Amphotericin Versus Posaconazole for Pulmonary Mucormycosis

A Randomized Controlled Trial of Amphotericin B Versus Posaconazole for Treating Pulmonary Mucormycosis

Pulmonary mucormycosis is a serious illness with high morbidity and mortality (approximately 57%). Surgery and antifungal therapy are central in the management of mucormycosis. Unlike rhino-orbital mucormycosis, surgery is not feasible in several patients with pulmonary mucormycosis. Hence, treatment is primarily with antifungal therapy. Amphotericin B is the standard of care in the medical management of mucormycosis. However, amphotericin B is expensive, has significant adverse events, and is available only in parenteral formulation. Posaconazole is effective against Mucorales, and is currently approved for salvage therapy of mucormycosis. Recent evidence suggest that in several patients, posaconazole may be effective as a monotherapy upfront. In the current study posaconazole versus amphotericin B will be evaluated for the management of pulmonary mucormycosis in a randomized clinical trial.

Study Overview

• Status: Recruiting
• Conditions: Mucormycosis; Pulmonary (Etiology)
• Intervention / Treatment: Drug: Liposomal Amphotericin B; Drug: Posaconazole 600 mg followed by posaconazole 300 mg once daily

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Valliappan Muthu; Phone Number: +917087001389; Email: muthu.valliappan@pgimer.edu.in

Study Locations

• India
  • Chandigarh, India, 160012
    • Recruiting
    • Postgraduate Institute of Medical Education and Research
    • Contact: Avadh Vithlani, MBBS, MD; Phone Number: 07087001389; Email: avadhv48@gmail.com
    • Principal Investigator: Avadh Vithlani, MBBS, MD
    • Principal Investigator: Valliappan Muthu, MD, DM

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Subjects with proven or probable pulmonary mucormycosis. Participants with a suspicion of pulmonary mucormycosis (as defined previously) based on compatible clinical presentation and compatible imaging will be screened for inclusion in the study.

Exclusion Criteria:

• Failure to provide informed consent
• Contraindications or hypersensitivity to amphotericin B, posaconazole or their components
• Already received >4 days of antifungals prior to randomization into the study
• Pregnant women
• High chances of mortality within 48 hours of enrolment into the study

Subjects with possible pulmonary mucormycosis will also be excluded, if their diagnosis is not confirmed within four working days of enrollment

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: Amphotericin B arm (standard of care); Intravenous liposomal amphotericin B [5 mg/kg per day] for at least 4 weeks followed by maintenance therapy. Maintenance therapy (after four weeks of treatment initiation) will be continued for at least 12 weeks or longer as decided by the treating physician. The maintenance therapy will be posaconazole. However, if therapeutic drug monitoring is not possible or the participants opt to use isavuconazole or amphotericin, the same will be permitted and noted	Drug: Liposomal Amphotericin B; All study subjects will be administered intravenous liposomal amphotericin B [5 mg/kg/day infusion in 5% dextrose solution] over at least 2 hours, as per recommendations. Amphotericin B will be administered for the first seven days in the experimental arm, whereas it will be administered atleast for four weeks in the active comparator arm. Premedication or intravenous hydration will not be routinely administered. For patients experiencing chills, fever, hypotension, nausea, or other non-anaphylactic immediate infusion-related reactions, premedication (acetaminophen, diphenhyramine or hydrocortisone) will be administered 30 to 60 minutes prior to the next dose of amphotericin infusion. The dose of intravenous amphotericin B will be modified further if required, based on the tolerability, and response to treatment.; Other Names: LAMB
Experimental: Posaconazole arm; Combination of liposomal amphotericin B (5 mg/kg per day) and posaconazole for first 7 days followed by oral posaconazole only (for induction as well as maintenance therapy). The first four weeks of therapy will be called induction therapy	Drug: Liposomal Amphotericin B; All study subjects will be administered intravenous liposomal amphotericin B [5 mg/kg/day infusion in 5% dextrose solution] over at least 2 hours, as per recommendations. Amphotericin B will be administered for the first seven days in the experimental arm, whereas it will be administered atleast for four weeks in the active comparator arm. Premedication or intravenous hydration will not be routinely administered. For patients experiencing chills, fever, hypotension, nausea, or other non-anaphylactic immediate infusion-related reactions, premedication (acetaminophen, diphenhyramine or hydrocortisone) will be administered 30 to 60 minutes prior to the next dose of amphotericin infusion. The dose of intravenous amphotericin B will be modified further if required, based on the tolerability, and response to treatment.; Other Names: LAMB; Drug: Posaconazole 600 mg followed by posaconazole 300 mg once daily; Posaconazole will be given as a delayed release tablet, the dose would be 600 mg in two divided doses on day 1, followed by 300 mg once a day from then on. If a subject vomits within 15 minutes of posaconazole tablet administration, the dosing should be repeated as soon as possible, following appropriate antiemetic treatment. The drug will be administered after a meal.; Other Names: In the experimental arm, the first seven days of posaconazole will be overlapped with liposomal amphotericin B 5 mg/kg body weight intravenous infusion (similar to the active comparator arm)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of participants achieving a successful outcome (complete response or partial response) at the completion of six weeks. The response assessment will be a composite of clinical and radiological as adjudged by a multidisciplinary team	Overall response based on clinical assessment at six weeks after randomization as described recently in a Delphi consensus statement and previous studies on invasive mold infection of the lung. (PMID: 35390293) Based on clinical and radiological response (assessed on CT scan using the two-dimensional measurement of the largest target lesion [WHO criteria, like in lung cancer response assessment]). The overall response will be classified as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or death. CR or PR will be labeled success, while SD, PD or death will be labeled as failure	six weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of participants achieving a successful outcome (complete response or partial response) at the completion of twelve weeks. The response assessment will be a composite of clinical and radiological as adjudged by a multidisciplinary team	Overall response based on clinical assessment at twelve weeks after randomization as described recently in a Delphi consensus statement and previous studies on invasive mold infection of the lung. (PMID: 35390293) Based on clinical and radiological response (assessed on CT scan using the two-dimensional measurement of the largest target lesion [WHO criteria, like in lung cancer response assessment]). The overall response will be classified as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or death. CR or PR will be labeled success, while SD, PD or death will be labeled as failure	telve weeks after randomization
90-day mortality	Survival at 90 days will be assessed either by in-person or telephonic follow-up	90 days after randomization
Adverse events related to therapy and the number of participants needing either discontinuation or modification of drug therapy due to adverse events	Adverse events to liposomal amphotericin B and posaconazole including deranged liver and renal functions will be assessed	First four weeks of randomization

Collaborators and Investigators

• Sponsor: Postgraduate Institute of Medical Education and Research

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: July 16, 2022
• First Submitted That Met QC Criteria: July 19, 2022
• First Posted (Actual): July 21, 2022

Study Record Updates

• Last Update Posted (Actual): November 27, 2023
• Last Update Submitted That Met QC Criteria: November 24, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Posaconazole; fungal pneumonia,; zygomycosis; invasive mold disease; Mucorales
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Mucormycosis; Zygomycosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Posaconazole; Amphotericin B; Liposomal amphotericin B
• Other Study ID Numbers: IEC-INT/2022/DM-262

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No