Cyclosporine in Patients With Moderate COVID-19

Study Overview
=================
Brief Summary
-----------------
Phase 1 safety study to determine the tolerability, clinical effects, and changes in laboratory parameters of short course oral or IV cyclosporine (CSA) administration in patients with COVID-19 disease requiring oxygen supplementation but not requiring ventilator support.

Detailed Description
-----------------
Our overall hypothesis is that CSA is safe in this patient population and that it will have antiviral and anti-cytokine effects as measured in laboratory tests. The initial dose will be 9 mg/kg/day oral divided q12h or 3 mg/kg/day by continuous IV infusion. Oral administration is generally preferred, however IV administration can be used if oral administration is not feasible or cannot be tolerated, or at the physician-investigator's clinical discretion. The dose will be adjusted to target a trough level of 200 to 300 ng/ml, which is in alignment with common clinical practice. The planned duration of CSA treatment is up to 14 days, with planned discontinuation upon discharge from the hospital. Dose reduction of 25% to 50% can be made for patients who experience adverse events such as hypertension or serum creatinine elevation. The end of study will be study day 30 for those patients who have been discharged from the hospital. If the patient remains in the hospital, the subject will still complete the end of study visit at day 30 as planned, but will continue to be followed until date of discharge.

Official Title
-----------------
Phase I Trial for the Prevention of Cytokine Release Syndrome (CRS) With Cyclosporine in Patients With Moderate COVID-19

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Drug: Cyclosporine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged >18. Admitted to hospital with laboratory confirmation of SARS-CoV-2 infection. Estimated creatinine clearance >50 ml/min using standard Cockcroft-Gault formula. Exclusion Criteria: Are admitted to the ICU at time of enrollment. Have an active uncontrolled infection with a non-COVID-19 agent. Have an active malignancy, not including non-melanoma skin cancer, superficial cervical or bladder cancer, MGUS, or prostate cancer with PSA <1.0. Are on chronic immune suppressive medications, including corticosteroid therapy at a prednisone equivalent dose of 10 mg per day or higher; therapy with calcineurin inhibitors or mTOR inhibitors. Are pregnant Are lactating Have a known allergic reaction to components of the CSA or its diluents. Are receiving investigational vaccine for SARS-CoV-2.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Cyclosporine; oral or IV route of administration, per investigator discretion. Duration of administration up to 14 days, as tolerated. | Drug: Cyclosporine<br>* • The initial dose will be 9 mg/kg/day oral divided q12h. For IV, the dose will be 3mg/kg/day by continuous IV infusion.<br>* Other names: Sandimmune, Neoral, Gengraf;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety-oxygen, ICU transfer and ventilation | Safety will be measured: By assessing the proportion of participants requiring increase in oxygen requirements, transfer to intensive care unit, and/or mechanical ventilation | 3 months | 
| Safety-changes in absolute lymphocyte count | Safety will be assessed: By monitoring changes in absolute lymphocyte counts | 3 months | 
| Safety-changes in creatinine clearance | Safety will be assessed: By monitoring changes in creatinine clearance. Creatinine clearance will be estimated using the Cockcroft-Gault formula. | 3 months | 
| Safety-secondary bacterial infections | Safety will be assessed: By monitoring the incidence of secondary bacterial infections complicating COVID-19 hospitalization | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Laboratory measurements of safety and antiviral efficacy related to COVID-19-SARS-CoV-2 by measuring the clearance of SARS-CoV-2 from respiratory secretions | To measure time to SARS-CoV-2 clearance (PCR negativity) at Days 7 and 14 by deep nasal swab | 3 months | 
| Laboratory measurements-D-dimer levels | To measure the laboratory correlatives of CRS/ Hemophagocytic lymphohistiocytosis (HLH) by measuring: D-dimer levels | 3 months | 
| Laboratory measurements-ferritin | To measure the laboratory correlatives of CRS/ Hemophagocytic lymphohistiocytosis (HLH) by measuring: ferritin levels | 3 months | 
| Laboratory measurements- IL-6 | To measure the laboratory correlatives of CRS/ Hemophagocytic lymphohistiocytosis (HLH) by measuring: IL-6 levels | 3 months |