Cardiovascular Function and Ribavirin Pharmacokinetics and Pharmacodynamics in Patients With Lassa Fever

Overview

Lassa fever carries a treated mortality in hospitalized patients of up to 50%. Lassa fever is often described as being characterized by vascular leak and shock in the terminal phase, but, whilst animal data supports this, there are limited data in humans. Therefore, an aim of this study therefore is to characterize cardiovascular function in patients with Lassa fever, with the ultimate goal of informing future trials of supportive or therapeutic strategies.

Ribavirin is the current standard of care. However, the efficacy of ribavirin has not been established in a randomised controlled trial (RCT). There is very limited pharmacokinetic (PK) data on ribavirin in patients with Lassa fever and the optimal dose of ribavirin for an RCT is unknown. Furthermore, there are various hypothesized mechanisms of action of ribavirin, none of which have been investigated in humans with Lassa fever. Further aims of this study therefore are to characterize the PK of ribavirin in Lassa fever, and identify any associations between ribavirin PK parameters, viral load and markers of immune/inflammatory status.

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: October 2020

Interventions

  • Drug: Ribavirin
    • Standard of care: Intravenous administration of ribavirin at currently recommended dosages. Loading dose of 30 mg/kg (maximum 2 g), followed by 15 mg/kg (maximum 1 g) intravenously QDS for four days, followed by 7.5 mg/kg intravenously (maximum 500 mg) TDS for six days.

Arms, Groups and Cohorts

  • Lassa fever

Clinical Trial Outcome Measures

Primary Measures

  • Cardiovascular function – primary
    • Time Frame: Up to 28 days during hospitalisation
    • Death during hospitalization
  • Ribavirin PK – primary
    • Time Frame: Up to 15 days during hospitalisation
    • Proportion of patients with ribavirin CMIN above the IC90 at all measured CMIN during therapy
  • Ribavirin PD (mechanism of action) – primary
    • Time Frame: Up to 15 days during hospitalisation
    • • Change in Lassa virus viral load (copies/ml) from baseline to day 3/5

Secondary Measures

  • Cardiovascular function – secondary
    • Time Frame: Up to 28 days during hospitalisation
    • • Shock (shock is defined as a systolic BP < 90mmgHg [age specific in children] OR a MAP < 65mmgHg AND a lactate > 2 mEq/L)
  • Cardiovascular function – secondary
    • Time Frame: Up to 28 days during hospitalisation
    • • Persistent shock (persistent shock is defined as a MAP < 65 mmHg OR a SBP < 90 mmHg [age specific in children] AND a lactate > 2 mEq/L on more than 2 occasions [at least 6 hours apart] DESPITE IV fluids +/- vasopressors)
  • Cardiovascular function – secondary
    • Time Frame: Up to 28 days during hospitalisation
    • • Respiratory distress (respiratory distress is defined as a respiratory rate > 24 (age specific in children) AND oxygen saturations < 94% OR use of supplemental oxygen)
  • Ribavirin PK – secondary
    • Time Frame: Up to 15 days during hospitalisation
    • • Proportion of patients with ribavirin CMIN above the IC50 at all measured CMIN during therapy
  • Ribavirin PK – secondary
    • Time Frame: Up to 15 days during hospitalisation
    • • Peak Plasma Concentration
  • Ribavirin PK – secondary
    • Time Frame: Up to 15 days during hospitalisation
    • • Minimum Plasma Concentration
  • Ribavirin PK – secondary
    • Time Frame: Up to 15 days during hospitalisation
    • • Area under the plasma concentration versus time curve
  • Ribavirin PK – secondary
    • Time Frame: Up to 15 days during hospitalisation
    • • Half life
  • Ribavirin PD (mechanism of action)
    • Time Frame: Up to 15 days during hospitalisation
    • • Change in ISG expression from baseline to day 3/5
  • Ribavirin PD (mechanism of action)
    • Time Frame: Up to 15 days during hospitalisation
    • • Change in RHI from baseline to day 3
  • Ribavirin PD (mechanism of action)
    • Time Frame: Up to 15 days during hospitalisation
    • • Time to negative blood PCR for Lassa virus
  • Ribavirin PD (mechanism of action)
    • Time Frame: Up to 15 days during hospitalisation
    • • Survival to hospital discharge
  • Ribavirin PD (mechanism of action)
    • Time Frame: Up to 15 days during hospitalisation
    • Change in aspartate aminotransferase concentrations (units/litre) from baseline to day 3/5
  • Ribavirin PD (mechanism of action)
    • Time Frame: Up to 15 days during hospitalisation
    • • Change in systemic nitric oxide concentrations from baseline to day 3/5

Participating in This Clinical Trial

Inclusion Criteria

  • Positive antigen or PCR test for Lassa fever
  • Aged 10 years or above

Exclusion Criteria

  • Patients for end of life care only

Gender Eligibility: All

Minimum Age: 10 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Oxford
  • Collaborator
    • National Institute for Health Research, United Kingdom
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Alex Salam, MD, Principal Investigator, University of Oxford
  • Overall Contact(s)
    • Annelies Gillesen, +441865 612959, annelies.gillesen@ndm.ox.ac.uk

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