Oral ARV-1801 Given in Combination With Intravenous Ceftazidime or Meropenem for Treatment of Melioidosis in Hospitalized Patients

A Randomized, Double-Blind, Placebo-Controlled, Exploratory Study to Assess the Efficacy, Safety and Tolerability of Oral ARV-1801 Given in Combination With Intravenous Ceftazidime or Meropenem for Intensive Phase Therapy of Melioidosis in Hospitalized Patients

The study investigates the effect of 14 days of twice daily doses of ARV-1801 or placebo in combination with meropenem or ceftazidime in patients hospitalized with melioidosis.

Study Overview

• Status: Completed
• Conditions: Melioidosis
• Intervention / Treatment: Drug: Ceftazidime or meropenem; Drug: Placebo; Drug: ARV-1801

Detailed Description

ARV-1801 is an oral dosage form and loading dose regimen of sodium fusidate. Sodium fusidate is a member of the fusidane class of antibiotics. Recent evidence demonstrates meaningful activity against multiple biothreat agents, including the intracellular pathogen B. pseudomallei, which causes melioidosis. Once melioidosis is suspected clinically, treatment typically involves intravenous antibiotics such as ceftazidime or meropenem during an initial "intensive" phase (typically 2 weeks) and oral antibiotics such as co trimoxazole during a more chronic "eradication" phase (typically 12 weeks). Nevertheless, mortality can still exceed 40% in some regions, with most deaths occurring early during the eradication phase of therapy.

The purpose of this study is to evaluate the effects of ARV-1801 administered for 14 days in conjunction with the current standard of care (meropenem or ceftazidime) against placebo in conjunction with the current standard of care. Day 1 dosing will include two doses of 1500mg of ARV-1801 or placebo administered 12 hours apart. Days 2-14 will include 600 mg doses of ARV-1801 or placebo administered every 12 hours.

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Director, Clinical Operations; Phone Number: 919-366-5500; Email: info@arrevus.com

Study Locations

• Thailand
  • Nai Muang, Thailand
    • Maharat Nakhonratchasima Hospital
  • Nai Muang, Thailand
    • Srinagarind Hospital, Khon Kaen University
  • Nai Muang, Thailand
    • Sunpasitthiprasong Hospital
  • Nai Muang, Thailand
    • Surin Hospital
  • Udon Thani, Thailand, 41000
    • Udon Thani Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient must provide written informed consent obtained prior to any study-specific procedure being performed.
2. Patient must be at least 18 years of age or older at time of consent.

3. Patient must be hospitalized with suspected community-acquired melioidosis, meeting at least one of the criteria below:

   • History of frequent contact with soil or surface water in an endemic area
   • Presence of a known underlying risk factor such as diabetes, renal insufficiency, renal stones or thalassemia
   • Special organ involvement such as splenic or hepatic abscess
   • An illness compatible with melioidosis, including the presence of sepsis, acute pneumonia, acute pyelonephritis, septic arthritis, parotid disease or skin or soft tissue infection
4. Patient must require intravenous antibiotics i.e., either ceftazidime or meropenem for treatment of suspected melioidosis.
5. Patient must agree to stay in hospital for duration of ARV-1801 therapy, i.e., 14 days.
6. Females of childbearing potential must use an acceptable method of birth control (surgically sterile, intrauterine device, vasectomized partner, oral contraceptive plus barrier contraceptive, hormone delivery system plus barrier contraceptive or condom in combination with contraceptive cream, jelly or foam) for the duration of the study drug administration phase and for 30 days thereafter.

Exclusion Criteria:

1. Patient is unable to tolerate oral therapy, either directly or via a nasogastric tube.
2. Patient has a known infection with an identified organism other than B. pseudomallei.
3. Patient is pregnant or lactating.
4. Patient has a known hypersensitivity to sodium fusidate, ceftazidime or meropenem.
5. Patient has been treated with IV antibiotics active against B. pseudomallei (including ceftazidime and meropenem) for longer than 48 hours prior to randomization.

6. Patient requires concomitant treatment with the following:

   • OATP1B1 and OATP1B3 substrates, in particular statins (e.g., HMG-CoA reductase inhibitors)
   • Medications metabolized by CYP2C8, such as glitazones (e.g., repaglinide)
   • CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital, and nafcillin)
7. Patient has had prior treatment with a CYP3A4 inducer, such as dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital, or nafcillin, within 7 days prior to enrollment.
8. Patient requires treatment with digoxin or warfarin unless a monitoring plan is in place to assess digoxin levels and/or prothrombin time as is relevant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Placebo; Patients are administered either IV ceftazidime or IV meropenem per standard of care and placebo. Placebo will be administered every 12 hours for Days 1-14.	Drug: Ceftazidime or meropenem; Patients will be prescribed ceftazidime or meropenem intravenously as per standard of care for at least 14 days while in the hospital; Drug: Placebo; Patients will be prescribed placebo every 12 hours for Days 1-14.
Experimental: ARV-1801 (ACG-701); Patients are administered either IV ceftazidime or IV meropenem per standard of care and active ARV-1801. Day 1 dosing will be two doses of 1500mg of ARV-1801 administered 12 hours apart. Days 2-14 dosing will be 600mg of ARV-1801 administered every 12 hours.	Drug: Ceftazidime or meropenem; Patients will be prescribed ceftazidime or meropenem intravenously as per standard of care for at least 14 days while in the hospital; Drug: ARV-1801; Patients will be prescribed ARV-1801 at 1500mg 12 hours apart on Day 1 and 600mg every 12 hours for Days 2-14.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
All-cause in-hospital mortality through Day 14 in the modified intent-to-treat population (mITT)	Measured at Day 14

Secondary Outcome Measures

Outcome Measure	Time Frame
All-cause in-hospital mortality in mITT population	Measured at study completion, on average 28 days (assessed up to 60 days)
All-cause in-hospital mortality through Day 14 in the ITT population	Measured at study completion, on average 28 days (assessed up to 60 days)
All-cause in-hospital mortality in the ITT population	Measured at study completion, on average 28 days (assessed up to 60 days)
Clearance of positive baseline B. pseudomallei blood cultures at Day 1, 3 and 7	Measured at Days 1, 3 and 7
Number of days in the ICU in the mITT population	Measured at study completion, on average 28 days (assessed up to 60 days)
Number of days on ventilator in the mITT population	Measured at study completion, on average 28 days (assessed up to 60 days)
Length of hospital stay in the mITT population	Measured at study completion, on average 28 days (assessed up to 60 days)
Melioidosis seriousness score in mITT population	Measured at Day 28
Number of patients experiencing adverse events	Measured at study completion, on average 28 days (assessed up to 60 days)

Collaborators and Investigators

• Sponsor: Arrevus Inc.
• Collaborators: Arnasi Group

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2022
• Primary Completion (Actual): October 10, 2023
• Study Completion (Actual): October 10, 2023

Study Registration Dates

• First Submitted: September 23, 2021
• First Submitted That Met QC Criteria: October 22, 2021
• First Posted (Actual): November 3, 2021

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: meropenem; ceftazidime; B. pseudomallei
• Additional Relevant MeSH Terms: Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Burkholderia Infections; Melioidosis; Anti-Infective Agents; Anti-Bacterial Agents; Meropenem; Ceftazidime
• Other Study ID Numbers: ARV-1801-001

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