A Multicenter, Randomized, Double-Blind, Comparative, Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous Imipenem/Cilastatin-XNW4107 in Comparison with Imipenem/Cilastatin/Relebactam in Adults with Hospital Acquired Bacterial Pneumonia or Ventilator Associated Bacterial Pneumonia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Evopoint Biosciences USA Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

Trial duration

19 Apr 2024 → 29 Sep 2024

Decision date (initial)

2023-05-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Evopoint Biosciences USA Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety

To evaluate the all-cause mortality rate through Day 14 post-randomization of subjects in the imipenem/cilastatin-XNW4107 (IMI-XNW4107) group compared to the imipenem/cilastatin/relebactam (IMI/REL) group in the Modified Intent-to-Treat (MITT) population.

Secondary objectives 8

1. To evaluate the all-cause mortality rate through Day 28 post-randomization of subjects in the IMI XNW4107 group compared to the IMI/REL group in the MITT population
2. To evaluate the all-cause mortality rate through Day 14 and through Day 28 post-randomization of subjects in the IMI-XNW4107 group compared to the IMI/REL group in the Microbiologic MITT (micro MITT), extended micro-MITT, clinically evaluable (CE), microbiologically evaluable (ME) and Carbapenem-resistant MITT (CR MITT) populations
3. To evaluate the clinical outcome of IMI-XNW4107 compared to IMI/REL at Day 4, End of Treatment (EOT), Test-of-Cure (TOC), and Late Follow-up (LFU) visits in the MITT, micro-MITT, extended micro-MITT, CE, ME, and CR-MITT populations
4. To evaluate the microbiological outcome of IMI-XNW4107 compared to IMI/REL at EOT, TOC, and LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT populations
5. To evaluate the by-pathogen microbiological outcome of IMI-XNW4107 compared to IMI/REL at EOT, TOC, and LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT populations
6. To evaluate the overall outcome of IMI-XNW4107 compared to IMI/REL at EOT, TOC, and LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT populations
7. To evaluate the safety and tolerability of IMI-XNW4107 administered by intravenous (IV) infusion compared to IMI/REL in subjects with HABP or VABP in the Safety population (SAF)
8. To evaluate the pharmacokinetics (PK) of IMI-XNW4107 in subjects with HABP/VABP, and to provide data for the population PK (PopPK) modeling and exposure-response modeling analysis in subjects with HABP or VABP

Conditions and MedDRA coding

Hospital-acquired bacterial pneumonia (HABP), including ventilated HABP (vHABP) and ventilator-associated bacterial pneumonia (VABP) caused by Gram-negative bacteria

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003326-PIP01-22

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Subjects willing and able to provide written informed consent or where consent is provided by legally authorized representatives.
2. Willing and able to comply with all study assessments and adhere to the protocol schedule.
3. Male or female subjects ≥18 years on the day of signing informed consent.
4. Has HABP or VABP as defined below and requires treatment with IV antibiotic therapy. NOTE: HABP is defined as the onset of acute bacterial pneumonia symptoms at least 48 hours after hospitalization or within 7 days after discharge from an inpatient acute or chronic care facility (e.g., long-term care, rehabilitation center, hospital, or skilled nursing home). Subjects may experience acute respiratory failure and require mechanical ventilation for HABP (vHABP). VABP is defined as acute bacterial pneumonia in a subject receiving mechanical ventilation via an endotracheal (or nasotracheal) tube or tracheostomy for ≥48 hours.
5. All subjects must fulfill at least 1 of the following clinical criteria at screening: a. New onset or worsening of pulmonary symptoms or signs, such as cough, dyspnea, tachypnea (e.g., respiratory rate >25 breaths/minute), expectorated sputum production, or requirement for mechanical ventilation / b. Hypoxemia (e.g., partial pressure of oxygen [PaO2] <60 mmHg while the subject is breathing room air, as determined by arterial blood gas [ABG], or worsening of the ratio of the PaO2 to the fraction of inspired oxygen [PaO2/FiO2]) / c. Need for acute changes in the ventilator support system to enhance oxygenation, as determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes in the amount of positive end-expiratory pressure / d. New onset of or increase in (characteristics or quantity) suctioned respiratory secretions, demonstrating evidence of inflammation and absence of contamination.
6. All subjects must have at least 1 of the following signs and symptoms/laboratory abnormalities at screening: a. Documented fever (i.e., core body temperature [tympanic, rectal, esophageal] ≥38°C [100.4°F], oral temperature ≥37.5°C [99.5°F], or axillary temperature ≥37°C [98.6°F]) / b. Hypothermia (i.e., core body temperature [tympanic, rectal, esophageal] ≤35°C [95.0°F], oral temperature ≤35.5°C [95.9°F] and axillary temperature ≤36°C [96.8°F]) / c. Leukocytosis with a total peripheral white blood cell (WBC) count ≥10,000 cells/mm^3 / d. Leukopenia with total peripheral WBC count <4500 cells/mm^3 / e. Greater than 15% immature neutrophils (bands) noted on peripheral blood smear.
7. All subjects must have a chest radiograph during screening or have a previous chest radiograph within 48 hours prior to randomization showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia. A computed tomography scan in the same time window showing the same findings could also be acceptable.
8. All subjects must have a suspected Gram-negative infection involving the lower respiratory tract by 1 or more of the following: a. Gram stain of lower respiratory tract secretions showing Gram-negative bacteria, either alone or mixed with Gram-positive bacteria at or within 48 hours prior to randomization / b. Microbiologic culture of lower respiratory tract secretions within 48 hours prior to randomization identifying Gram-negative aerobic bacteria / c. Other diagnostic tests, including molecular tests, which provide evidence of Gram-negative bacterial infection of the lower respiratory tract / d. Pneumonia highly suspected to be due to Gram-negative bacteria based on sites of primary infection, prior antibiotic use, or local epidemiologic evidence of Gram-negative infection outbreak.
9. Agree to allow any bacterial isolates obtained from protocol-required specimens related to the current infection to be provided to the Central Microbiology Reference Laboratory for study-related microbiological testing, long-term storage, and other future testing.
10. Female subjects of childbearing potential, who are willing to use a highly effective method of birth control during the study and for at least 30 days following the last dose of study medication. a. Childbearing potential is defined as any female who has experienced menarche and does not meet the criteria for postmenopausal, which is defined as the past 12 months with no menses without an alternative medical cause or permanently sterilized (e.g., has undergone bilateral tubal occlusion/ligation, hysterectomy, bilateral oophorectomy, bilateral salpingectomy) / b. A highly effective method of birth control is defined as one that results in a low failure rate (i.e., <1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence, or a vasectomized partner.
11. Male subjects with female sexual partners of childbearing potential are eligible for inclusion if they agree to use medically acceptable birth control for 90 days following the last dose of study medication. Sexual abstinence, vasectomy, or a condom used with a spermicide are medically acceptable birth control methods for males. Male subjects must agree not to donate sperm for a period of 90 days after the last dose of study treatment.

Exclusion criteria 20

1. If a Gram stain from a respiratory sample is available and shows only Gram-positive cocci.
2. Subjects who have known or suspected community-acquired bacterial pneumonia, atypical pneumonia, viral pneumonia including Coronavirus disease (COVID-19), or chemical pneumonia (including aspiration of gastric contents, inhalation injury).
3. Subjects who have HABP/VABP caused by an obstructive process, including lung cancer (or other malignancy metastatic to the lungs resulting in pulmonary obstruction) or other known obstruction.
4. Have received effective systemic and inhaled Gram-negative antibacterial drug therapy for the index infection of HABP/VABP for a continuous duration of more than 24 hours during the previous 72 hours prior to randomization. NOTE: Subjects who have objective documentation of clinical failure (i.e., have persistent/worsening signs and/or symptoms of HABP/VABP at screening) while receiving any duration of prior antibacterial drug therapy for the treatment of HABP/VABP can be enrolled.
5. Has a concurrent condition or infection that, in the investigator's judgment, would preclude evaluation of therapeutic response (e.g., active tuberculosis, cystic fibrosis, granulomatous disease, a disseminated fungal infection, invasive fungal pulmonary infection, or endocarditis).
6. Subjects who have central nervous system infection (e.g., meningitis, brain abscess, shunt infection).
7. Documented presence of immunodeficiency or an immunocompromised condition including hematologic malignancy, bone marrow transplant, known history of human immunodeficiency virus infection with a CD4 count <200/mm^3, or requiring frequent or prolonged use of systemic corticosteroids (≥20 mg of prednisone/day or equivalent for >4 weeks) or other immunosuppressive drugs (e.g., for organ transplantation or autoimmune conditions).
8. Documented hypersensitivity to any carbapenem antibacterial agent or documented severe hypersensitivity to any other type of β-lactam antibacterial agent, or previous severe adverse drug reaction to any β-lactam antibiotics, or any of the excipients used in the study drug formulations.
9. History of a seizure disorder (requiring ongoing treatment with anti-convulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years).
10. Renal function at screening as estimated glomerular filtration rate (eGFR) <15 mL/min or ＞250 mL/min, calculated as individual eGFR derived from Modification of Diet in Renal Disease formula.
11. Subject is receiving hemodialysis or peritoneal dialysis or micro-dialysis or continuous venovenous hemofiltration or continuous venovenous hemodialysis.
12. Subject is anticipated to be treated with any of the following medications during the course of study therapy: a. Valproic acid or divalproex sodium (or has used valproic acid or divalproex sodium in the 2 weeks prior to screening) NOTE: Subjects who are receiving valproic acid or divalproex sodium for seizure prophylaxis (e.g. for head trauma) without history of seizure disorder may be enrolled as judged by the investigator / b. Concomitant systemic (IV or oral) Gram-negative antibacterial agents in addition to those designated in the study treatment groups / c. Concomitant systemic (IV or oral) antifungal or antiviral therapy for the index infection of HABP/VABP.
13. Life expectancy is <3 days.
14. Subjects in refractory septic shock, defined as persistent hypotension despite adequate fluid resuscitation and vasopressive therapy at the time of randomization.
15. Subjects with 1 or more of the following laboratory abnormalities in baseline specimens: aspartate aminotransferase, alanine aminotransferase >3 × the upper limit of normal (ULN), total bilirubin level >2 × ULN (except for isolated hyperbilirubinemia due to known Gilbert’s disease), neutrophils <500 cells/mm^3, platelet count <40,000/mm^3.
16. History of active liver disease or cirrhosis.
17. Subjects with an APACHE II score of >30.
18. A female who is pregnant or breastfeeding or has a positive pregnancy test at screening.
19. Subject is participating in any clinical study of any investigational medication (i.e., non-licensed medication) during the 30 days prior to randomization. COVID-19 vaccines that are given under emergency use authorization are not considered investigational agents.
20. Any other condition or prior therapy, which, in the opinion of the investigator, would make the subject unsuitable for this study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the Day 14 all-cause mortality rate in the MITT population

Secondary endpoints 6

1. Day 28 all-cause mortality rate in the MITT population
2. Day 14 and Day 28 all-cause mortality rate in the micro-MITT, extended micro-MITT, CE, ME, and CR-MITT populations
3. The proportion of subjects with clinical success as evaluated by the investigator at Day 4, EOT, TOC, and LFU visits in the MITT, micro-MITT, extended micro-MITT, CE, ME, and CR-MITT populations
4. The proportion of subjects with microbiological success at EOT, TOC, and LFU visits in the micro-MITT, extended micro-MITT, CR-MITT, and ME populations
5. The proportional of subjects with microbiological success by pathogen at EOT, TOC, and LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT populations
6. The proportion of subjects with overall success at EOT, TOC, and LFU visits in the micro-MITT, extended micro-MITT, ME, and CR-MITT populations

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Evopoint Biosciences USA Inc.

Sponsor organisation

Evopoint Biosciences USA Inc.

Address

300 Baker Avenue Suite 300

City

Concord

Postcode

01742-2124

Country

United States

Scientific contact point

Organisation

Evopoint Biosciences USA Inc.

Contact name

Clinical Trial Management

Public contact point

Organisation

Evopoint Biosciences USA Inc.

Contact name

Clinical Trial Management

Third parties 6

Locations

2 EU/EEA countries · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications