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

Study Overview
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Brief Summary
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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. 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. 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.

Detailed Description
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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.

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

Conditions
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Lassa Fever

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Ribavirin only<br>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<br>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?
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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 |