxel volume (in voxel)
timeFrame: Day 10, Day 28, Day 90
measure: Lung densitometry: volumes histogram of lung density distribution (<-750, -750~-300, -300~50, >50) at day 10, 28 and 90.
timeFrame: Day 10, Day 28, Day 90
measure: Time to clinical improvement in 28 days.
timeFrame: Day 28
measure: Oxygenation index( PaO2/FiO2)
timeFrame: Day 6, Day 10, Day 28
measure: Duration of oxygen therapy(days)
timeFrame: Day 28, Day 90
measure: Blood oxygen saturation
timeFrame: Day 6, Day 10, Day 28
measure: 6-minute walk test
timeFrame: Day 28, Day 90
measure: Maximum vital capacity (VCmax)
timeFrame: Baseline, Day 10, Day 14, Day 21, Day 28, Day 90
measure: Diffusing Capacity (DLCO)
timeFrame: Baseline, Day 10, Day 14, Day 21, Day 28, Day 90
measure: mMRC (Modified Medical Research Council) dyspnea scale
timeFrame: Day 28, Day 90
measure: Changes of absolute lymphocyte counts and subsets from baseline to day 6, 10, 28 and 90.
timeFrame: Day 6, Day 10, Day 28, Day 90
measure: Changes of cytokine/chemokine levels from baseline to day 6, 10, 28 and 90.
timeFrame: Day 6, Day 10, Day 28, Day 90
measure: Adverse events
timeFrame: Day 0 through Day 90
measure: Serious adverse events
timeFrame: Day 0 through Day 90
measure: All-cause mortality
timeFrame: Day 0 through Day 90
Other outcomes:
Locations:
city: Wuhan
country: China
facility: General Hospital of Central Theater Command
state: Hubei
city: Wuhan
country: China
facility: Maternal and Child Hospital of Hubei Province
state: Hubei
city: Wuhan
country: China
facility: Wuhan Huoshenshan Hospital
state: Hubei
Study officials:
affiliation: Beijing 302 Hospital
name: Fu-Sheng Wang, MD, PhD
role: STUDY_CHAIR
References:
citation: Shi L, Yuan X, Yao W, Wang S, Zhang C, Zhang B, Song J, Huang L, Xu Z, Fu JL, Li Y, Xu R, Li TT, Dong J, Cai J, Li G, Xie Y, Shi M, Li Y, Zhang Y, Xie WF, Wang FS. Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial. EBioMedicine. 2022 Jan;75:103789. doi: 10.1016/j.ebiom.2021.103789. Epub 2021 Dec 25.
citation: Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, Wang S, Zhang C, Yuan X, Xu Z, Huang L, Fu JL, Li Y, Zhang Y, Yao WQ, Liu T, Song J, Sun L, Yang F, Zhang X, Zhang B, Shi M, Meng F, Song Y, Yu Y, Wen J, Li Q, Mao Q, Maeurer M, Zumla A, Yao C, Xie WF, Wang FS. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021 Feb 10;6(1):58. doi: 10.1038/s41392-021-00488-5.