LAssa Fever Adjunct Treatment With DEXamethasone (LADEX)

Safety and Tolerability of Adjunct Dexamethasone in Addition to Standard of Care Antiviral Therapy Compared to Standard of Care Antiviral Therapy Alone for the Treatment of Moderate to Severe Lassa Fever

Dexamethasone is a corticosteroid which can modulate inflammatory-mediated tissue damage associated with a wide range of infectious diseases. Dexamethasone is routinely used for treatment of tuberculous meningitis and for pneumococcal meningitis in adults. In Coronavirus Disease 2019 (COVID-19) dexamethasone is also effectively preventing immune mediated damage of the lungs. There is also indication that dexamethasone may be promising in severe LF.

Study Overview

• Status: Not yet recruiting
• Conditions: Lassa Fever
• Intervention / Treatment: Drug: Ribavirin; Drug: Dexamethasone

Detailed Description

Lassa fever (LF) is a severe and often fatal systemic disease in humans. It is caused by the Lassa virus (LASV). Vaccines are not available yet and treatment options are limited to supportive care and ribavirin. Recent LF outbreaks in Nigeria showed an exceptionally high and increasing incidence of LF cases LF affects a large number of countries in West Africa. The pathophysiology of LF is not fully understood yet. It is hypothesized that the damage mediated by the host's defence is plays a key role in the pathophysiology of severe LF. Dexamethasone is considered to dampen the overactive immune response in a range of infectious diseases and thus preventing consecutive damage mediated by the host's immune system, while the antiinfective therapy is effectively treating the underlying pathogen. At the Irrua Specialist Teaching Hospital (ISTH) in Nigeria, one of the largest treatment centres for LF in West-Africa, dexamethasone has been successfully used in clinical practice to manage co-infections of LASV and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2).

To evaluate Dexamethasone for the treatment of moderate to severe LF cases, a prospective open label randomized controlled phase II clinical trial will be conducted:

1. Standard of care antiviral ribavirin therapy
2. Standard of care antiviral ribavirin therapy + dexamethasone

The primary objective is to assess safety and tolerability of dexamethasone in moderate to severe LF when administered as adjunct treatment. Secondary objectives are to assess the effect of the study intervention on disease progression; to assess immunological and virological impact of dexamethasone therapy and the characterization of population pharmacokinetic characteristics for patients treated with adjunct dexamethasone therapy.

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mirjam Groger, Dr.; Phone Number: +49 40 285380 480; Email: groger@bnitm.de
• Study Contact Backup: Name: Stephan Günther, Prof.; Phone Number: +49 40 285380 547; Email: guenther@bnitm.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years
• LF confirmed by RT-PCR (reverse-transcription polymerase chain reaction) with a cycle threshold (Ct) value < 30
• Signs of significant health impairment as evidenced by any of the following:
• Alert, confusion, voice, pain, unresponsive (ACVPU) other than A
• Systolic blood pressure < 90 mmHg
• Seizure(s), meningism, coma, focal neurological deficit
• AST (GOT) >3xULN
• ALT (GPT) > 3xULN
• KDIGO 2 or more severe based on serum creatinine only
• Active macroscopic bleeding
• O2 saturation < 92

Exclusion Criteria:

• Pregnancy (evidenced by positive urine pregnancy test in women of child-bearing potential)
• Lactation following live birth
• Known intolerance and contra-indications to ribavirin or dexamethasone
• Patients who already received a corticosteroid within the preceding 7 days
• Investigator's valuation that patient might be put to substantial risk by participating in this trial
• Patients receiving end-of-life care as judged by the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care; Standard of care antiviral ribavirin therapy	Drug: Ribavirin; Ribavirin treatment will be administered iv for 10 days, as recommended in the Nigeria Centre for Disease Control and Prevention National Guidelines for LF Case Management.
Experimental: Standard of care + dexamethasone; Standard of care antiviral ribavirin therapy + dexamethasone	Drug: Ribavirin; Ribavirin treatment will be administered iv for 10 days, as recommended in the Nigeria Centre for Disease Control and Prevention National Guidelines for LF Case Management.; Drug: Dexamethasone; Dexamethasone will be administered for 10 days. For the first 48 hours, dexamethasone will be given iv. After 48 hours, a switch to oral dexamethasone (same dosage) is permitted at the discretion of the study physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of treatment emergent adverse events and treatment emergent serious adverse events	Documentation of events	Participants will be followed up until day 10 after enrollment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Unfavourable outcome	The outcome is measured by the proportion of participants reaching a composite endpoint. The outcome is reached if there is a new onset of any of the following: acute kidney injury (KDIGO 3), acute respiratory distress syndrome (SpO2/FiO2 ≤ 315), shock (mean blood pressure < 65 mmHg or systolic blood pressure < 90 mmHg ), encephalopathy (CVPU or seizure), death (yes/no);	Participants will be followed up until day 10 after enrollment.
Mean/median decline and area under the curve (AUC) of AST, ALT, CK, LDH and CRP	Blood analyses	Participants will be followed up until day 10 after enrollment.
Description of: proinflammatory plasma cytokine levels and lymphocyte phenotype under treatment	Assays such as the enzyme-linked immunosorbent assays (ELISA) and/or immunofluorescence assays will be used to retrospectively determine LASV IgM and IgG, as well as further IgG subclassification if needed, and to monitor the development of LASV specific antibodies in blood. Longitudinal development of inflammatory biomarkers such as IFNα, TNFα, IL-6, and IL-8 will be measured in plasma using bead-based multiplex assays. The phenotype of lymphocytes will be described using flow cytometry.	Participants will be followed up until day 10 after enrollment.
Description of evolution of viral loads and infectious titers over time until day 10	Virus titers will be determined. Viral growth, isolation of LASV in cell culture, virus sequencing and unbiased metagenomic sequencing will be used on selected samples to study the longitudinal impact of drug treatment (ribavirin and dexamethasone) on LASV genomes.	Participants will be followed up until day 10 after enrollment.
Evolution of selected virus gene sequences under treatment	Virus sequencing	Participants will be followed up until day 10 after enrollment.
Peak plasma concentration (Cmax)	Compartmental analysis	Participants will be followed up until day 10 after enrollment.
Time to peak plasma concentration (Tmax)	Compartmental analysis	Participants will be followed up until day 10 after enrollment.
Area under the plasma concentration versus time curve (AUC)	Compartmental analysis	Participants will be followed up until day 10 after enrollment.
Half life (T 1/2)	Compartmental analysis	Participants will be followed up until day 10 after enrollment.
Volume of distribution (Vd)	Compartmental analysis	Participants will be followed up until day 10 after enrollment.

Collaborators and Investigators

• Sponsor: Bernhard Nocht Institute for Tropical Medicine
• Investigators: Study Director: Stephan Günther, Prof., Bernhard Nocht Institute for Tropical Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 29, 2023
• First Submitted That Met QC Criteria: January 15, 2024
• First Posted (Actual): January 25, 2024

Study Record Updates

• Last Update Posted (Actual): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: December 1, 2023

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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-Inflammatory Agents; Antimetabolites; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Ribavirin
• Other Study ID Numbers: 1.0 (17 July 2023); 20231908/486 (Other Identifier: ISTH EC, Nigeria); 2023-101164-BO-ff (Other Identifier: EC Hamburg, Germany)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Case by case decision upon request

Drug and device information, study documents

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