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NCT Number: NCT04285034

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

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.

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Key information

Conditions

Lassa Fever Arenaviridae Infections Hemorrhagic Fevers, Viral Infections RNA Virus Infections Virus Diseases

Age range

10 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Owo Federal Medical Centre

Owo, Ondo State, PMB 1053, Nigeria

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Primary outcomes

  1. Cardiovascular

    Time frame: through study completion, an average of 2 weeks

    Mean Arterial Pressure is less than 65mmHg or Systolic Blood Pressure is less than 90mmgHg or pulse pressure < 20mmHg

  2. Ribavirin Pharmacokinetics

    Time frame: through study completion, an average of 2 weeks

    Proportion of patients with ribavirin CMIN above the IC90 at > 80% of measured CMIN during therapy

  3. Ribavirin Pharmacodynamics

    Time frame: 5 days

    Change in Lassa virus Viral Load from baseline to day 5

Secondary outcomes

  1. Cardiovascular

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of shock

  2. Cardiovascular

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of persistent shock

  3. Cardiovascular

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of respiratory distress

  4. Cardiovascular

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of shock and respiratory distress

  5. Cardiovascular

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of Death

  6. Ribavirin Pharmacokinetics

    Time frame: through study completion, an average of 2 weeks

    Proportion of patients with ribavirin CMIN above the IC50 at all measured CMIN during therapy

  7. Ribavirin Pharmacokinetics

    Time frame: through study completion, an average of 2 weeks

    Duration of time that ribavirin levels are above the IC90 and IC50

  8. Ribavirin Pharmacokinetics

    Time frame: through study completion, an average of 2 weeks

    Calculation of AUC [AUC∞ and AUCLAST] (ribavirin, ribavirin metabolites)

  9. Ribavirin Pharmacokinetics

    Time frame: through study completion, an average of 2 weeks

    Calculation of CMAX (ribavirin, ribavirin metabolites)

  10. Ribavirin Pharmacokinetics

    Time frame: through study completion, an average of 2 weeks

    Calculation of CMIN (ribavirin, ribavirin metabolites)

  11. Ribavirin Pharmacokinetics

    Time frame: through study completion, an average of 2 weeks

    Calculation of T1/2 (ribavirin, ribavirin metabolites)

  12. Ribavirin Pharmacokinetics

    Time frame: through study completion, an average of 2 weeks

    Volume of distribution (ribavirin, ribavirin metabolites)

  13. Ribavirin Pharmacokinetics

    Time frame: through study completion, an average of 2 weeks

    Calculation of Clearance (ribavirin, ribavirin metabolites)

  14. Ribavirin Pharmacodynamics

    Time frame: 10 days

    Change in Lassa virus Viral Load from baseline to day 3 and day 10

  15. Ribavirin Pharmacodynamics

    Time frame: 10 days

    Change in AST, ALT concentrations from baseline to day 3, 5, 10

  16. Ribavirin Pharmacodynamics

    Time frame: 10 days

    Change in eGFR from baseline to day 3, 5, 10

  17. Ribavirin Pharmacodynamics

    Time frame: 10 days

    Change in Haemoglobin from baseline to day 5, 10

  18. Ribavirin Pharmacodynamics

    Time frame: 5 days

    Change in ISG expression from baseline to day 3, 5

  19. Ribavirin Pharmacodynamics

    Time frame: through study completion, an average of 2 weeks

    Time to negative blood RT-PCR for Lassa virus

  20. Ribavirin Pharmacodynamics

    Time frame: through study completion, an average of 2 weeks

    Requirement for blood transfusion during hospitalisation

  21. Ribavirin Pharmacodynamics

    Time frame: through study completion, an average of 2 weeks

    Reaching KDIGO stage 3 during hospitalisation

  22. Ribavirin Pharmacodynamics

    Time frame: through study completion, an average of 2 weeks

    Requirement for dialysis during hospitalisation

  23. Ribavirin Pharmacodynamics

    Time frame: through study completion, an average of 2 weeks

    Duration of hospitalisation

Other outcomes

  1. Cardiovascular Explanatory

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of vascular leak

  2. Cardiovascular Explanatory

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of cardiac function

  3. Cardiovascular Explanatory

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of total peripheral resistance

  4. Cardiovascular Explanatory

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of total body water

  5. Cardiovascular Explanatory

    Time frame: through study completion, an average of 2 weeks

    To identify the frequency of Reactive hyperaemic index

  6. Ribavirin Pharmacokinetics Explanatory

    Time frame: through study completion, an average of 2 weeks

    Age

  7. Ribavirin Pharmacokinetics Explanatory

    Time frame: through study completion, an average of 2 weeks

    Gender

  8. Ribavirin Pharmacokinetics Explanatory

    Time frame: through study completion, an average of 2 weeks

    Calculation of eGFR

  9. Ribavirin Pharmacokinetics Explanatory

    Time frame: through study completion, an average of 2 weeks

    Calculation of Total body water

  10. Ribavirin Pharmacokinetics Explanatory

    Time frame: through study completion, an average of 2 weeks

    ITPA, SLC28 gene polymorphisms

  11. Ribavirin Pharmacodynamics Explanatory

    Time frame: through study completion, an average of 2 weeks

    Calculation of AUC [AUC∞ and AUCLAST]

  12. Ribavirin Pharmacodynamics Explanatory

    Time frame: through study completion, an average of 2 weeks

    Calculation of CMAX

  13. Ribavirin Pharmacodynamics Explanatory

    Time frame: through study completion, an average of 2 weeks

    Calculation of CMIN

  14. Ribavirin Pharmacodynamics Explanatory

    Time frame: through study completion, an average of 2 weeks

    ITPA, IL28B and SLC28/29 gene polymorphisms

Sponsors and collaborators

Lead sponsor

University of Oxford

Other

Registry information

Official study title

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

Important dates

Study start
2019
Primary completion
2021
Study completion
2021
First posted
Feb 26, 2020
Registry last updated
Oct 13, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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