Cardiovascular Function and Ribavirin PK/PD in Lassa Fever in Lassa Fever

Cardiovascular Function and Ribavirin Pharmacokinetics and Pharmacodynamics in Lassa Fever Patients in Nigeria: a Prospective Observational Cohort Study

Arenaviruses are included in the World Health Organisation R&D Blueprint list of high priority pathogens, since this virus group includes several epidemic-prone highly pathogenic viruses for which there are inadequate diagnostic, therapeutic, and preventative interventions. Junin, Machupo, Guanarito, Sabia, Lujo, and Lassa virus can all cause a viral haemorrhagic fever with high case fatality in hospitalised cases. Lassa fever is the most common severe arenavirus disease and is endemic across many low and middle income countries in West Africa, with an estimated 37.7 million people in 14 countries living in areas at risk of Lassa virus. Despite the discovery of Lassa virus in 1972 and an estimated 300,000 cases and 5000-10,000 deaths annually, there remain gaps in our understanding of the natural history of disease and in the availability of evidence based interventions.

The protocol has two components. Sites may implement one or both components.

1. Cardiovascular function in Lassa fever: Lassa fever in humans is often described in the literature as being characterized by vascular leak and shock in the terminal phase, this being the main pathway to death. Whilst animal data supports this, there are very limited data in humans. One of the main aims 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 to improve vascular leak.
2. Ribavirin pharmacokinetics and pharmacodynamics: The recommended treatment for Lassa is ribavirin, but its efficacy has not been established in randomized controlled trials and its mechanism of action is not fully understood. There are very limited PK data on ribavirin in patients with Lassa fever and the optimal dose of ribavirin for an RCT has not been established. Furthermore, there are various hypothesized mechanisms of action of ribavirin, none of which have been investigated in humans with Lassa fever. Therefore, further aims of this study are to characterize the PK of ribavirin and ribavirin metabolites (RMP, RDP, RTP) in Lassa fever patients and to identify potential mechanisms of action ribavirin in Lassa fever. Understanding Ribavirin's mechanism of action in Lassa fever is important for the optimal design of a future RCT.

Study Overview

• Status: Completed
• Conditions: Lassa Fever

Detailed Description

Summary of cardiovascular function study Lassa fever carries a treated mortality in hospitalized patients of up to 30%. 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. A further 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.

Summary of ribavirin pharmacokinetics and pharmacodynamics sub-study Lassa fever carries a treated mortality in hospitalized patients of up to 30% in Nigeria. Ribavirin is the current standard of care. However, the efficacy of ribavirin has not been established in RCTs. There is very limited PK data on ribavirin in patients with Lassa fever and the optimal dose of ribavirin for an RCT is unknown. The aim of this study is to characterize the PK of ribavirin in Lassa fever, and identify any associations between ribavirin PK parameters and viral load and markers of inflammatory status.

• Study Type: Observational
• Enrollment (Actual): 158

Contacts and Locations

Study Locations

• Nigeria
  • Ondo State
    • Owo, Ondo State, Nigeria, PMB 1053
      • Owo Federal Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients admitted to Lassa fever treatment centres with a diagnosis of suspected or RT-PCR confirmed Lassa fever.

Description

Cardiovascular Study:

Inclusion Criteria:

• Suspected or RT-PCR confirmed Lassa fever diagnosis
• Aged 10 years or above

Exclusion Criteria:

• None

Ribavirin PK/PD study

Inclusion Criteria:

• Suspected or RT-PCR confirmed Lassa fever diagnosis
• Patient will receive ribavirin therapy
• Aged 10 years or above

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Ribavirin only; Patients will receive ribavirin in accordance with Nigerian treatment guidelines. Patients will either receive the McCormick regimen or the Irrua regimen. PK blood tests will be done on Day 1,2,5,6,10,11,12,13, discharge; Paxgene RNA blood test on day 1, 3, 5, discharge Haematocrit finger prick test on day 1,2, 5, 6, 10, discharge
Cardiocascular study only; Cardiac tests (NICAS (daily), ECG (Day 1, 5, 10, discharge), Echocardiogram (Day 1, 5, discharge), Ultrasound (Day 1, 3, 5, 7, 10), Endopat (Day 1 and discharge)) will be done throughout; Haematocrit finger prick test daily PAXgene RNA blood test on day 1, 5, discharge

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular	Mean Arterial Pressure is less than 65mmHg or Systolic Blood Pressure is less than 90mmgHg or pulse pressure < 20mmHg	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics	Proportion of patients with ribavirin CMIN above the IC90 at > 80% of measured CMIN during therapy	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics	Change in Lassa virus Viral Load from baseline to day 5	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular	To identify the frequency of shock	through study completion, an average of 2 weeks
Cardiovascular	To identify the frequency of persistent shock	through study completion, an average of 2 weeks
Cardiovascular	To identify the frequency of respiratory distress	through study completion, an average of 2 weeks
Cardiovascular	To identify the frequency of shock and respiratory distress	through study completion, an average of 2 weeks
Cardiovascular	To identify the frequency of Death	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics	Proportion of patients with ribavirin CMIN above the IC50 at all measured CMIN during therapy	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics	Duration of time that ribavirin levels are above the IC90 and IC50	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics	Calculation of AUC [AUC∞ and AUCLAST] (ribavirin, ribavirin metabolites)	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics	Calculation of CMAX (ribavirin, ribavirin metabolites)	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics	Calculation of CMIN (ribavirin, ribavirin metabolites)	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics	Calculation of T1/2 (ribavirin, ribavirin metabolites)	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics	Volume of distribution (ribavirin, ribavirin metabolites)	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics	Calculation of Clearance (ribavirin, ribavirin metabolites)	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics	Change in Lassa virus Viral Load from baseline to day 3 and day 10	10 days
Ribavirin Pharmacodynamics	Change in AST, ALT concentrations from baseline to day 3, 5, 10	10 days
Ribavirin Pharmacodynamics	Change in eGFR from baseline to day 3, 5, 10	10 days
Ribavirin Pharmacodynamics	Change in Haemoglobin from baseline to day 5, 10	10 days
Ribavirin Pharmacodynamics	Change in ISG expression from baseline to day 3, 5	5 days
Ribavirin Pharmacodynamics	Time to negative blood RT-PCR for Lassa virus	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics	Requirement for blood transfusion during hospitalisation	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics	Reaching KDIGO stage 3 during hospitalisation	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics	Requirement for dialysis during hospitalisation	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics	Duration of hospitalisation	through study completion, an average of 2 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular Explanatory	To identify the frequency of vascular leak	through study completion, an average of 2 weeks
Cardiovascular Explanatory	To identify the frequency of cardiac function	through study completion, an average of 2 weeks
Cardiovascular Explanatory	To identify the frequency of total peripheral resistance	through study completion, an average of 2 weeks
Cardiovascular Explanatory	To identify the frequency of total body water	through study completion, an average of 2 weeks
Cardiovascular Explanatory	To identify the frequency of Reactive hyperaemic index	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics Explanatory	Age	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics Explanatory	Gender	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics Explanatory	Calculation of eGFR	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics Explanatory	Calculation of Total body water	through study completion, an average of 2 weeks
Ribavirin Pharmacokinetics Explanatory	ITPA, SLC28 gene polymorphisms	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics Explanatory	Calculation of AUC [AUC∞ and AUCLAST]	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics Explanatory	Calculation of CMAX	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics Explanatory	Calculation of CMIN	through study completion, an average of 2 weeks
Ribavirin Pharmacodynamics Explanatory	ITPA, IL28B and SLC28/29 gene polymorphisms	through study completion, an average of 2 weeks

Collaborators and Investigators

• Sponsor: University of Oxford

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 26, 2019
• Primary Completion (ACTUAL): July 15, 2021
• Study Completion (ACTUAL): July 15, 2021

Study Registration Dates

• First Submitted: February 18, 2020
• First Submitted That Met QC Criteria: February 25, 2020
• First Posted (ACTUAL): February 26, 2020

Study Record Updates

• Last Update Posted (ACTUAL): October 13, 2021
• Last Update Submitted That Met QC Criteria: October 12, 2021
• Last Verified: October 1, 2021

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
• Other Study ID Numbers: 04-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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