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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
Cardiovascular Function and Ribavirin Pharmacokinetics and Pharmacodynamics in Patients With Lassa Fever

Conditions
-----------------
Lassa Fever

Intervention / Treatment
-----------------
* Drug: Ribavirin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Positive antigen or PCR test for Lassa fever Aged 10 years or above Exclusion Criteria: Patients for end of life care only

Ages Eligible for Study
-----------------
Minimum Age: 10 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Lassa fever<br> | Drug: Ribavirin<br>* 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.<br>|

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 |