A study to investigate pharmacokinetics, safety, and tolerability of Cefepime-Enmetazobactam administered by intra-venous infusion over 2 hours in participants aged from birth to less than 18 years hospitalized with cUTI including AP.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Allecra Therapeutics

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

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

Trial duration

20 Jan 2023 → ongoing

Decision date (initial)

2024-12-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Allecra Therapeutics SAS

External identifiers

EU CT number

2024-518003-22-00

EudraCT number

2022-001832-27

ClinicalTrials.gov

NCT05826990

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Others

The primary objectives are to determine the pharmacokinetics, safety, and tolerability of cefepime-enmetazobactam in all paediatric population subsets from birth to less than 18 years of age with cUTI .

Secondary objectives 1

1. The secondary objectives of this study are to assess efficacy of the combination of cefepime-enmetazobactam in all paediatric population subsets from birth to less than 18 years of age with cUTI.

Conditions and MedDRA coding

Complicated urinary tract infections including acute pyelonephritis

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002240-PIP02-17

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Participant must be from birth to <18 years of age. Participants up to 2 months must have been born at term or preterm with a gestational age ≥32 weeks.
2. Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from participant (if age appropriate according to local regulations).
3. If female and has reached menarche, or has reached Tanner stage 3 development, (even if not having reached menarche) the participant is authorized to participate in this clinical study if the following criteria are met: i. Participant has a negative urine and/or serum human chorionic gonadotropin test at screening visit. As serum tests may miss an early pregnancy, relevant menstrual history, and sexual history, including methods of contraception, should be considered ii. Participant agrees to avoid conception from the time of screening until 7 days after receipt of study intervention and agrees not to attempt pregnancy from the time of screening until 7 days after EOT with study intervention, and participant agrees to follow guidelines received regarding continuation of abstinence, initiation of abstinence or about allowed contraception, and iii. Participant reports sexual abstinence for the prior 3 months or reported the use of at least 1 of the acceptable methods of contraception, including an intrauterine device (with copper banded coil), levonorgestrel intrauterine system or regular medroxyprogesterone injections, or participant agrees to initiate sexual abstinence from the time of screening until 7 days after end of treatment (EOT) with study intervention.
4. Participant has a clinically suspected and/or bacteriologically documented complicated urinary tract infection (cUTI) or acute pyelonephritis judged by the investigator to require the participant to be hospitalized for treatment with intravenous (i.v.) therapy.
5. The causative pathogen is confirmed to be either susceptible to cefepime (if results are available) or suspected to be susceptible to cefepime-enmetazobactam, and the patient is suitable for treatment with cefepime according to the investigator judgement.
6. Participant has pyuria, defined as dipstick analysis positive for leukocyte esterase OR: a) If ≥1 year of age: White blood cell (WBC) count >10 cells/µL in unspun urine or ≥10 cells/high power field in spun urine. b) If <1 year of age: WBC count >5 cells/µL in unspun urine or ≥5 cells/high power field in spun urine.
7. Participant demonstrates clinical signs and/or symptoms of either acute pyelonephritis or cUTI at the Screening Visit, as defined by the following criteria: a. For pyelonephritis, participants must have at least 2 of the following new or worsening signs and/or symptoms: i. If 0 to <2 years of age: • Fever (as defined by the investigator) • Failure to thrive • Recent weight loss • Irritability • Poor feeding • Lack of normal level of activity • Abdominal tenderness on physical examination • Vomiting ii. If 2 to <18 years of age: • Fever (as defined by the investigator) • Dysuria • Urinary urgency • Urinary frequency • New-onset urinary incontinence • Suprapubic pain, flank pain, or abdominal pain • Suprapubic tenderness or CVA tenderness on physical examination • Nausea or vomiting OR b. For cUTI, participants must have at least 2 of the new or worsening signs and/or symptoms listed above AND must have at least 1 of the following complicating factors: • Obstructive uropathy • Congenital, functional, or anatomic abnormality of the urogenital tract • Temporary indwelling urinary catheter • Bladder instrumentation within <24 hours • Recurrent UTI (≥2 events within a 12-month period)
8. Have a baseline urine culture specimen obtained within 48 hrs prior to the first dose of the study intervention. (Participants may be enrolled in this study and start i.v. study intervention therapy before the Investigator knows the results of the baseline urine culture in the event the causative pathogen is suspected to be susceptible to cefepime-enmetazobactam). Specimen is to be obtained by suprapubic aspiration, clean intermittent urethral catheterization, indwelling urethral catheter, or mid- stream clean catch.
9. Likely to survive the current illness or hospitalization.
10. Sufficient intravascular access (peripheral or central) to receive study intervention.

Exclusion criteria 17

1. History of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to cefepime, any cephalosporin, penicillins, β-lactamase inhibitors (e.g., tazobactam, sulbactam, or clavulanic acid), or other βlactam agents
2. Previous enrolment in this study, or in another interventional study ≤30 days before i.v. administration of study intervention.
3. Concurrent infection requiring systemic antibiotics in addition to the i.v. study intervention therapy at the time of first study intervention administration.
4. Receipt of systemic antibiotics within 24 hours before obtaining the study qualifying pretreatment baseline urine sample and before study intervention therapy. Exception are: • Receipt up to 24 hours of short-acting antibacterial agent with a daily dose not completed. (Refer protocol ► Section 10.5, Appendix 5 for the list of allowed and disallowed antibiotics). • Patients who received prior antimicrobial therapy for the current cUTI/AP, and 1) in the Investigator’s opinion, failed that prior antibiotic therapy (i.e., presented with worsening signs and symptoms), AND 2) were documented that the pathogen is non-susceptible to the prior antibiotic therapy. • Patients who have received antimicrobial prophylaxis for recurrent cUTI and then presented signs and symptoms consistent with an active new cUTI or AP.
5. A permanent indwelling bladder catheter or instrumentation including nephrostomy or current urinary catheter or anticipation of urinary catheter placement that would not be removed during the course of i.v. study intervention therapy administration.
6. Participant has suspected or known complete obstruction of any portion of the urinary tract, perinephric abscess, or ileal loops.
7. Participant has trauma to the pelvis or urinary tract.
8. Participant has undergone renal transplantation.
9. Participant has a condition or history of any illness that, in the opinion of the investigator, would have made the participant unsuitable for the study (e.g., may have confounded the results of the study or posed additional risk in administering the study therapy to the participant).
10. Participant is considered unlikely to survive the 6-week study period or had a rapidly progressive illness, including septic shock, that was associated with a high risk of mortality.
11. At the time of first study intervention administration, known presence of a cUTI caused by pathogens resistant to Cefepime - enmetazobactam.
12. Presence of any of the following clinically significant laboratory abnormalities: a. Haematocrit <25% or haemoglobin <8 g/dL (<80 g/L, <4.9 mmol/L) for children ≥ 1 month, or <13 g/dL (<130 g/L, <8.0 mmol/L) for children < 1 month. b. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>3 times the age-specific upper limit of normal (ULN), or total bilirubin >2 times ULN (except known Gilbert’s disease) and Absolute Neutrophil count<1000/ mm3 . c. eGFR <30 mL/min/1.73m2 . (updated creatinine-based “Bedside Schwartz” equation (Schwartz et al. 2009))
13. Participant has baseline QTcB (corrected Bazett’s formula) of greater than 450 msec.
14. History of seizures, excluding well-documented febrile seizures of childhood.
15. If female, currently pregnant or breast feeding.
16. If male with a partner of childbearing potential who is pregnant, planning to become pregnant or is breastfeeding.
17. Participant has acidosis and a history of L-arginine hypersensitivity

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Cmax, Tmax, AUClast, AUC0-tau (repeat dose) , AUC0-inf , AUCextr, half-life, λz, CL, Vd, Cmin, CLss (repeat dose), Vss (repeat dose), Accumulation ratio (repeat dose)
2. Treatment emergent adverse events including monitoring of adverse events of special interests: o Any increase in ALT or AST >3 times the age-specific upper limit of normal or total bilirubin >2 times ULN. o Clostridium difficile-associated diarrhoea CDAD)/Pseudomembranous colitis o Hypersensitivity reactions, anaphylactic reactions, angioedema o Encephalopathy/ seizures / convulsions//delirium
3. Laboratory parameters, ECGs, vital signs, and physical examination

Secondary endpoints 3

1. Overall success rate (Combined clinical and microbiological success rate)
2. Clinical response
3. Microbiological response

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Allecra Therapeutics

Sponsor organisation

Allecra Therapeutics

Address

10 Rue Alexandre Freund

City

Saint-Louis

Postcode

68300

Country

France

Scientific contact point

Organisation

Allecra Therapeutics

Contact name

Patrick VELICITAT

Public contact point

Organisation

Allecra Therapeutics

Contact name

Head of Regulatory Affairs

Third parties 5

Locations

6 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 6 · Art. 38 CTR

Results and documents

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

Documents 46 files

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

Application history

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