Conditions: SARS (Disease)
Keywords: COVID-19 SARS-COV-2 Corona Virus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: yes

Brief summary:
Phase IIa clinical trial in which 75 non-ICU hospital inpatients will be randomized 2:1 to 7 days of an oral formulation of cyclosporine, Neoral (2.5mg/kg PO BID) + standard of care (SOC) or no Neoral + SOC. The primary endpoint is disease severity based on the World Health Organization (WHO) COVID Ordinal Outcomes Scale, on day 14. Secondary endpoints include safety and changes in serum inflammatory markers.

Detailed description:
1. OBJECTIVES

   1.1 Primary Objectives

   1.1.1 To assess the effect of a 7-day course of oral cyclosporine Neoral on clinical outcome using the World Health Organization (WHO) COVID Ordinal Clinical Outcomes Scale, on day 14.

   1.2 Secondary Objectives

   1.2.1 To establish the safety of Neoral in this patient population (adverse events).

   1.2.2 To determine the effect of Neoral on serum inflammatory markers (CRP, d-dimer, ferritin, ANC (Absolute Neutrophil Count), absolute lymphocyte count, WBC, PLT (daily while inpatient and including day 14 and 28 for those discharged).

   1.2.3 To determine the effect Neoral on viral SARS-CoV2 PCR positivity from baseline (day 0 to -2) before receiving Neoral to day 14, and from baseline to day 28.

   1.2.4 To determine the effect of Neoral on survival (days 14 and 28).

   1.2.5 To determine the effect of Neoral on disease improvement (alive and free of invasive or non-invasive mechanical ventilation; days 14 and 28).

   1.2.6 To determine the effect of Neoral on proportion of those requiring invasive mechanical ventilation.

   1.2.7 To determine the effect of Neoral on incidence of deep vein thrombosis.

   1.2.8 To determine the effect of Neoral on proportion of patients discharged on day 28.

   1.2.9 To determine the effect of Neoral on time to hospital discharge.

   1.2.10 To determine the effect of Neoral on disease resolution (alive and discharged home without oxygen; days 14 and 28).
2. BACKGROUND

2.1 Study Disease(s)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that causes coronavirus disease 2019 (COVID-19). Since initial detection of the virus, more than 10 million cases of COVID-19 have been confirmed worldwide, and COVID-19 is responsible for more than 505,500 deaths. The United States has seen over 2.5 million cases of COVID-19 and 126,000 deaths from this disease (as of June, 30, 2020). SARS-CoV-2 is efficiently transmitted from person-to-person and the World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19) to be a pandemic.

COVID-19 primarily spreads through the respiratory tract, by droplets, respiratory secretions, and direct contact. Current data suggest an incubation period of 1-14 days, in most cases 3-7 days. The virus is highly transmissible in humans and causes severe problems especially in the elderly and people with underlying chronic diseases. COVID-19 patients typically present with specific, similar symptoms, such as fever, malaise, and cough. Most adults or children infected with SARS-CoV-2 have presented with mild flu-like symptoms, but a few patients are in critical condition and rapidly develop acute respiratory distress syndrome (ARDS), respiratory failure, multiple organ failure, and death. The case fatality rate increases with the severity of illness and can reach up to 49% in critically ill patients.

Unfortunately, specific and effective therapies for COVID-19 are highly limited. Recent evidence suggest that administration of the anti-viral agent, Remdesivir, to hospital inpatients with COVID-19 decreases time to recovery from 15 to 11 days and decreases mortality at 14 days from 11.9% to 7.1%. A preliminary, unpublished analysis from a large, multicenter, randomized, open-label trial for hospitalized patients in the United Kingdom showed that patients who were randomized to receive dexamethasone had a reduced rate of mortality compared to those who received standard of care. This benefit was observed in patients with severe COVID-19 and was greatest in those who required mechanical ventilation at enrollment (RECOVERY Trial). These 2 agents are considered in the standard of care (SOC) for treating patients with COVID-19. However, additional therapies with larger effect sizes and that are administered at earlier stages to prevent progression to severe COVID-19 are critically needed.

2.1.1 IND (Investigational New Drug) Agent(s)

The PI has filed an IND with cross-reference letter from Novartis and has received a Safe to Proceed determination (IND #152065).The rationale for the proposed starting dose is based on the standard renal transplantation dose, which has a time-honored profile of safety in this population.

2.2 Rationale

Severe COVID-19. Initial reports from cases identified between February 12 to March 16 in the United States (U.S.) show rates of hospitalization for COVID-19 to be 21-31%, intensive care unit (ICU) admissions to be 5- 12%, and fatality to be 2%-3%. High-risk groups for severe COVID-19 have been identified as the elderly population and those with underlying comorbidities such as cardiovascular disease, liver disease, pulmonary disease, renal disease, and diabetes mellitus.

Severe COVID-19 results from a dysregulated hyperimmune state. Severe symptoms of COVID-19 are associated with a hyperimmune response referred to as a cytokine storm. In one study, all 41 patients with COVID-19 admitted to the hospital demonstrated elevated plasma levels of cytokines and chemokines compared with healthy volunteers that included IL (Interleukin) -1, -1R, -7, -8, -9, -10, and basic FGF2, GCSF, GMCSF, IFN-γ, IP10, MCP1, M1P1A, MIP1B, PDGF, TNF-α, and VEGF. Patients admitted to the ICU had higher levels of IL-2, IL-7, IL-10, GCSF, IP10, MCP1, MIP1A, and TNF-α than patients who did not require ICU admission. Emerging data has shown that early rapid SARS-CoV-2 replication causes massive epithelial and endothelial cell death that initiates a cytokine storm and vascular leakage, causes pyroptosis in macrophages and lymphocytes, and results in exhaustion of T cells and NK (Natural Killer) cells.

COVID-19 similarities to hemophagocytic lymphohistiocytosis (HLH). HLH is an under-recognized, hyperinflammatory syndrome characterized by a fulminant and fatal cytokine storm and multi-organ failure. In adults, HLH is most commonly triggered by viral infections and occurs in 3.7% to 4.3% cases of sepsis. Cardinal features include unremitting fever, cytopenias, and hyperferritinemia. Pulmonary involvement (including ARDS) occurs in \~50% of patients. Each of these clinical features and a highly overlapping cytokine profile is seen in severe COVID-19. This demonstrates that the clinical presentation and pathologic mechanisms of severe COVID-19 is similar to, or is HLH.

Cyclosporine (CSA) suppresses hyperimmune states. Calcineurin inhibitors such as CSA suppress the phosphatase activity of calcineurin, which results in decreased IL-2 production and IL-2 receptor expression. This interrupts a central pathway of T-cell activation and dampens T cell responses and their associated cytokine storms. CSA is approved by the FDA for three indications including 1) prophylaxis of organ rejection in kidney, liver, and heart transplants, 2) treatment of severe active rheumatoid arthritis, and 3) treatment of adult severe recalcitrant plaque psoriasis. It is critical to consider whether dampening of T-cell responses using CSA would curtail the vigor of T-cell hyperactivity in COVID-19 disease and provide an opportunity for these patients to recover.

CSA for COVID-19. Proposed is the use of the calcineurin inhibitor, CSA, for the treatment of patients with COVID-19. This is based on: 1) observations that COVID-19 disease is associated with a hyperimmune response very similar to HLH, for which treatment with CSA is effective and recommended, 2) COVID-19 is associated with dysregulated macrophage activation similar to macrophage activation syndrome (MAS) which is also therapeutically suppressed by CSA, and 3) in vitro studies demonstrating that CSA specifically inhibits the replication of coronaviruses including SARS-CoV-2 with a high degree of specificity.

CSA specifically inhibits coronavirus replication. Coronaviruses are RNA viruses with large genomes that enter host cells through binding of its transmembrane spike protein with angiotensin-converting enzyme 2 (ACE2) receptors expressed by host target cells, which is the same mechanism utilized by SARS-CoV (i.e., SARS). Cyclophilins appear to play a critical role in the replication of many viruses including coronaviruses, HIV, and hepatitis C virus. Although the exact mechanisms are not yet well understood, in vitro studies suggest that the coronavirus' nonstructural protein (Nsp) and nucleocapsid protein bind to cyclophilins, and knockdown of cyclophilin expression results in near complete inhibition of coronavirus replication. These data show that viral protein binding to cyclophilins is an important step for successful coronavirus replication, and inhibition of this interaction by CSA prevents viral replication. An important study demonstrated that CSA dominantly inhibited replication of human coronavirus 229E (HCoV-229E), mouse hepatitis virus (MHV), and SARS, and that treatment with increasing doses of CSA caused a dose-dependent decrease in SARS-CoV replication in human cells in vitro without affecting cell viability. The same group demonstrated that CSA inhibited replication of MERS-CoV without affecting cell viability of mock-infected cells. An independent group demonstrated that increasing concentrations of CSA treatment of SARS-CoV-infected human cells resulted in a dose-dependent decrease in viral replication, and inhibited the replication of other coronaviruses, including human CoV-NL63, CoV-229E, feline CoV serotypes I and II, porcine transmissible gastroenteritis virus (TGEV), avian infection bronchitis virus (IBV), and two isolates of SARS-CoV. Taken together it is proposed a dual mechanism in which (1) calcineurin inhibition by CSA inhibits the phosphorylation of NFAT-P, thus preventing the production of IL-2 and other proinflammatory cytokines, and (2) CSA inhibits viral replication of coronaviruses, likely through blockade of calcineurin, causing the inhibition of cyclophilins required for viral replication. Most recently, it was demonstrated that CSA is highly specific and effective at inhibiting SARS-CoV-2 replication in various human cells, via inhibition of Cyclophilin.

Safety of CSA in COVID-19. Since April 2020 mounting evidence from various patient populations has strongly suggested that CSA can be used safely in patients with COVID-19. It was recently demonstrated that patients with "Immune Mediated Inflammatory Diseases" (IMID) on various immunosuppressive drugs related to CSA have a "significantly reduced incidence of SARS-CoV-2 infection". It was reported no significant increase in the incidence or severity of COVID-19 disease in patients undergoing CSA therapy for Psoriasis, but rather suggested a potentially milder disease in these patients. Another study of over 4000 patients in Madrid, Spain demonstrated "a universal relationship between the use of Cyclosporine A and better outcomes" in patients with COVID-19 disease. In line with the findings from Spain, Cavagna in Italy observed that transplant patients with ongoing Calcineurin Inhibitor therapy developed only mild symptoms of COVID-19 disease and concluded that "Calcineurin inhibitor-based immunosuppressive regimens appear safe" in COVID-19 disease and should not be discontinued. These recent clinical outcomes data suggest that the use of CSA in patients with COVID-19 is safe and potentially effective.

2.3 Correlative Studies Background

Correlative studies in this protocol are included as secondary endpoints and are based on: 1) serum inflammatory markers used clinically as biomarkers to monitor the severity of COVID-19 (CRP, d-dimer, ferritin, ANC, absolute lymphocyte count, WBC (White Blood Cells), PLT), and 2) SARS-CoV-2 viral load by a clinical PCR (Polymerase Chain Reaction) test.

6\. TREATMENT AND/OR IMAGING PLAN

6.1 Agent Administration

Treatment will be administered on an inpatient basis.

Arm A Regimen Description Agent Neoral, Investigational, Generic Acceptable, N=50 Patients 2.5 mg/kg PO BID 7 days

Arm B Regimen Description Agent None\*, N= 25 Patients 7 days

\*Note: The PI has undertaken thorough discussions with the sponsor and generation of placebo capsules is not feasible for the timing of this study.

Arms:
arm 1: Neoral, N=50 Patients 2.5 mg/kg PO BID 7 days arm 2: Standard of Care Treatment, N= 25 Patients 7 days

Interventions: intervention 1: Cyclosporine intervention 2: Standard of Care Treatment
Intervention descriptions: intervention 1: 2.5 mg/kg PO BID 7 days intervention 2: Standard of Care Treatment, N= 25 Patients, 7 days

Protocol document:
Prot_SAP_000.pdf: 
 
 
RANDOMIZED PHASE IIA CLINICAL TRIAL OF CYCLOSPORINE FOR THE 
TREATMENT OF COVID-19(+) NON-ICU HOSPITAL INPATIENTS 
 
 
Principal Investigator: 
Bryan M. Burt, MD, FACS 
Baylor College of Medicine 
One Baylor Plaza MS: BCM390 
Houston, TX 77030 
Office: 713-798-6376 
Fax: 713-798-8131 
bryan.burt@bcm.edu 
 
Coordinating Center: 
Baylor College of Medicine 
 
Local Protocol #: 
H-48163 
 
FDA IND #: 152065 
IND Sponsor: Bryan M. Burt, MD 
 
ClinicalTrials.gov Identifier:   NCT04492891 
 
 
Participating Organizations: 
1. Baylor College of Medicine (BCM); Houston; TX 
2. The Brigham and Women's Hospital (BWH); Boston, MA 
 
 
Study Personnel: 
 
Co-Investigator: 
 
Statistician: 
 
Lubna Qazim, MD 
Chris Amos, PhD 
 
Baylor St Luke's Medical Center 
Baylor College of Medicine 
 
6560 Fannin Ste 1632 
One Baylor Plaza MS BCM451 
 
Houston Texas 77030 
Houston Texas 77030 
 
713-790-8025 
713-798-2102 
 
Lubna.Kazim@Bcm.Edu 
Chris.Amos@Bcm.Edu 
 
Co-Investigator: 
 
Statistician: 
 
Marion Hemmersbach-Miller, MD 
Susan Hilsenbeck, PhD 
 
Baylor College of Medicine 
Baylor College of Medicine 
 
7200 Cambridge BCM902 
One Baylor Plaza MS BCM600  
 
Houston Texas 77030 
Houston Texas 77030 
 
713-798-9149 
713-798-1627 
 
Marion.Hemmersbach-Miller@Bcm.Edu 
sgh@bcm.edu 
 


Phase IIa Trial of Cyclosporine for COVID-19 
Version Date: 09/18/2020 (version 3) 
 
 
 
Co-Investigator: 
 
Co-Investigator: 
 
Ivan Rosas, MD 
Subhassis Chatterjee, MD 
 
Baylor College of Medicine 
Baylor College of Medicine 
 
7200 Cambridge, MS BCM901 
7200 Cambridge BCM390 
 
Houston Texas 77030 
Houston Texas 77030 
 
713-798-8842 
713-798-4321 
 
Ivan.Rosas@Bcm.Edu 
Subhasis.Chatterjee@Bcm.Edu 
 
Co-Investigator:  
 
Co-PI: 
 
Farrah Kheradmand, MD 
Hilary Goldberg, MD 
 
Baylor College of Medicine 
The Brigham and Women’s Hospital 
 
One Baylor Plaza, MS BCM 285 
75 Francis St. 
 
Houston Texas 77030 
Boston, MA 02115 
 
713-798-8622 
617-732-7420 
 
farrahk@bcm.edu 
hjgoldberg@bwh.harvard.edu 
 
Consultant: 
 
Site Coordinator (BCM): 
 
Carl H. June, MD 
Monica Espinosa  
 
University of Pennsylvania 
Baylor College of Medicine 
 
295 John Morgan, 3620 Hamilton Walk 
One Baylor Plaza MS: BCM390 
 
Philadephia, PA 19104 
Houston, Texas 77030 
 
215-573-3269 
Office: 713-798-5530 
 
cjune@upenn.edu 
Fax: 713-798-8131 
 
 
Monica.Espinoza@bcm.edu 
 
Site Coordinator (BWH): 
 
Statistician: 
 
TBD  
Eunji Jo, MS 
 
 
Baylor College of Medicine 
 
 
One Baylor Plaza, MS BCM600 
 
 
Houston Texas 77030 
 
 
713-798-4923 
 
 
ejo@bcm.edu 
 
Project Manager:  
 
 
 
 
Clinical Pharmacist: 
Michelle Almarez 
 
 
 
 
 
Stephen Michaud, PharmD 
Baylor College of Medicine 
 
 
 
 
 
Baylor St. Lukes Medical Center 
One Baylor Plaza MS: BCM390  
 
 
 
 
6720 Bertner, Houston, TX 77030 
Houston, Texas 77030 
 
 
 
 
 
office: 832-355-6746 
Office: 713-798-3680 
 
 
 
 
 
smichaud@stlukeshealth.org 
Fax: 713-798-8131 
Michelle.Almarez@bcm.edu 
 
 
Investigational Agent:  Cyclosporine (Neoral); Novartis 
 
Protocol Type / Version # / Version Date: 
[Original / Version 3 / 09/18/2020] 


Phase IIa Trial of Cyclosporine for COVID-19 
Version Date: 09/18/2020 (version 3) 
 
 
 
 
 
SCHEMA 
 
Phase IIa clinical trial in which 75 non-ICU hospital inpatients will be randomized 2:1 to 7 days 
of an oral formulation of cyclosporine, Neoral  (2.5mg/kg PO BID) + standard of care (SOC) or 
no Neoral + SOC. The primary endpoint is disease severity based on the World Health 
Organization (WHO) COVID Ordinal Outcomes Scale, on day 14. Secondary endpoints include 
safety and changes in serum inflammatory markers.   


 
 
TABLE OF CONTENTS 
SCHEMA 
......................................................................................................................3 
1. 
OBJECTIVES 
1.1 
Primary Objectives...................................................................................................6 
1.2 
Secondary Objectives...............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Disease(s).......................................................................................................6 
2.2 
Rationale ..................................................................................................................7 
2.3 
Correlative Studies Background ..............................................................................9 
3. 
PATIENT SELECTION ....................................................................................................10 
3.1 
Eligibility Criteria ..................................................................................................10 
3.2 
Exclusion Criteria ..................................................................................................10 
3.3 
Inclusion of Women and Minorities ......................................................................11 
4. 
REGISTRATION PROCEDURES ...................................................................................11 
4.1 
Patient Registration ................................................................................................11 
4.2 
General Guidelines.................................................................................................12 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................12 
5.1 
Specimen Collection ..............................................................................................12 
5.4 
Biomarker Plan ......................................................................................................13 
6. 
TREATMENT AND/OR IMAGING PLAN .....................................................................13 
6.1 
Agent Administration.............................................................................................13 
6.2 
General Concomitant Medication and Supportive Care Guidelines ......................14 
6.3 
Duration of Therapy ...............................................................................................19 
6.4 
Duration of Follow-Up ..........................................................................................19 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................19 
8. 
STUDY CALENDAR .......................................................................................................20 
 
9.         PHARMACEUTICAL INFORMATION……………………………………………….23 
 
10.       MEASUREMENT OF EFFECT……………………………..………………………….23 
11. 
STATISTICAL CONSIDERATIONS...............................................................................24 
11.1 
Study Design/Endpoints.........................................................................................24 
11.2 
Sample Size/Accrual Rate ......................................................................................24 
11.3 
Stratification Factors ..............................................................................................26 
11.4 
Populations for Analysis ........................................................................................26 
11.5 
Analysis of Secondary Endpoints ..........................................................................27 
11.6 
Stopping Rules .......................................................................................................28 


 
 
12. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................28 
12.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............29 
12.2 
Adverse Event Characteristics ...............................................................................29 
12.3 
Expedited Adverse Event Reporting ......................................................................29 
12.4 
Routine Adverse Event Reporting .........................................................................30 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................30 
13.1 
Study Oversight .....................................................................................................30 
13.2 
Data Reporting .......................................................................................................31 
13.3 
Multicenter Guidelines...........................................................................................31 
14. 
REFERENCES ..................................................................................................................32 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................35 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING 
SERUM CREATININE .....................................................................................................36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To assess the effect of a 7-day course of oral cyclosporine (Neoral) on clinical outcome 
using the World Health Organization (WHO) COVID Ordinal Clinical Outcomes Scale, 
on day 14.  
 
1.2 
Secondary Objectives 
 
1.2.1 To establish the safety of Neoral in this patient population (adverse events). 
  
1.2.2 To determine the effect of Neoral on serum inflammatory markers (CRP, d-dimer, 
ferritin, ANC, absolute lymphocyte count, WBC, PLT (daily while inpatient and 
including day 14 and 28 for those discharged). 
 
1.2.3 To determine the effect Neoral on viral SARS-CoV2 PCR positivity from baseline (day 
0 to -2) before receiving Neoral) to day 14, and from baseline to day 28. 
 
1.2.4 To determine the effect of Neoral on survival (days 14 and 28) 
 
1.2.5 To determine the effect of Neoral on disease improvement (alive and free of invasive or 
non-invasive mechanical ventilation; days 14 and 28). 
 
1.2.6 To determine the effect of Neoral on proportion of those requiring invasive mechanical 
ventilation. 
 
1.2.7 To determine the effect of Neoral on incidence of deep vein thrombosis. 
 
1.2.8 To determine the effect of Neoral on proportion of patients discharged on day 28. 
 
1.2.9 To determine the effect of Neoral on time to hospital discharge. 
 
1.2.10 To determine the effect of Neoral on disease resolution (alive and discharged home 
without oxygen; days 14 and 28). 
 
 
 
2. 
BACKGROUND 
 
2.1 
Study Disease(s) 
 
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus 
that causes coronavirus disease 2019 (COVID-19). Since initial detection of the virus, more than 
10 million cases of COVID-19 have been confirmed worldwide, and COVID-19 is responsible 
for more than 505,500 deaths. The United States has seen over 2.5 million cases of COVID-19 


 
 
and 126,000 deaths from this disease (as of June, 30, 2020, source: Johns Hopkins University). 
SARS-CoV-2 is efficiently transmitted from person-to-person and the World Health 
Organization (WHO) has declared coronavirus disease 2019 (COVID-19) to be a pandemic.  
COVID-19 primarily spreads through the respiratory tract, by droplets, respiratory secretions, 
and direct contact. Current data suggest an incubation period of 1–14 days, in most cases 3–
7 days. The virus is highly transmissible in humans and causes severe problems especially in the 
elderly and people with underlying chronic diseases. COVID-19 patients typically present with 
specific, similar symptoms, such as fever, malaise, and cough. Most adults or children infected 
with SARS-CoV-2 have presented with mild flu-like symptoms, but a few patients are in critical 
condition and rapidly develop acute respiratory distress syndrome (ARDS), respiratory failure, 
multiple organ failure, and death. The case fatality rate increases with the severity of illness and 
can reach up to 49% in critically ill patients (Wu).  
 
Unfortunately, specific and effective therapies for COVID-19 are highly limited. Recent 
evidence suggest that administration of the anti-viral agent, Remdesivir, to hospital inpatients 
with COVID-19 decreases time to recovery from 15 to 11 days and decreases mortality at 14 
days from 11.9% to 7.1% (Beigel). A preliminary, unpublished analysis from a large, 
multicenter, randomized, open-label trial for hospitalized patients in the United Kingdom 
showed that patients who were randomized to receive dexamethasone had a reduced rate of 
mortality compared to those who received standard of care. This benefit was observed in patients 
with severe COVID-19 and was greatest in those who required mechanical ventilation at 
enrollment (RECOVERY Trial). These 2 agents are considered in the standard of care (SOC) for 
treating patients with COVID-19. However, additional therapies with larger effect sizes and that 
are administered at earlier stages to prevent progression to severe COVID-19 are critically 
needed.  
 
 
2.1.1 IND Agent(s) 
 
The PI has filedan IND with cross-reference letter from Novartis and has received a Safe to 
Proceed determination (IND #152065).  
 
The rationale for the proposed starting dose is based on the standard renal transplantation dose, 
which has a time-honored profile of safety in this population. Please see United States Product 
Insert (USPI) for full detail on summaries of nonclinical and clinical studies, nonclinical and 
clinical pharmacokinetics, and major route of elimination 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/050715s035,050716s038lbl.pdf).   
 
 
2.2 
Rationale 
 
Severe COVID-19. Initial reports from cases identified between February 12 to March 16 in the 
United States (U.S.) show rates of hospitalization for COVID-19 to be 21-31%, intensive care 
unit (ICU) admissions to be 5- 12%, and fatality to be 2%-3% [CDC COVID-19 Response Team 
2020]. High-risk groups for severe COVID-19 have been identified as the elderly population and 


 
 
those with underlying comorbidities such as cardiovascular disease, liver disease, pulmonary 
disease, renal disease, and diabetes mellitus [Xu 2020; Huang 2020].  
 
Severe COVID-19 results from a dysregulated hyperimmune state. Severe symptoms of 
COVID-19 are associated with a hyperimmune response referred to as a cytokine storm. In one 
study, all 41 patients with COVID-19 admitted to the hospital demonstrated elevated plasma 
levels of cytokines and chemokines compared with healthy volunteers that included IL -1, -1R, -
7, -8, -9, -10, and basic FGF2, GCSF, GMCSF, IFN-γ, IP10, MCP1, M1P1A, MIP1B, PDGF, 
TNF-α, and VEGF. Patients admitted to the ICU had higher levels of IL-2, IL-7, IL-10, GCSF, 
IP10, MCP1, MIP1A, and TNF-α than patients who did not require ICU admission [Huang 
2020]. Emerging data has shown that early rapid SARS-CoV-2 replication causes massive 
epithelial and endothelial cell death that initiates a cytokine storm and vascular leakage, causes 
pyroptosis in macrophages and lymphocytes, and results in exhaustion of T cells and NK cells 
[Yang 2020][Chen2020][Zheng 2020]. 
 
COVID-19 similarities to hemophagocytic lymphohistiocytosis (HLH). HLH is an under-
recognized, hyperinflammatory syndrome characterized by a fulminant and fatal cytokine storm 
and multi-organ failure. In adults, HLH is most commonly triggered by viral infections and 
occurs in 3.7% to 4.3% cases of sepsis. Cardinal features include unremitting fever, cytopenias, 
and hyperferritinemia. Pulmonary involvement (including ARDS) occurs in ~50% of patients. 
Each of these clinical features and a highly overlapping cytokine profile is seen in severe 
COVID-19. This demonstrates that the clinical presentation and pathologic mechanisms of 
severe COVID-19 is similar to, or is HLH. 
 
Cyclosporine (CSA) suppresses hyperimmune states. Calcineurin inhibitors such as CSA 
suppress the phosphatase activity of calcineurin, which results in decreased IL-2 production and 
IL-2 receptor expression. This interrupts a central pathway of T-cell activation and dampens T 
cell responses and their associated cytokine storms [Holzner 2019]. CSA is approved by the 
FDA for three indications including 1) prophylaxis of organ rejection in kidney, liver, and heart 
transplants, 2) treatment of severe active rheumatoid arthritis, and 3) treatment of adult severe 
recalcitrant plaque psoriasis. It is critical to consider whether dampening of T-cell responses 
using CSA would curtail the vigor of T-cell hyperactivity in COVID-19 disease and provide an 
opportunity for these patients to recover.  
 
CSA for COVID-19. Proposed is the use of the calcineurin inhibitor, CSA, for the treatment of 
patients with COVID-19. This is based on: 1) observations that COVID-19 disease is associated 
with a hyperimmune response very similar to HLH, for which treatment with CSA is effective 
and recommended [La Rosee 2019], 2) COVID-19 is associated with dysregulated macrophage 
activation similar to macrophage activation syndrome (MAS) which is also therapeutically 
suppressed by CSA [Merad M 2020; Liddacoat A 2019 ], and 3) in vitro studies demonstrating 
that CSA specifically inhibits the replication of coronaviruses including SARS-CoV-2 with a 
high degree of specificity [Dittmar 2020]. 
 
CSA specifically inhibits coronavirus replication. Coronaviruses are RNA viruses with large 
genomes that enter host cells through binding of its transmembrane spike protein with 
angiotensin-converting enzyme 2 (ACE2) receptors expressed by host target cells, which is the 


 
 
same mechanism utilized by SARS-CoV (i.e., SARS) [Walls 2020; Fu 2020]. Cyclophilins 
appear to play a critical role in the replication of many viruses including coronaviruses, HIV, and 
hepatitis C virus [de Wilde 2018; Tanaka 2013; Baugh 2012]. Although the exact mechanisms 
are not yet well understood, in vitro studies suggest that the coronavirus’ nonstructural protein 
(Nsp) and nucleocapsid protein bind to cyclophilins, and knockdown of cyclophilin expression 
results in near complete inhibition of coronavirus replication [de Wilde 2018; Baugh 2012]. 
These data show that viral protein binding to cyclophilins is an important step for successful 
coronavirus replication, and inhibition of this interaction by CSA prevents viral replication. An 
important study demonstrated that CSA dominantly inhibited replication of human coronavirus 
229E (HCoV-229E), mouse hepatitis virus (MHV), and SARS, and that treatment with 
increasing doses of CSA caused a dose-dependent decrease in SARS-CoV replication in human 
cells in vitro without affecting cell viability [de Wilde 2011]. The same group demonstrated that 
CSA inhibited replication of MERS-CoV without affecting cell viability of mock-infected cells 
[de Wilde 2013]. An independent group demonstrated that increasing concentrations of CSA 
treatment of SARS-CoV-infected human cells resulted in a dose-dependent decrease in viral 
replication, and inhibited the replication of other coronaviruses, including human CoV-NL63, 
CoV-229E, feline CoV serotypes I and II, porcine transmissible gastroenteritis virus (TGEV), 
avian infection bronchitis virus (IBV), and two isolates of SARS-CoV (Frankfurt and Hongkong) 
[Pfefferle 2011]. Taken together, Tanaka et al (2013) proposed a dual mechanism in which (1) 
calcineurin inhibition by CSA inhibits the phosphorylation of NFAT-P, thus preventing the 
production of IL-2 and other proinflammatory cytokines, and (2) CSA inhibits viral replication 
of coronaviruses, likely through blockade of calcineurin, causing the inhibition of cyclophilins 
required for viral replication. Most recently, Dittmar et al., demonstrated that CSA is highly 
specific and effective at inhibiting SARS-CoV-2 replication in various human cells, via 
inhibition of Cyclophilin [Dittmar 2020]. 
 
Safety of CSA in COVID-19. Since April 2020 mounting evidence from various patient 
populations has strongly suggested that CSA can be used safely in patients with COVID-19. 
Simon et al, recently demonstrated that patients with “Immune Mediated Inflammatory 
Diseases” (IMID) on various immunosuppressive drugs related to CSA have a “significantly 
reduced incidence of SARS-CoV-2 infection” (Simon 2020). Di Lernia et al., reported no 
significant increase in the incidence or severity of COVID-19 disease in patients undergoing 
CSA therapy for Psoriasis, but rather suggested a potentially milder disease in these patients 
(Di Lernia 2020). Another study of over 4000 patients in Madrid, Spain by Heili-Fredas et 
al., demonstrated “a universal relationship between the use of Cyclosporine A and better 
outcomes” in patients with COVID-19 disease (Heili-Frades S 2020). In line with the findings 
from Spain, Cavagna et al. in Italy observed that transplant patients with ongoing Calcineurin 
Inhibitor therapy developed only mild symptoms of COVID-19 disease and concluded that 
“Calcineurin inhibitor-based immunosuppressive regimens appear safe” in COVID-19 disease 
and should not be discontinued (Cavagna 2020). These recent clinical outcomes data suggest that 
the use of CSA in patients with COVID-19 is safe and potentially effective.  
 
 
2.3 
Correlative Studies Background 
Correlative studies in this protocol are included as secondary endpoints and are based on: 1) 
serum inflammatory markers used clinically as biomarkers to monitor the severity of COVID-19 


 
 
(CRP, d-dimer, ferritin, ANC, absolute lymphocyte count, WBC, PLT), and 2) SARS-CoV-2 
viral load by a clinical PCR test. 
 
 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Laboratory-confirmed SARS-CoV-2 infection within the past 10 days. 
 
3.1.2 Patients admitted to non-ICU hospital floors or in an emergency department awaiting 
admission to a non-ICU hospital bed. 
 
3.1.3 WHO COVID Scale Score 4 (Oxygen by mask or nasal prongs) or WHO COVID Scale 
Score 5 (non-invasive ventilation or high-flow oxygen) 
 
3.1.4 Age 18 to 90 years old. 
 
3.1.5 ECOG performance status ≤2 (see Appendix A). 
 
3.1.6 Patients receiving or who have received standard of care therapy for COVID-19 can be 
included. This includes Remdesivir, Dexamethasone (or other steroids), and 
convalescent plasma.  
 
3.1.7 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Allergy and/or hypersensitivity to CSA. 
 
3.2.2 GFR<30 mL/min. 
 
3.2.3 ALT or AST >3X upper limits of normal. 
 
3.2.4 Resistant hypertension (BP>140/90 mm Hg despite adherence to maximal doses of three 
antihypertensive agents). 
 
3.2.5 Active bacterial or mycobacterial infection. 
 
3.2.6 Pregnant and/or nursing patients. 
 


 
 
3.2.7 Participation in a COVID-19 therapeutic drug trial. 
 
3.2.8 Patients who have received or who are receiving anti-viral medications including 
hydroxychloroquine will not be excluded. 
 
3.2.9 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.10 Total cholesterol is < 100 (increased risk of seizure) 
 
3.2.11 Concomitant dosing with Tacrolimus is a relative contraindication (increases overall 
immunosuppression and decrease seizure threshold 
 
3.2.12 Concomitant malignancy is a relative contraindication (Neoral can increase 
susceptibility to development of neoplasia) 
 
3.2.13 Inability to swallow oral medication 
 
3.2.14 Treatment with immunomodulators or immunosuppressant drugs, including but not 
limited to IL-6 inhibitors, TNF inhibitors, anti-IL-1 agents, and JAK inhibitors. 
 
3.2.15 Investigational Antiviral agents 
 
 
3.3 
Inclusion of Women and Minorities 
 
Women and minorities will be included in this study.  
 
 
4. 
REGISTRATION PROCEDURES 
 
IRB Approval   
 
• IRB approval is pending at each of the 2 sites (BCM and BWH) 
 
4.1 
Patient Registration 
 
To register a patient, the following documents will be completed by the research nurse or data 
manager and faxed and/or e-mailed to the Study Coordinator: 
• Copy of required laboratory tests 
• Signed patient consent form 
• Eligibility Screening Worksheet  
 
The research nurse or data manager at the participating site will then call and/or e-mail the Study 
Coordinator at each site to verify eligibility.  To complete the registration process, each 
Coordinator will: 


 
 
• assign a patient study number 
• register the patient on the study 
• randomize the patient to one arm or the other by entering data into OnCore 
• fax or e-mail the patient study number and result of randomization to the participating 
site 
• call the research nurse or data manager at the participating site and verbally confirm 
registration and randomization 
 
 
4.2 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 2 days. Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
Additionally, we will record the number of days between the onset of symptoms and the 
initiation of treatment for each subject and we will include this information in the final study 
report. 
 
4.3 
Randomization 
 
Patients will be randomized in a 2:1 ratio to receive either CSA or placebo (no CSA). 
Randomization will be open-label, using the permuted block method and will be stratified by age 
(<60 or >60 years), WHO severity (4 vs. 5), presence or absence of comorbidities (at least one of 
the following – hypertension, coronary artery disease, congestive heart failure, or diabetes). 
Randomization will be performed centrally at the Baylor College of Medicine by the Project 
Manager.  
 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Biomarkers of disease severity will be: 
1. Circulating cellular and protein inflammatory markers including CRP, d-dimer, ferritin, 
ANC, absolute lymphocyte count, WBC, and PLT. 
2. SARS-CoV-2 positivity 
 
 
5.1 
Specimen Collection 
 
Blood biomarkers will be drawn as described in Table 1 (Schedule of Events). 
1. Blood biomarkers are all standard hospital tests with standard blood draw collection 
protocols. 
2. SARS-CoV-2 viral positivity will be determined from nasopharyngeal swabs using in-
house hospital real-time RT-PCR by the Cepheid GeneXpert platform. Both nostrils will 
be used for virologic assessment. Please see the package insert for full detail. 


 
 
(https://www.cepheid.com/Package%20Insert%20Files/Xpress-SARS-CoV-
2/Xpert%20Xpress%20SARS-CoV-
2%20Assay%20ENGLISH%20Package%20Insert%20302-3750%20Rev.%20C.pdf) 
 
 
5.2 
Specimen Procurement Kits and Scheduling 
 
5.2.1 Specimen Procurement Kits  
 
All specimens will be processed by site hospital laboratories using standard clinical use blood 
tubes or standard clinical SARS-COV-2 nasopharyngeal swabs. 
 
5.2.2 Scheduling of Specimen Collections 
 
Blood biomarkers will be drawn as described in the Table 1 (Schedule of Events). 
 
 
5.3 
Specimen Collection. 
 
5.3.1 Blood Collection. Described in Table 1(Schedule of Events).  
 
5.3.2 SARS-CoV-2 positivity. Described in Table 1 (Schedule of Events).  
 
 
5.4 
Biomarker Plan  
 
According to the schedule described in Table 1, below, we will determine the effect of Neoral on 
circulating inflammatory markers including CRP, d-dimer, ferritin, ANC, absolute lymphocyte 
count, WBC, and PLT; and also on SARS-CoV-2 positivity using PCR. 
 
 
6. 
TREATMENT AND/OR IMAGING PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an inpatient basis.  Reported adverse events and potential 
risks are described in Section 10.  Appropriate dose modifications are described in Section 7 
 
 
Arm A Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Neoral,  
Investigational,  
Generic Acceptable, 
NA 
2.5 mg/kg 
PO 
BID 
7 days 


 
 
N=50 Patients 
 
 
Arm B Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
None*,  
N= 25 Patients 
NA 
NA 
NA 
NA 
7 days 
 
*Note: The PI has undertaken thorough discussions with the sponsor and generation of placebo 
capsules is not feasible for the timing of this study. 
 
 
6.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of Neoral with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential for drug interactions. The study team 
should check a frequently-updated medical reference for a list of drugs to avoid or minimize use 
of (shown below). Patients in this study may receive Neoral in combination with other standard 
of care agents for COVID-19. These include Remdesivir and Dexamethasone. Adverse drug 
interactions between Neoral and these agents are not described but will be rigorously monitored.  
 
The data that follow are also found in the USPI for Neoral 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/050715s035,050716s038lbl.pdf): 
 
 
6.2.1 Drug Interactions: Effect of Drugs and Other Agents on Cyclosporine 
Pharmacokinetics and/or Safety 
 
6.2.1.1 
Renal Impairment: All of the individual drugs cited below are well substantiated to 
interact with cyclosporine. In addition, concomitant non-steroidal anti-inflammatory 
drugs, particularly in the setting of dehydration, may potentiate renal dysfunction. 
 
 
During the concomitant use of a drug that may exhibit additive or synergistic renal impairment 
with cyclosporine, close monitoring of renal function (in particular serum creatinine) will be 


 
 
performed. If a significant impairment of renal function occurs, the dosage of the co-
administered drug should be reduced or an alternative treatment considered.  
 
6.2.1.2 
Cytochrome P450 System: Cyclosporine is extensively metabolized by CYP 3A 
isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux 
transporter P-glycoprotein. Various agents are known to either increase or decrease 
plasma or whole blood concentrations of cyclosporine usually by inhibition or 
induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that 
decrease cyclosporine absorption such as orlistat should be avoided. Appropriate 
Neoral dosage adjustment to achieve the desired cyclosporine concentrations is 
essential when drugs that significantly alter cyclosporine concentrations are used 
concomitantly. 
 
6.2.1.3 
HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are 
known to inhibit cytochrome P-450 3A and thus could potentially increase the 
concentrations of cyclosporine, however no formal studies of the interaction are 
available. Care should be exercised when these drugs are administered concomitantly.  
 
6.2.1.4 
Grapefruit, grapefruit juice, pomegranate, and orange juice affect metabolism, 
increasing blood concentrations of cyclosporine, thus should be avoided. 
 
 
6.2.1.5 
Drugs/dietary supplements that decrease cyclosporine concentrations include the 
following agents: 
 
6.2.1.5.1 
Bosentan: Coadministration of bosentan (250 to 1000 mg every 12 hours based on 
tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to 
achieve a Cmin of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in 
decreases in the cyclosporine mean dose-normalized AUC, Cmax, and trough 
concentration of approximately 50%, 30%, and 60%, respectively, compared to 
when cyclosporine was given alone (See also Effect of Cyclosporine on the 
Pharmacokinetics and/or Safety of Other Drugs or Agents). Coadministration of 
cyclosporine with bosentan should be avoided.  
6.2.1.5.2 
Boceprevir: Coadministration of boceprevir (800 mg three times daily for 7 days) 
and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in 


 
 
the mean AUC and Cmax of cyclosporine approximately 2.7-fold and 2-fold, 
respectively, compared to when cyclosporine was given alone.  
6.2.1.5.3 
Telaprevir: Coadministration of telaprevir (750 mg every 8 hours for 11 days) 
with cyclosporine (10 mg on day 8) in healthy subjects resulted in increases in the 
mean dose-normalized AUC and Cmax of cyclosporine approximately 4.5-fold 
and 1.3-fold, respectively, compared to when cyclosporine (100 mg single dose) 
was given alone.  
6.2.1.5.4 
St. John’s Wort: There have been reports of a serious drug interaction between 
cyclosporine and the herbal dietary supplement St. John’s Wort. This interaction 
has been reported to produce a marked reduction in the blood concentrations of 
cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, 
and graft loss.  
6.2.1.5.5 
Rifabutin: Rifabutin is known to increase the metabolism of other drugs 
metabolized by the cytochrome P-450 system. The interaction between rifabutin 
and cyclosporine has not been studied. Strict precaution should be taken when 
these two drugs are administered concomitantly.  
 
 
 
6.2.2 Drug Interactions: Effect of Cyclosporine on the Pharmacokinetics and/or Safety 
of Other Drugs or Agents. 
 
6.2.2.1 
Cyclosporine is an inhibitor of CYP3A4 and of multiple drug efflux transporters (e.g., 
P-glycoprotein) and may increase plasma concentrations of comedications that are 
substrates of CYP3A4, P-glycoprotein or organic anion transporter proteins.  
6.2.2.2 
Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-
CoA reductase inhibitors (statins), and, aliskiren, bosentan, dabigatran, repaglinide, 
NSAIDs, sirolimus, etoposide, and other drugs.  
6.2.2.3 
Digoxin: Severe digitalis toxicity has been seen within days of starting cyclosporine 
in several patients taking digoxin. If digoxin is used concurrently with cyclosporine, 
serum digoxin concentrations should be monitored.  
6.2.2.4 
Colchicine: There are reports on the potential of cyclosporine to enhance the toxic 
effects of colchicine such as myopathy and neuropathy, especially in patients with 
renal dysfunction. Concomitant administration of cyclosporine and colchicine results 
in significant increases in colchicine plasma concentrations. If colchicine is used 


 
 
concurrently with cyclosporine, a reduction in the dosage of colchicine is 
recommended.  
6.2.2.5 
HMG-CoA reductase inhibitors (statins): Literature and postmarketing cases of 
myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, 
have been reported with concomitant administration of cyclosporine with lovastatin, 
simvastatin, atorvastatin, pravastatin, and, rarely fluvastatin. When concurrently 
administered with cyclosporine, the dosage of these statins should be reduced 
according to label recommendations. Statin therapy needs to be temporarily withheld 
or discontinued in patients with signs and symptoms of myopathy or those with risk 
factors predisposing to severe renal injury, including renal failure, secondary to 
rhabdomyolysis.  
6.2.2.6 
Repaglinide: Cyclosporine may increase the plasma concentrations of repaglinide and 
thereby increase the risk of hypoglycemia. In 12 healthy male subjects who received 
two doses of 100 mg cyclosporine capsule orally 12 hours apart with a single dose of 
0.25 mg repaglinide tablet (one-half of a 0.5mg tablet) orally 13 hours after the 
cyclosporine initial dose, the repaglinide mean Cmax and AUC were increased 1.8 
fold (range: 0.6 to –3.7 fold) and 2.4 fold (range 1.2 to 5.3 fold), respectively. Close 
monitoring of blood glucose level is advisable for a patient taking cyclosporine and 
repaglinide concomitantly.  
6.2.2.7 
Ambrisentan: Coadministration of ambrisentan (5 mg daily) and cyclosporine (100 to 
150 mg twice daily initially, then dosing to achieve Cmin 150 to 200 ng/mL) for 8 
days in healthy subjects resulted in mean increases in ambrisentan AUC and Cmax of 
approximately 2-fold and 1.5–fold, respectively, compared to ambrisentan alone. 
When coadministering ambrisentan with cyclosporine, the ambrisentan dose should 
not be titrated to the recommended maximum daily dose  
6.2.2.8 
Anthracycline antibiotics: High doses of cyclosporine (e.g., at starting intravenous 
dose of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics (e.g., 
doxorubicin, mitoxantrone, daunorubicin) in cancer patients.  
6.2.2.9 
Aliskiren: Cyclosporine alters the pharmacokinetics of aliskiren, a substrate of P-
glycoprotein and CYP3A4. In 14 healthy subjects who received concomitantly single 
doses of cyclosporine (200 mg) and reduced dose aliskiren (75 mg), the mean Cmax 
of aliskiren was increased by approximately 2.5-fold (90% CI: 1.96 to 3.17) and the 
mean AUC by approximately 4.3 fold (90% CI: 3.52 to 5.21), compared to when 
these subjects received aliskiren alone. The concomitant administration of aliskiren 
with cyclosporine prolonged the median aliskiren elimination half-life (26 hours 
versus 43 to 45 hours) and the Tmax (0.5 hours versus 1.5 to 2.0 hours). The mean 
AUC and Cmax of cyclosporine were comparable to reported literature values. 
Coadministration of cyclosporine and aliskiren in these subjects also resulted in an 
increase in the number and/or intensity of adverse events, mainly headache, hot flush, 
nausea, vomiting, and somnolence. The coadministration of cyclosporine with 
aliskiren is not recommended.  
6.2.2.10 
Bosentan: In healthy subjects, coadministration of bosentan and cyclosporine resulted 
in time-dependent mean increases in dose-normalized bosentan trough concentrations 
(i.e., approximately 21-fold on day 1 and 2 fold on day 8 (steady state)) compared to 


 
 
when bosentan was given alone as a single dose on day 1. Coadministration of 
cyclosporine with bosentan should be avoided.  
6.2.2.11 
Dabigatran: The effect of cyclosporine on dabigatran concentrations had not been 
formally studied. Concomitant administration of dabigatran and cyclosporine may 
result in increased plasma dabigatran concentrations due to the P-gp inhibitory 
activity of cyclosporine. Coadministration of cyclosporine with dabigatran should be 
avoided.  
6.2.2.12 
Potassium-Sparing Diuretics: Cyclosporine should not be used with potassium-
sparing diuretics because hyperkalemia can occur. Caution is also required when 
cyclosporine is coadministered with potassium-sparing drugs (e.g., angiotensin 
converting enzyme inhibitors, angiotensin II receptor antagonists), potassium-
containing drugs as well as in patients on a potassium rich diet. Control of potassium 
levels in these situations is advisable.  
6.2.2.13 
Nonsteroidal Anti-inflammatory Drug (NSAID) Interactions: Clinical status and 
serum creatinine should be closely monitored when cyclosporine is used with 
NSAIDs in rheumatoid arthritis patients. Pharmacodynamic interactions have been 
reported to occur between cyclosporine and both naproxen and sulindac, in that 
concomitant use is associated with additive decreases in renal function, as determined 
by 99mTc-diethylenetriaminepentaacetic acid (DTPA) and (p-aminohippuric acid) 
PAH clearances. Although concomitant administration of diclofenac does not affect 
blood concentrations of cyclosporine, it has been associated with approximate 
doubling of diclofenac blood concentrations and occasional reports of reversible 
decreases in renal function. Consequently, the dose of diclofenac should be in the 
lower end of the therapeutic range.  
6.2.2.14 
Methotrexate Interaction: Preliminary data indicate that when methotrexate and 
cyclosporine were coadministered to rheumatoid arthritis patients (N=20), 
methotrexate concentrations (AUCs) were increased approximately 30% and the 
concentrations (AUCs) of its metabolite, 7-hydroxy methotrexate, were decreased by 
approximately 80%. The clinical significance of this interaction is not known. 
Cyclosporine concentrations do not appear to have been altered (N=6).  
6.2.2.15 
Sirolimus: Elevations in serum creatinine were observed in studies using sirolimus in 
combination with full-dose cyclosporine. This effect is often reversible with 
cyclosporine dose reduction. Simultaneous coadministration of cyclosporine 
significantly increases blood levels of sirolimus. To minimize increases in sirolimus 
concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine 
administration.  
6.2.2.16 
Nifedipine: Frequent gingival hyperplasia when nifedipine is given concurrently with 
cyclosporine has been reported. The concomitant use of nifedipine should be avoided 
in patients in whom gingival hyperplasia develops as a side effect of cyclosporine.  
6.2.2.17 
Methylprednisolone: Convulsions when high dose methylprednisolone is given 
concurrently with cyclosporine have been reported.  
6.2.2.18 
Other Immunosuppressive Drugs and Agents: Psoriasis patients receiving other 
immunosuppressive agents or radiation therapy (including PUVA and UVB) should 


 
 
not receive concurrent cyclosporine because of the possibility of excessive 
immunosuppression. 
 
6.2.3 Effect of Cyclosporine on the Efficacy of Live Vaccines: During treatment with 
cyclosporine, vaccination may be less effective. The use of live vaccines should 
be avoided.  
 
 
6.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 7 days or 
until one of the following criteria applies: 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Patient decides to withdraw from the study 
 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
• 
Patient non-compliance 
 
• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
 
6.4 
Duration of Follow-Up 
 
Patients will be followed for 60 days after beginning the 7. day course of neoral or until death, 
whichever occurs first. Please refer to the schedule of events (Table 1), below. Patients 
experiencing adverse event(s) that require cessation of Neoral will be followed until resolution or 
stabilization of the adverse event. 
 
6.5 
Missing Data  
 
To minimize missing data, we will differentiate treatment discontinuation from study 
withdrawal. Study withdrawal will be considered as withdrawal of consent or loss of follow-up. 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 


 
 
7.1.1 The dose of Neoral is 2.5mg/kg PO BID, based on the renal transplant dose, and 
Neoral will be administered for 7 days.  
7.1.2 A blood cyclosporine trough level will be obtained on day 3 to avoid toxicity due 
to high concentrations.  If this level is greater than 250 ng/ml, the Neoral dose 
will be decreased by 25-50%. If the level is 250 ng/ml or less, no modifications 
will be made. 
7.1.3 Cyclosporine trough levels will be also obtained on day 6 and day 9. If this level 
is greater than 250 ng/ml on day 6 the Neoral dose will be decreased by 25-50% 
for the rest of the study period (7 days).  
 
8. 
STUDY CALENDAR 


 
 
Table 1 
Schedule of Study Events (Part 1) 
 
Screening 
Baseline 
Treatment1 
Follow-up2 
Visit 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Study Day 
-21 to -1 
-2 to 0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Assign Screening Number 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
 
 
 
 
 
 
 
WHO COVID-19 Severity Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assign Enrollment Number 
 
X 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (BP, HR, RR, Temp, SpO2) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FIO2 Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test for Female Patients 
X 
 
 
 
 
 
 
 
 
 
 
 
Cyclosporine Administration 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
12-Lead ECG  
X 
 
 
 
 
 
 
 
X 
 
 
X 
Chest X-ray 
X 
 
 
 
 
 
 
 
X 
 
 
X 
BMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LFTs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ANC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Absolute Lymphocyte Count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Total Cholesterol 
X 
X 
 
 
 
 
 
 
 
 
 
 
Ferritin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
D-Dimer 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Magnesium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phosphorus 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/PTT 
X 
X 
 
 
 
 
 
 
X 
 
 
 
SARS-CoV-2 PCR 
X 
 
 
 
 
 
 
 
 
 
 
 
AE Assessment  
-----------------------------------------Continuous Monitoring from Signing of the Informed Consent------------------------------------► 
Concomitant Medications/Therapies 
-----------------------------------------Continuous Monitoring from Signing of the Informed Consent------------------------------------► 
ANC =Absolute neutrophil count; BMP =basic metabolic panel; BP = blood pressure; CBC = complete blood count; CRP = c-reactive protein; ECG = Electrocardiogram; FIO2 = oxygen requirement; HR = heart 
rate; LDH = lactate dehydrogenase;  LFTs = liver function tests; PT = prothrombin time; PTT = partial thromboplastin time;  RR = respiratory rate; SpO2 = oxygen saturation; WHO = World Health Organization. 
1Treatment assessments will be performed every 24±6 hours. Treatment is Neoral for 7 days and will discontinued on the day of discharge if the patient is discharged before the 7d course is completed. If the 
patient is discharged before 7 days, the patient will not undergo any assessments until the first outpatient visit. 
2Follow up will be performed every 24±6 hours while inpatient. Once patient is discharged, follow up will be at days 14±3 days, 28±3 days, and 60±3 days either by in person clinic visit or telemedicine visit. 
 
 


 
 
Table 1 
Schedule of Study Events (Part 2) 
 
Follow-up2 
Visit 
11 
12 
13 
14 
15-27 
28 
60 
 
 
 
 
 
Study Day 
11 
12 
13 
14 
15-27 
28 
60 
 
 
 
 
 
Written Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
Assign Screening Number 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
 
 
 
 
 
 
 
 
 
 
 
 
WHO COVID-19 Severity Scale 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Assign Enrollment Number 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination  
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, Temp, SpO2) 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
FIO2 Assessment 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Pregnancy Test for Female Patients 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclosporine Administration 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG  
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
 
 
 
 
 
 
 
 
 
 
 
 
BMP 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
LFTs 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
CBC 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
ANC 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Absolute Lymphocyte Count 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Ferritin 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
D-Dimer 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
CRP 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
LDH 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Magnesium 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Phosphorus 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
PT/PTT 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Cyclosporine Level3 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 PCR 
 
 
 
X 
 
X 
X 
 
 
 
 
 
AE Assessment  
-----------------------------------------Continuous Monitoring from Signing of the Informed Consent------------------------------------► 
Concomitant Medications/Therapies 
-----------------------------------------Continuous Monitoring from Signing of the Informed Consent------------------------------------► 
 
ANC =Absolute neutrophil count; BMP =basic metabolic panel; BP = blood pressure; CBC = complete blood count; CRP = c-reactive protein; ECG = Electrocardiogram; FIO2 = oxygen requirement; HR = heart 
rate; LDH = lactate dehydrogenase;  LFTs = liver function tests; PT = prothrombin time; PTT = partial thromboplastin time;  RR = respiratory rate; SpO2 = oxygen saturation; WHO = World Health Organization. 
1Treatment assessments will be performed every 24±6 hours. Treatment is Neoral for 7 days and will begin as an inpatient and will be discontinued if the patient is discharged before the 7d course is completed. If 
the patient is discharged before 7 days, the patient will not undergo any assessments until the first outpatient visit. 
2Follow up will be performed every 24±6 hours while inpatient. Once patient is discharged, follow up will be at days 14±3 days, 28±3 days, and 60±3 days either by in person clinic visit or telemedicine visit. 
3Cyclosporine trough levels will be checked on day 3. If >250 mg/ml, the dose will be decreased by 25-50%. Additional levels will be at the discretion of treating physicians but will be performed on day 6 and 
day 9 if the participant is an inpatient.  


 
 
 
9. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated Neoral can be found in Section 10.1. 
 
9.1 
IND Agent 
 
9.1.1 Neoral 
 
Availability 
 
Neoral is an investigational agent supplied to investigators by Novartis. 
 
9.1.2 Agent Ordering and Agent Accountability 
 
9.1.2.1 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of Neoral including, strength, formulation and ordering investigator on 
this protocol. 
 
9.1.3 Investigator Brochure Availability 
 
The sponsor does not have an investigator brochure for Neoral, however the USPI will be 
available to all investigators 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/050715s035,050716s038lbl.pdf)  
 
10. MEASUREMENT OF EFFECT 
 
The primary outcome of this study is the WHO COVID-19 clinical severity scale on day 14. 
Please, see the Table 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Table 2. WHO COVID-19 Ordinal Outcomes Scale 
 
 
11. STATISTICAL CONSIDERATIONS 
This is a multicenter, open-label randomized phase IIa trial study to assess the effect and 
safety of Neoral (CSA) for treatment of COVID-19 (+) non-ICU hospital inpatients.  
11.1 
Primary Endpoint and Analytic Plan 
The primary endpoint is the clinical outcome based on the World Health Organization (WHO) 
COVID Ordinal Clinical Improvement Scale (Table 2) on day 14. Wilcoxon rank sum test will be 
used to compare the ordinal scale between groups on day 14.  
11.2 
Sample Size /Justification 
We expect to see higher grades of WHO COVID ordinal clinical scale in control group 
compared to the CSA treatment group, and propose to use a 1 to 2 randomization in favor of 
CSA group. 
The total sample size of 75 evaluable participants will provide 81% power to reject the null 
hypothesis that the grade in control group is less than or equal to the CSA group with a 10% 
one-sided significance level when the true effect side, as measured by the probability that 


 
 
Control grade is greater than CSA grade, is 0.65 or greater. Sample size and/or power for the 
various scenarios were calculated using nQuery 8 (StatSols Version 8.5.2.0). 
The following provides the rationale for the alternate hypothesis effect size. We have 
assumed that all participants will be starting in category 4. Based on review of hospital data, 
about one third of such patients end-up in the ICU and about half of those patients will die. 
Of the two thirds that do not go to the ICU, most will be discharged in 2 weeks or less. We 
have therefore hypothesized that at 2 weeks following enrollment, the control group will be 
distributed as shown in the table 3. 
We have hypothesized several scenarios to estimate the sample size needed to detect a CSA 
effect with reasonable power. We expect the effect of CSA will be to reduce ICU admissions, 
or to shorten time in the ICU and reduce deaths, so that the fraction in categories 6, 7, and 8 
on Day 14 will be reduced and less ill patients will go home earlier, increasing the fraction of 
1 and 2’s on day 14. 
Since the outcome is ordinal, a Wilcoxon rank sum test is used to control (no CSA) and CSA 
on day 14. The one-tailed null hypothesis is that the distribution of WHO scores is the same 
in two groups or worse in CSA, and the alternative is that the distribution of WHO scores in 
the CSA group is shifted lower. The effect size (P1=Pr(Control>CSA) ) is the probability that 
a randomly selected observation from the control group has a score greater than one from 
CSA group. The null value for P1 is 0.5 and the closer P1 to 1, the bigger the effect.  
A sample size of 25 in the control group and 50 in the CSA group will have 81% power to 
reject the null hypothesis (based on the 8 observable category probabilities for each group 
shown in table 3) in favor of the alternative hypothesis that an observation in the control 
group has a higher score on day 14 than an observation in the CSA group using a Wilcoxon 
(Mann-Whitney) rank-sum test with the type 1 error of 10% one-sided significance level.  
 
 
 
 
 
 
 
 


 
 
Table 3. Scenarios and associated sample size and power. 
 
11.3 
Stratification Factors 
 Randomization will be stratified by 1) age (<60 or ≥60 years), 2) WHO severity (4 vs. 5), and 3) 
presence or absence of comorbidities (at least one of the following- hypertension, coronary artery 
disease, congestive heart failure, or diabetes) with total of up to 8 strata and employ permutated 
block size of 3. 
 
11.4 Populations for Analysis 
 
11.4.1 Safety population 
 
All patients will be evaluable for toxicity from the time of their first treatment with Neoral and 
throughout the study period. In this study, patients will receive 7 days of Neoral and incidence of 
Neoral-associated toxicity events (see 11.5) and all AEs will be assessed daily. 
 
11.4.2 Intent to treat (ITT) population 
All randomized patients in the study will be assessed for response to treatment, even if there are 
major protocol treatment deviations. Each patient will be assigned one of the WHO COVID 
scale categories outlined in Table 2. Primary and secondary objectives will be analyzed.  
 
11.4.3 Modified intent to treat (MITT) population 
Primary and secondary objectives will be analyzed in all randomized patients who complete 7 
days of Neoral. 
 
11.4.4 Per-protocol analysis population 
Sub-analyses may then be performed on the basis of a subset of ITT population, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, these sub-analyses 
 
 
At Accrual 
Control 
CSA 
Scenario 1 
~50% 
benefit 
CSA 
Scenario 2 
~40% 
benefit 
CSA 
Scenario 3 
~30% 
benefit 
8 
Death 
0 
17% 
8% 
10% 
12% 
7 
Hospitalized, vented, pressors 
0 
8% 
4% 
5% 
5% 
6 
Hospitalized w invasive ventilation 
0 
8% 
4% 
5% 
6% 
5 
Hospitalized non-invasive ventilation 
0 
5% 
2% 
3% 
3% 
4 
Hospitalized on O2  
100% 
5% 
2% 
3% 
3% 
3 
Hospitalized not on O2 
0 
10% 
2% 
4% 
7% 
2 
Not hospitalized with symptoms 
0 
24% 
39% 
35% 
32% 
1 
Not hospitalized with no symptoms 
0 
23% 
39% 
35% 
32% 
Effect Size (P1=Pr(Control>CSA) 
 
0.65 
0.61 
0.59 
Power & sample size (α=10%, 1-tailed) 
 
 
 
 
 
Power with N=25 control, 50 CSA 
 
81% 
62% 
48% 
 
Sample size for ~80% power; Ctl:CSA 
 
25:50 
45:90 
75:150 


 
 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported.   
 
11.5 Analysis of Secondary Endpoints 
The secondary objectives are mostly concerned with the safety and effects of Neoral (CSA) in this patient 
population. The secondary endpoints include Neoral-associated toxicity events, serum inflammatory 
markers (CRP, d-dimer, ferritin, ANC, absolute lymphocyte count, WBC, PLT (daily while inpatient and 
including day 14 and 28 for those discharged), Viral load (days 14 and 28), vital status (days 14 and 28), 
disease improvement (days 14 and 28), proportion of those requiring invasive mechanical ventilation, 
incidence of deep vein thrombosis, proportion of patients discharged on day 28, time to hospital 
discharge, and disease resolution (days 14 and 28).  
For safety, Neoral-associated toxicity events include nephrotoxicity, resistant hypertension, 
hepatotoxicity, signs of CNS toxicity, or superinfection. AE’s and SAE’s by CTCAE v5 will be 
summarized descriptively with frequencies and rates. Rates and 95% CI’s of grade 3 and above AE’s will 
be reported. 
Serum inflammatory markers are viewed as interval scales and after appropriate normalizing 
transformation (if needed), will be analyzed using general linear mixed models to account for within 
patient dependencies to allow comparisons between groups. 
Viral positivity between groups at days 14 and days 28 will be tested by Wilcoxon rank sum test. 
Survival analysis methods will be used to describe overall survival experience, to estimate survival at 
selected time points, and to compare groups. Cumulative incidence analysis methods will be used if there 
are competing risks. The same approach will be used with disease improvement (alive and free invasive 
or non-invasive mechanical ventilation) and disease resolution (alive and discharged home without 
oxygen).  
Fisher’s exact test will be used to compare rates of need for invasive mechanical ventilation bench 
marked to a particular time, and ever need.  If required, this endpoint will include deaths before intubation 
in the rare cases in which this occurs.  
In exploratory analyses, we will use logistic regression to model ventilator need as a function of treatment 
group and other baseline characteristics. Survival analysis methods will be used to analyze time to 
mechanical ventilation, with censoring at last follow-up for those not needing ventilation. 
Day 28 discharge will be trichotomized as death prior to day 28, discharge by day 28, hospitalized after 
day 28. Groups will be compared using Chi square test for independence. 
Survival analysis methods will be used with death prior to discharge considered as a competing risk. 
 
 
 


 
 
11.6 Stopping Rules 
There is not planned interim analysis for efficacy. 
11.6.1 Death possibly, probably to definitely related to CSA: Any death in the Neoral group that is 
assessed as at least possibly related to Neoral will result in a pause to study accrual and a review 
be the DSMB. 
 
11.6.2 Targeted Toxicities: Other expected toxicities will be continuously monitored using the 
method of Ivanova et al [Ivanova, A., Qaqish, B.F., and Schell, M.J. (2005). Continuous 
toxicity monitoring in phase II trials in oncology. Biometrics 61: 540-545.]. The method 
generates a Pocock-type boundary for repeated testing for toxicity. This is a Pocock-type 
stopping boundary that yields the probability of crossing the boundary at most 5% when 
the rate of grade 3 or greater target toxicity is equal to the acceptable rate  of 20%. The 
method will stop the trial early with 40% and 86% probability if the toxicity rate is 30% 
or 40%, respectively.  
 
11.6.3 Data Safety Monitoring Board (DSMB): The conduct of this study will be overseen by a 
DSMB of 3 experts who are not participating in this study. The DSMB will be 
responsible for recommendations to the Principal Investigator regarding possible trial 
closure and/or early reporting of the study. The study team (with the exception of the 
study statistician) will not have access to the summary outcome data until released by the 
DSMB. 
  
Table 4. Toxicity monitoring boundaries. The following table will be used. Targeted toxicities include 
renal dysfunction, hypertension and liver toxicity. The trial will be paused and reported to the DSMB if 
the number of patients with grade 3 or greater AE’s for any of the targeted toxicities is equal to or exceeds 
bn out of n patients with completed follow-up (Day 7). 
 
 
 
 
 
 
 
 
 
 
12. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting will be undertaken for 1) Neoral-associated 
toxicity events including nephrotoxicity, resistant hypertension, hepatotoxicity, signs of CNS 
toxicity, or new bacterial/mycobacterial infection; as well as 2) other AEs. 
 
Safety duration is at 60 days and we will follow up all AEs and mortality at day 60. 
 
 
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- - 3 4 4 5 5 5 6 6 6 7 7 7 8 8 8 9 9 9 
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
Boundary, bn 
10 10 10 11 11 11 11 12 12 12 13 13 13 13 14 14 14 14 15 15 
Number of Patients, n 41 42 43 44 45 46 47 48 49 50  
 
 
 
 
 
 
 
 
 
Boundary, bn 
15 16 16 16 16 17 17 17 17 18  
 
 
 
 
 
 
 
 
 


 
 
12.1 Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
12.1.1.1 
Adverse Event List(s) for Neoral. For a comprehensive list of adverse events, please 
see the product insert: 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/050715s035,050716s03
8lbl.pdf). 
 
12.1.1.2 
Most Common Adverse Events. Cyclosporine is FDA approved for indications of: 1) 
Kidney, Liver, and Heart Transplantation 2) Rheumatoid Arthritis, and 3) Psoriasis. 
a. In Transplant, the principal adverse reactions of cyclosporine therapy are renal 
dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia. 
b. In Rheumatoid Arthritis, the principal are renal dysfunction (See WARNINGS), 
hypertension (See PRECAUTIONS), headache, gastrointestinal disturbances, and 
hirsutism/hypertrichosis. 
c. In Psoriasis, principal adverse reactions associated with the use of cyclosporine 
are renal dysfunction, headache, hypertension, hypertriglyceridemia, 
hirsutism/hypertrichosis, paresthesia or hyperesthesia, influenza-like symptoms, 
nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and musculoskeletal 
or joint pain. 
 
12.1.1.3 Taken together, and based on data from >1000 patients available in the USPI, the most 
common adverse events of Neoral that may be encountered in this study are: Renal 
dysfunction, hypertension, hirsutism, tremor, headache, nausea, and abdominal pain. 
 
 
12.2 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
12.3 Expedited Adverse Event Reporting 
 
12.3.1 Expedited Reporting Guidelines 
 


 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality as long as the death occurred within 30 days after the last administration of the 
investigational agent.  Attribution to treatment or other cause must be provided. 
 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational Agent 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64). These will be reported 
to the FDA and to the Sponsor.  
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the Sponsor via 
electronic submission within 7 calendar days of learning of the AE. 
 
 
12.4 Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.   
 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data required for this at all times.  
 
There are 2 sites in this protocol. The lead site is Baylor College of Medicine. The PI from 
Baylor College of Medicine (Burt) and the PI from the second site, Brigham and Women’s 


 
 
Hospital (Goldberg) will have a conference at least monthly to review enrollment, AEs, and 
administrative elements of this protocol.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via the mechanism described elsewhere in this section.  
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 Data Reporting 
 
13.2.1 Method 
 
Each of the 2 hospital sites will have a dedicated monitor. These individuals, in collaboration 
with the study monitor, will submit cumulative protocol- and patient-specific data at least every 
two weeks to a central Encore database. This reporting consists of Patient Demographics, 
Baseline Abnormalities, On/Off Treatment/Study Status, Treatment/Course/Dosing information, 
Adverse Events, Late Adverse Events, and Response data as applicable. On-site audits will be 
conducted two times annually (one annual site visit and one data audit).   
 
13.2.2 Responsibility for Data Submission 
 
It is the responsibility of the PI(s) at the site to ensure that all investigators at both sites 
understand the procedures for data submission and that protocol specified data are submitted 
accurately and in a timely manner to the CTMS via the electronic data capture system.  Data are 
to be submitted to this system on a real-time basis, but no less than once every 2 weeks.  Metrics 
for timeliness will be followed and assessed on a quarterly basis.  For the purpose of Institutional 
Performance Monitoring, data will be considered delinquent if it is greater than 4 weeks past 
due. 
 
13.3 Multicenter Guidelines 
 
The Principal Investigator/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
 
 
 
 
 


 
 
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Cell and Molecule Immunology. 2020. https://doi.org/10.1038/s41423-020-0401-
3 
 


 
 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
5 
Dead. 
 
 
 


 
 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM 
CREATININE 
 
Formulas to estimate renal function using serum creatinine provided by the NCI’s Investigational 
Drug Steering Committee (IDSC) Pharmacological Task Force in table below. 
 
1. Estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) (Levey et al., 2009). 
 
Formulae: 
 
Race and 
Sex 
Serum Creatinine (SCr), 
µmol/L (mg/dL) 
Equation 
Black 
 
 
Female 
≤62 (≤0.7) 
GFR = 166 × (SCr/0.7)−0.329 × (0.993)Age 
 
>62 (>0.7) 
GFR = 166 × (SCr/0.7)−1.209 × (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 163 × (SCr/0.9)−0.411 × (0.993)Age 
 
>80 (>0.9) 
GFR = 163 × (SCr/0.9)−1.209 × (0.993)Age 
 
 
 
White or 
other 
 
 
Female 
≤62 (≤0.7) 
GFR = 144 × (SCr/0.7)−0.329 × (0.993)Age 
 
>62 (>0.7) 
GFR = 144 × (SCr/0.7)−1.209 × (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 141 × (SCr/0.9)−0.411 × (0.993)Age 
 
>80 (>0.9) 
GFR = 141 × (SCr/0.9)−1.209 × (0.993)Age 
 
SCr in mg/dL; Output is in mL/min/1.73 m2 and needs no further conversions. 
 
2. eGFR using the Modification of Diet in Renal Disease (MDRD) Study (Levey et al., 2006). 
 
175 x SCr–1.154 × age–0.203 × 0.742 (if female) × 1.212 (if black) 
Output is in mL/min/1.73 m2 and needs no further conversions. 
3. Estimated creatinine clearance (ClCr) by the Cockcroft-Gault (C-G) equation (Cockcroft and 
Gault, 1976). 
 
 
Followed by conversion to a value normalized to 1.73 m2 with the patient’s body surface area 
(BSA). 
 
References 
1. Levey, A.S., L.A. Stevens, C.H. Schmid, et al.  (2009).  A new equation to estimate 
glomerular filtration rate.  Ann Inter Med.  150:604-612. 
2. Levey, A.S., J. Coresh, T. Greene, et al.  (2006).  Using standardized serum creatinine 
values in the modification of diet in renal disease study equation for estimating 
glomerular filtration rate.  Ann Intern Med.  145:247-254. 
3. Cockcroft, D.W. and M.H. Gault.  (1976).  Prediction of creatinine clearance from serum 
creatinine.  Nephron.  16:31-41.