Immunoregulatory Therapy for 2019-nCoV

Immunoregulatory Therapy for 2019-nCoV-induced Severe Pneumonia Patients

Sepsis, including viral infections, are major causes of death worldwide. Studies show that in 2017, the number of sepsis patients worldwide reached as high as 48.9 million, of which 11 million patients died. Studies in China also showed that more than 1 million patients died of sepsis in 2015. Previous studies have suggested that sepsis are often secondary to excessive inflammatory response syndrome. However, treatment measures targeting excessive inflammatory response failed to effectively improve the prognosis of patients. PD-1 and PD-L1 are key mediators in T cell depletion in sepsis patients. Therefore, the investigators try to performe a clinical research to investigate the efficacy of PD-1 and thymosin in patients with severe pneumonia associated with lymphocytopenia in 2019 novel coronavirus infection.

Study Overview

• Status: Unknown
• Conditions: 2019 nCoV, PD-1
• Intervention / Treatment: Drug: PD-1 blocking antibody+standard treatment; Drug: Thymosin+standard treatment; Other: standard treatment

Detailed Description

Sepsis, including viral infections, are major causes of death worldwide. Studies show that in 2017, the number of sepsis patients worldwide reached as high as 48.9 million, of which eleven million patients died. Studies in China also showed that more than one million patients died of sepsis in 2015. Therefore, how to effectively reduce the mortality of patients with sepsis has become a focus of clinical and basic research.

Previous studies have suggested that sepsis are often secondary to excessive inflammatory response syndrome. However, treatment measures targeting excessive inflammatory response failed to effectively improve the prognosis of patients. The reason is that sepsis-related immune dysfunction can increase the risk of secondary infection and even affect the fatality rate.

The immune checkpoint pathway is the endogenous component of the immune system, which is responsible for checking the immune response and keeping it in a normal physiological state. Tumor cells can evade host recognition through this pathway. One of these immunocheckpoint pathways is the PD-1 and PD-L1 pathways. PD-1 is a receptor expressed on the surface of T cells and ACTS as a negative regulator of T cell function. Monoclonal antibody blocking the activity of PD-1 can successfully reduce tumor load and has been widely used in the clinical treatment of various tumors.

The immune imbalance in patients with sepsis has many similarities tumors. PD-1 and PD-L1 are key mediators in T cell depletion in sepsis patients. Animal models have shown that blocking PD-1 or PD-L1 can prevent T cell death, regulate cytokine production, reduce organ dysfunction and reduce death in sepsis. Previous study showed the clinical safety of anti-PD-1 antibody in sepsis patients through randomized, placebo-controlled trials.

Thymosin has also been proved to regulate cellular immunity in sepsis patients. Some studies have shown that thymosin can significantly reduce the mortality of sepsis patients. At present, phase III clinical research is in progress to further clarify the role of thymosin in patients with sepsis. The purpose of this study was to investigate the efficacy of PD-1 and thymosin in patients with severe pneumonia associated with lymphocytopenia in 2019 novel coronavirus infection.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult SARI patients with 2019-ncov infection confirmed by PCR;
2. Absolute value of lymphocytes < 0. 6x 109/L;
3. Severe respiratory failure within 48 hours and requires admission to ICU. (severe respiratory failure was defined as PaO2/FiO2 < 200 mmHg and was supported by positive pressure mechanical ventilation (including non-invasive and invasive mechanical ventilation, PEEP>=5cmH2O))

Exclusion Criteria:

1. Age < 18
2. Pregnant
3. Allergic to experimental drugs
4. The underlying disease is very serious and the expected survival time is less than 6 months (such as advanced malignant tumor);
5. COPD or end-stage lung disease requires home oxygen therapy
6. Expected survival time not exceeding 48 hours
7. Participated in other clinical intervention trials within the last 3 months
8. Autoimmune diseases
9. A history of organ, bone marrow or hematopoietic stem cell transplantation 10. Received radiotherapy and chemotherapy for malignant tumor within 6 months

11.HIV infected patients or diagnosed with acquired immunodeficiency within the past year (CD4 T cells <=200/mm3) 12. Patients receiving anti-hcv treatment 13.90 days of retinal detachment or eye surgery 14. Permanent blindness in one eye 15. History of iritis, endophthalmitis, scleral inflammation or retinitis 16. The competent physician considered it inappropriate to participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PD-1 group; Anti-PD-1 antibody, 200mg, IV, one time	Drug: PD-1 blocking antibody+standard treatment; After randomization, PD-1 blocking antibody 200mg iv, one time. Standard treatment is according to the protocol of treatment of 2019-nCoV infection
Experimental: thymosin group; Thymosin, 1.6 mg sc qd, last for 5 days	Drug: Thymosin+standard treatment; Thymosin 1.6 mg sc qd, last for 5 days. Standard treatment is according to the protocol of treatment of 2019-nCoV infection
Placebo Comparator: control group; stand treatment	Other: standard treatment; Standard treatment is according to the protocol of treatment of 2019-nCoV infection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
lung injury score	proportion of lung injury score decreased 1 or more points	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
absolute lymphocyte counts	lymphocyte counts at day 7, 14 and 28 after randimization	7, 14 and 28 days
serum level of CRP, PCT and IL-6	serum level of CRP, PCT and IL-6 at day 3,7 and 14 after randimization	3, 7 and 14 days
SOFA score	SOFA score at Day 7, with scores range from 0 to 24 and higher score means worse outcome	7 days
all cause mortality rate	died at day 28	28 days
ventilation free days		28 days
ICU free days		up to 28 days

Collaborators and Investigators

• Sponsor: Southeast University, China

Study record dates

Study Major Dates

• Study Start (Anticipated): February 10, 2020
• Primary Completion (Anticipated): April 30, 2020
• Study Completion (Anticipated): October 31, 2020

Study Registration Dates

• First Submitted: February 8, 2020
• First Submitted That Met QC Criteria: February 12, 2020
• First Posted (Actual): February 13, 2020

Study Record Updates

• Last Update Posted (Actual): February 13, 2020
• Last Update Submitted That Met QC Criteria: February 12, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: immunotherapy; respiratory failure; PD-1; 2019-ncov
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunologic Factors; Antibodies; Antibodies, Blocking
• Other Study ID Numbers: 2020YFC0841300-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No