A Phase 3, Multicenter, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Contezolid Acefosamil and Contezolid Compared to Linezolid Administered Intravenously and Orally to Adults with Moderate or Severe Diabetic Foot Infections
- Trial ID
- 2022-500257-16-00
- Protocol
- MRXC-302
- Sponsor
- Micurx Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **clinical response** at the Day 35 visit in subjects with **Diabetic Foot Infections** receiving contezolid acefosamil/contezolid compared to those receiving linezolid, within the modified intent-to-treat (MITT) analysis set. This assessment is crucial for determining the efficacy of contezolid acefosamil/contezolid as a treatment option, potentially offering an alternative to linezolid for managing moderate to severe diabetic foot infections. Additionally, the study aims to evaluate the safety and tolerability of contezolid acefosamil (IV) and contezolid (PO) compared with linezolid (IV and PO).
Secondary objectives include: - Evaluating the investigator's assessment of clinical response at the end-of-therapy (EOT) visit in the MITT analysis set and at the Day 35 visit in the clinically evaluable (CE) at Day 35 (CE-D35) analysis set. - Evaluating per-subject microbiological response at Day 35 in the Microbiological-MITT (Micro-MITT) and Microbiologically Evaluable (ME) at Day 35 (ME-D35) analysis sets. - Evaluating per-pathogen microbiological response at Day 35 in the Micro-MITT and ME-D35 analysis sets, and at EOT in the Micro-MITT and ME at EOT (ME-EOT) analysis sets. - Evaluating the composite endpoint of death, unplanned amputation, and infectious complications of the primary diabetic foot infection by Day 35 in the MITT and CE-D35 analysis sets. - Evaluating early clinical response as a reduction of 20% or more in the surface area of redness, edema, and/or induration of the primary diabetic foot infection site at Day 5 (±1 day), compared to baseline, in patients who did not receive any rescue antibiotic therapy and are alive in the MITT analysis set.
Participants
The clinical trial involves a total of **605 participants** diagnosed with **Diabetic Foot Infections**. The study population includes both male and female subjects aged 18 years and older, with a confirmed diagnosis of diabetes mellitus (type 1 or 2) as per the American Diabetes Association criteria. Participants were selected based on their willingness and ability to provide written informed consent and the presence of a foot infection that meets specific criteria, including classification as moderate or severe according to the IWGDF DFI criteria. The trial population is characterized by individuals who have experienced an acute onset or worsening of infection symptoms within the past 14 days and have received less than 48 hours of potentially effective antibiotic treatment prior to the study. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive measures if of childbearing potential. The trial includes a vulnerable population, ensuring comprehensive safety and ethical considerations are in place.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the safety and efficacy of **Contezolid Acefosamil** and **Contezolid** compared to **Linezolid** in adults with moderate or severe **diabetic foot infections**. The trial will involve both intravenous and oral administration of the investigational drugs. The study is expected to run until June 30, 2026, with recruitment having started on December 6, 2022. Participants will be involved in the study for a maximum treatment period of 28 days, with the primary endpoint being the investigator's assessment of clinical response at the Day 35 visit.
Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, diabetes status, and infection characteristics. Following the screening, participants will undergo regular follow-up visits to assess clinical response, safety, and tolerability. The end-of-study visit will occur at Day 35, where the primary endpoint will be evaluated. Participants may be withdrawn from the study early if they experience adverse events, fail to adhere to the study protocol, or withdraw consent.
The trial will include several key elements of research methodology, such as the use of a **placebo** to match **Contezolid** and **Linezolid** tablets, ensuring the double-blind nature of the study. The trial will also involve a **modified intent-to-treat (MITT)** analysis set to evaluate the primary objective. Secondary endpoints include assessments of clinical response at the end of therapy, microbiological responses, and a composite endpoint of death, unplanned amputation, and infectious complications by Day 35. The study aims to provide robust data on the comparative efficacy and safety of the investigational drugs in treating diabetic foot infections.
Treatment
The clinical trial involves the administration of **Contezolid acefosamil**, a **solution for infusion**. This experimental medication is administered via **intravenous infusion**. The active substance is sodium o-acetyl-(R)-isoxazol-3-yl((2-oxo-3-(2,3,5-trifluoro-4-(4-oxo-3,4-dihydropyridin-1(2H)-yl)phenyl)oxazolidin-5-yl)methyl)phosphoramidate. The maximum daily dose is 3000 mg, with a total maximum dose of 57000 mg over a treatment period of up to 28 days. Participant compliance is monitored through regular assessments.
**Contezolid** is administered in **tablet** form for oral use. The active substance is contezolid, and the maximum daily dose is 1600 mg, with a total maximum dose of 44000 mg over a 28-day treatment period. This medication is also part of the experimental treatment group.
**Linezolid** is used as a comparator treatment in this study. It is available in two forms: **injection** for intravenous infusion and **tablets** for oral administration. The active substance is linezolid, with a maximum daily dose of 1200 mg and a total maximum dose of 33600 mg for the injection form, and 33000 mg for the tablet form, both over a 28-day period.
**Flagyl 400mg Tablets**, containing the active substance **metronidazole**, are used as a non-experimental treatment. These **film-coated tablets** are administered orally, with a maximum daily dose of 800 mg and a total maximum dose of 5600 mg over a 7-day treatment period.
**METRONIDAZOL BRAUN 5 mg/ml**, a **solution for infusion**, is another non-experimental treatment containing metronidazole. It is administered via infusion, with a maximum daily dose of 1000 mg and a total maximum dose of 10000 mg over a 10-day period.
**AZTREONAM** is used as a comparator treatment, available as a **solution for injection/infusion**. It can be administered via intravenous or intramuscular injection. The active substance is aztreonam, with a maximum daily dose of 120 mg/kg and a total maximum dose of 3360 mg/kg over a 28-day period. Additionally, a formulation with a maximum daily dose of 8 g and a total maximum dose of 224 g is available for the same duration.
A **placebo** is included in the study to match the contezolid and linezolid tablets. The placebo is used to maintain the double-blind nature of the trial, ensuring unbiased assessment of the experimental treatments' efficacy and safety.
Efficacy
The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoint focuses on the Investigator's assessment of clinical response at the Day 35 (D35) visit in subjects receiving **contezolid acefosamil** or **contezolid** compared to those receiving **linezolid** in the modified intent-to-treat (MITT) analysis set. Additionally, the safety and tolerability of contezolid acefosamil (intravenous) and contezolid (oral) will be evaluated in comparison to linezolid (both intravenous and oral).
Secondary endpoints include the Investigator's assessment of clinical response at the End-of-Therapy (EOT) visit in the MITT analysis set, and at the D35 visit in the Clinically Evaluable (CE) at D35 (CE-D35) analysis set. Microbiological responses per subject and per pathogen at D35 and EOT will also be evaluated. A composite endpoint will assess death, unplanned amputation, and infectious complications of the primary diabetic foot infection (DFI) by Day 35. An early clinical response will be evaluated as a reduction of 20% or more in the surface area of redness, edema, and/or induration of the primary DFI site at Day 5 (±1 day), compared to Baseline, in patients who did not receive any rescue antibiotic therapy and are alive in the MITT analysis set.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Males or females ≥18 years of age
- Willing and able to provide written informed consent
- Have diabetes mellitus (type 1 or 2) per the American Diabetes Association criteria
- Have a foot infection that started at or below the malleolus and does not extend above the knee. If the subject has multiple infections that meet all the criteria below, the one with the highest IWGDF classification and the largest size will be designated as the primary DFI
- Foot infection that meets the IWGDF DFI criteria for classification 3 (moderate infection) or 4 (severe infection) (Appendix 8) that are confirmed or suspected to be due to a Gram-positive bacterial pathogen
- Foot infection had acute onset or worsening of signs and symptoms within the past 14 days
- Received <48 hours administration of a potentially effective antibiotic (ie, active against all pathogens known to be present) to treat the current target infection within 96 hours before the start of study drug administration
- Females must be either postmenopausal for ≥2 years or surgically sterile (having undergone tubal ligation, hysterectomy, or bilateral oophorectomy) or, if of childbearing potential, must have a negative pregnancy test at Screening/Baseline and, if sexually active with male partners, be willing to use a highly effective method of contraception throughout the study, such as 1 of the following: a. Hormonal contraception that inhibits the ovulation (stable dose for 3 months) b. Intrauterine device/intrauterine hormone- releasing system
- Males, if nonsterile and sexually active with female partners of childbearing potential, must abstain from sexual intercourse or have partner(s) who will follow the contraception criteria for female study participants. Male must be willing to continue to use such highly effective birth control measures while participating in the study and for 60 days following participation in the study. Males must also refrain from sperm donations during this time.
Exclusion Criteria
- Previous DFI known or suspected to be caused by Gram-positive pathogens that are resistant to oxazolidinone antibiotics
- Receipt of chemotherapy, radiotherapy, or potent, noncorticosteroid immunosuppressant drugs (eg, cyclosporine, azathioprine, tacrolimus, immune-modulating monoclonal antibody therapy) within the past 3 months, or the receipt of corticosteroids ≥10 mg of prednisone (or equivalent) per day for >14 days in the prior 30 days
- Known or suspected pheochromocytoma or thyrotoxicosis or severe uncontrolled hypertension.
- QT interval corrected for heart rate by Fridericia's formula (QTcF) duration >450 msec for males and >470 msec for females obtained as an average from the triplicate Screening/Baseline ECGs, history of QT prolongation, hypokalemia (serum potassium <3.0 mEq/L) at Screening/Baseline, or other proarrhythmic conditions
- Concomitant condition that, in the opinion of the Investigator, would preclude an evaluation of a response or make it unlikely that the contemplated course of therapy could be completed
- History of known or suspected serotonin syndrome, neuroleptic malignant syndrome, or carcinoid syndrome
- History of known or suspected Clostridioides difficile-associated diarrhea
- History of drug-related peripheral or optic neuropathy (diabetic neuropathy is allowed)
- History of a seizure disorder or known or suspected central nervous system condition that may predispose to seizures or lower the seizure threshold
- Females who are pregnant or breastfeeding
- Prior receipt of any formulation of contezolid acefosamil or contezolid
- DFI with presumptive evidence or suspicion of osteomyelitis based on three diagnostic methods: X-ray, probe to bone test and erythrocyte sedimentation rate. Either an X-ray from the primary DFI site consistent with osteomyelitis, a positive probe to bone test, or an erythrocyte sedimentation rate (ESR) ≥70 mm/hour, will be evidence enough to suspect osteomyelitis (unless the ESR value only has any other plausible explanation such as rheumatologic disease, cancer, a large DFI infection, and the medical monitor approved such ESR value after his/her assessment). If osteomyelitis is diagnosed or suspected using methods different from those requested during this study (e.g., CT scan or MRI) such patients should not be enrolled either. EXCEPTION: if all infected bone was clearly removed (e.g., toe amputation) within 48 hours before the start of study drug administration but there remains infected soft tissue, the subject is acceptable for enrollment.
- Prior (within the past 2 weeks) administration of, or expected or required concomitant (from the start of the study drug to EOT) administration of: a. Systemic adrenergic, dopaminergic, or serotonergic medications b. Monoamine oxidase inhibitors (eg, isocarboxazid, isoniazid, nialamide, phenelzine, procarbazine, and hydracarbazine)
- Expected concurrent hemodialysis, hemofiltration, peritoneal dialysis, or plasmapheresis
- Inability to tolerate a PO study drug for duration of study treatment (eg, nausea, vomiting, diarrhea, or any other condition that might impair ingestion or absorption of PO study drug)
- Poor venous access
- History of any intolerance, hypersensitivity, or allergic reaction to any oxazolidinone antibiotic or excipient in an oxazolidinone antibiotic
- History of any intolerance, hypersensitivity, or allergic reaction to aztreonam or its excipients; note that while cross-reactivity of aztreonam with other β-lactams is rare, this drug should be administered with caution to any subject with a history of hypersensitivity to β-lactams (eg, penicillins, cephalosporins, carbapenems)
- History of any intolerance, hypersensitivity, or allergic reaction to metronidazole or metronidazole excipient.
- Taken any investigational drugs or used any investigational devices within 30 days or 5 half-lives of the study drug, whichever is longer, before randomization
- Inability to cooperate fully with the requirements of the study protocol, including the schedule of events, or likely to be noncompliant with any study requirements, or the Investigator determines that the subject should not participate in the study
- DFI without presumptive evidence of osteomyelitis anticipated to require >28 days of antibiotic treatment
- Necrotizing fasciitis, crepitant cellulitis, wet gangrene, gas gangrene, ecthyma gangrenosum, septic arthritis, or severely impaired arterial supply to any portion of the affected foot which may need revascularization before the end of the study
- Infected prosthetic materials or devices at the primary DFI site that will not be removed before or at the time of enrollment
- Anticipated requirement for complete resection or amputation (i.e., removal of all infected tissue with clean margins) of the infected DFI anatomical site within 30 days
- Known or suspected concurrent infection of any type that would require treatment with a systemic antibacterial agent with activity against Gram-positive bacteria
- Life expectancy <3 months or evidence of immediately life-threatening disease, including, but not limited to, current or impending respiratory failure, shock, acute coronary syndrome, unstable arrhythmias, hypertensive emergency, acute hepatic failure, active gastrointestinal bleeding, profound metabolic, or acute cerebrovascular events
- Evidence of significant hepatic, renal, hematologic, or immunologic disease
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Recruiting | 06 Dec 2022 | 106 |
 Croatia | Not Recruiting | 06 Dec 2022 | 23 |
 Czechia | Not Recruiting | 06 Dec 2022 | 96 |
 Estonia | Recruiting | 06 Dec 2022 | 28 |
 France | Not Recruiting | 06 Dec 2022 | 26 |
 Greece | Not Recruiting | 06 Dec 2022 | 18 |
 Hungary | Not Recruiting | 06 Dec 2022 | 64 |
 Italy | Recruiting | 06 Dec 2022 | 10 |
 Latvia | Recruiting | 06 Dec 2022 | 30 |
 Lithuania | Not Recruiting | 06 Dec 2022 | 27 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Contezolid acefosamil | Test | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 3000 | 28 | PRD9537054 |
Linezolid | Comparator | INJECTION | INTRAVENOUS INFUSION | 1200 | 28 | PRD9756895 |
AZTREONAM | Other | — | INTRAVENOUS INJECTION/INFUSION, INTRAMUSCULAR INJECTION | 8 | 28 | SUB05664MIG |
Contezolid | Test | TABLET | ORAL USE | 1600 | 28 | PRD9537055 |
Flagyl 400mg Tablets | Other | TABLETS | ORAL USE | 800 | 7 | PRD426935 |
AZTREONAM | Other | — | INTRAVENOUS INJECTION/INFUSION, INTRAMUSCULAR INJECTION | 120 | 28 | SUB05664MIG |
METRONIDAZOL BRAUN 5 mg/ ml, soluţie perfuzabilă | Other | SOLUŢIE PERFUZABILĂ | SOLUTION FOR INFUSION | 1000 | 10 | PRD568107 |
Linezolid Tablets 600mg | Comparator | TABLET | ORAL | 1200 | 28 | PRD9756896 |
Placebo to match contezolid and Linezoloid tablets | Placebo | N/A | — | — | — | N/A |