Amphotericin Versus Posaconazole for Pulmonary Mucormycosis

Sponsor

Postgraduate Institute of Medical Education and Research (Other)

Overall Status

Recruiting

CT.gov ID

NCT05468372

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Mucormycosis; Pulmonary (Etiology)	Drug: Posaconazole 600 mg followed by posaconazole 300 mg once daily Drug: Liposomal Amphotericin B	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jul 1, 2022

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Jun 30, 2024

Arms and Interventions

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: 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) 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

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: 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)

Drug: Liposomal Amphotericin B

Other Names:

LAMB

Outcome Measures

Primary Outcome Measures

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 [six weeks after randomization]
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

Secondary Outcome Measures

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 [telve weeks after randomization]
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
90-day mortality [90 days after randomization]
Survival at 90 days will be assessed either by in-person or telephonic follow-up
Adverse events related to therapy and the number of participants needing either discontinuation or modification of drug therapy due to adverse events [First four weeks of randomization]
Adverse events to liposomal amphotericin B and posaconazole including deranged liver and renal functions will be assessed

Eligibility Criteria

Criteria

Ages Eligible for Study:

13 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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