Cyclosporine For The Treatment Of COVID-19(+)
Condition: SARS (Disease)
MeSH terms: COVID-19
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Cyclosporine; Standard of Care Treatment
Intervention type(s): Drug; Other
Intervention description(s): 2.5 mg/kg PO BID 7 days; Standard of Care Treatment, N= 25 Patients, 7 days
Other intervention name(s): Neoral
Intervention MeSH terms: Cyclosporine; Cyclosporins
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Phase IIa clinical trial in which 75 non-ICU hospital inpatients will be randomized 2:1 to 7 days of Neoral (2.5mg/kg PO BID) + standard of care (SOC) or no CSA + SOC.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: COVID-19; SARS-COV-2; Corona Virus