Evaluation of Alisporivir for the Treatment of Hospitalised Patients With Infections Due to SARS-CoV-2 (COVID-19)
Condition: SARS-CoV-2
MeSH terms: Infections
Study type: Interventional
Phase: Phase 2

Summary: 
      COVID-19 is a viral respiratory and systemic disease that has been rapidly spreading globally
      since the first cases were reported in December 2019 and has now become pandemic. The
      causative agent of COVID-19 was identified as a novel coronavirus named severe acute
      respiratory syndrome coronavirus 2 (SARS-CoV-2, first designated as 2019-nCoV).

      The disease manifestations of COVID-19 can range from mild, self-resolving respiratory
      disease to severe pneumonia, ARDS, multiorgan failure, and ultimately death. In early
      reports, the mortality rate among patients admitted to hospital and with confirmed SARS-CoV-2
      infection was reported to be between 4 and 15%. Although the disease can afflict all age
      groups, elderly patients and patients with underlying comorbidities such as high body mass
      index, hypertension, diabetes, cardiovascular disease, or cerebrovascular disease are at risk
      of developing severe disease and dying.

      There are currently no etiologic treatments for COVID-19, and efforts are underway to
      identify therapeutics that could be effective in controlling this disease.
    

Detailed description: 
      Cyclophilins are cellular (host) peptidyl-prolyl cis/trans isomerases (molecular chaperones)
      involved in protein folding, maturation, and trafficking. Cyclophilins have been shown to
      play a key role in the lifecycle of many coronaviruses, including human coronaviruses 229E
      (HCoV-229E) and NL-63 (HCoV-NL63), feline infectious peritonitis coronavirus (FPIV), SARS-CoV
      and Middle-East-Respiratory-Syndrome coronavirus (MERS-CoV). Cyclosporin A (CsA), a potent
      cyclophilin inhibitor, blocks the replication of various coronaviruses in vitro, including
      HCoV-229E, HCoV-NL63, FPIV, mouse hepatitis virus (MHV), avian infectious bronchitis virus,
      and SARS-CoV.

      Alisporivir is a non-immunosuppressive analogue of CsA with potent cyclophilin inhibition
      properties. In vitro, alisporivir inhibits the replication of HCoV-229E, HCoV-NL63, MHV,
      SARS-CoV and MERS-CoV at low micromolar concentrations without cytotoxic effect. Although
      alisporivir has not demonstrated activity against coronaviruses in in vivo models to date,
      recent experiments showed that alisporivir bears concentration-dependent properties against
      CoV-2 in vitro.

      Preclinical pharmacology data indicate that, after oral administration, alisporivir is widely
      distributed in the whole body, including the lungs. Furthermore, the EC90 of alisporivir
      against SARS-CoV-2 in VeroE6 cells appears to be clinically achievable in patients. In
      addition, because alisporivir inhibits all cellular cyclophilins, it also blocks
      mitochondrial cyclophilin-D, a key regulator of mitochondrial permeability transition pore
      (mPTP) opening, a mechanism involved in triggering cell death.

      Therefore, besides its antiviral properties, alisporivir may also be effective in preventing
      lung tissue damage.
    

Intervention name(s): Alisporivir; Standard of care (SOC)
Intervention type(s): Drug; Other
Intervention description(s): Administration of alisporivir at the dose of 600 mg p.o. BID from D1 to D14 to patients and standard of care (SOC).; Locally accepted regimen protocols for patient care and select agents based on the underlying diagnosis and the severity of COVID 19 (excepting e.g. azithromycin and other antibiotics listed as prohibited medications)
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a randomised, open-label, proof of-concept, Phase 2 study to evaluate the efficacy, safety and tolerability of alisporivir plus SOC as compared to SOC for the treatment of hospitalised patients with infections due to SARS-CoV-2
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Alisporivir; Viral Load; efficacy; safety; tolerability