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

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 Overview

• Status: Terminated
• Conditions: Lassa Fever
• Intervention / Treatment: Drug: Ribavirin

• Study Type: Observational
• Enrollment (Actual): 2

Contacts and Locations

Study Locations

• Sierra Leone
  • Kenema, Sierra Leone
    • Kenema Government Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients admitted to KGH with a positive antigen or PCR test for Lassa virus.

Description

Inclusion Criteria:

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

Exclusion Criteria:

• Patients for end of life care only

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Lassa fever	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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: London School of Hygiene and Tropical Medicine; Public Health England; National Institute for Health Research, United Kingdom; Kenema Government Hospital
• Investigators: Principal Investigator: Alex Salam, MD, University of Oxford

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2019
• Primary Completion (Actual): October 1, 2020
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: March 13, 2019
• First Submitted That Met QC Criteria: March 21, 2019
• First Posted (Actual): March 26, 2019

Study Record Updates

• Last Update Posted (Actual): July 6, 2022
• Last Update Submitted That Met QC Criteria: July 1, 2022
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Body Temperature Changes; Hemorrhagic Fevers, Viral; Arenaviridae Infections; Fever; Lassa Fever; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Ribavirin
• Other Study ID Numbers: 38-18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No