Efficacy of Temocillin Compared to Standard of Care in the Treatment of Neisseria Gonorrhoeae Infections

Phase 3Not Yet RecruitingNCT07631364

Assistance Publique - Hôpitaux de Paris360 enrolled

Overview

Neisseria gonorrhoeae (Ng) infections are common and increasing in incidence. Treatment with a third generation cephalosporin, i.e ceftriaxone 1g, single dose, intramuscular (IM), is recommended as a first line treatment. Ceftriaxone is a broad-spectrum antibiotic with high impact on the intestinal microbiota associated with the acquisition of multidrug-resistant bacteria, particularly extended spectrum beta lactamase producing Enterobacteracerales (ESBL-E). Among populations at high risk for sexually transmitted infections (STI), the colonization rate of ESBL-E is particularly high, up to 30%, implying (i) a risk of transmission within the community and (ii) a risk of infections caused by multidrug-resistant organisms, which are difficult to treat. Temocillin, a narrow-spectrum antibiotic is known for its low ecological impact, appears to be a highly promising option. Ng strains currently circulating in France appear to be sensitive to it. Thus, temocillin could be as effective as ceftriaxone to treat Ng infections while avoiding the deleterious impact of broad-spectrum β-lactams on the acquisition of multidrug-resistant bacteria by patients

Sexually transmitted infections (STIs) are a major global public health issue. Ng infections are highly prevalent, with 100,000 cases reported in Europe in 2023, over 50% in men who have sex with men (MSM). Globally, WHO (World Health Organization) estimated 82.4 million new cases in 2020 among individuals aged 15-49, with incidence rates of 19 per 1000 women and 23 per 1000 men. In France, Ng infections have been rising since the 2000s, particularly in MSM, with positivity rates 5-6 times higher than in heterosexual men and 7 times higher than in heterosexual women. Infections are mostly asymptomatic (\~95%), though urethritis, cervicitis, proctitis, arthritis, and disseminated infections can occur. Ng rapidly develops antimicrobial resistance due to genetic plasticity. Multidrug-resistant strains have emerged globally, but in France nearly all strains remain ceftriaxone-sensitive, with only 0.2% resistant in 2022. Standard treatment is ceftriaxone 1 g IM, a critical antibiotic impacting microbiota, and the only effective current option. Vaccine development is ongoing: the Bexsero vaccine showed 22% efficacy in reducing infections, and Phase 1/2 trials of Ng-specific vaccines are underway. Vaccine hesitancy and heterogeneous coverage, even in high-risk populations such as HIV (Human Immunodeficiency Virus) positive MSM, may limit rapid impact. Alternative therapies include antibiotic combinations and new agents such as zoliflodacin, though pharyngeal efficacy is lower and broad-spectrum use is limited due to resistance concerns. Repositioning antibiotics has been explored: gentamicin shows low microbiota impact but lower pharyngeal efficacy; fosfomycin is ineffective for Ng; carbapenems (ertapenem) are effective but reserved for multidrug-resistant cases; temocillin, a narrow-spectrum β-lactam, preserves microbiota and colonization resistance and may improve pharyngeal clearance when given IV (Intravenous) or IM. Patient-centered outcomes, including perceived care quality, speed, and pain, will be assessed using short satisfaction questionnaires. The main objective of this study is to demonstrate the non-inferiority of 2g IV or IM temocillin treatment compared to the reference treatment with 1g IM ceftriaxone (Standard of Care (SOC)) for Neisseria gonorrhoeae infections at day 21 (negative PCR (Polymerase Chain Reaction) in urine/vagina, throat and/or anus). The primary endpoint is the proportion of participants with therapeutic success at day 21. The participants will be adults' patients consulting in the inclusion centers, having positive PCR for Ng (urine/vagina, throat or anus). We will focus on asymptomatic patients. This trial will then have 3 arms: - Arm 1, patients will receive a single 1 g dose of IM ceftriaxone (SOC). -Arm 2, patients will receive a single 2 g dose of IM temocillin - Arm 3, patients will receive a single 2 g dose of IV temocillin. The total duration of the study is planned to be 27 months, Follow-up visits will be scheduled at Day 21 and Day 90.

Interventions

Temocillin (NEGABAN®) 2 g intravenous with lidocaine (3ml)DRUG

patients will receive a single 2 g dose of IV temocillin diluted in 20 mL of water for injection. In this trial, we chose to test the IV route, as the classical intramuscular (IM) injection is often described as painful. We hypothesize that the IV route may be more comfortable for patients. Moreover, after administration of a 2 g IV a slow intravenous injection (over 3 to 4 minutes), the peak plasma concentration reaches approximately 220-250 mg/L, and temocillin concentrations remain detectable after 12 hours (the dosing interval) at around 15 mg/L. We hypothesize that this high plasma concentration could improve treatment of pharyngeal infection.

Rectal swab for ESBL-E and microbiota (Eswab)OTHER

consists of collecting a rectal specimen using a sterile eSwab system. The swab is gently inserted into the rectum and rotated to obtain a sample of rectal flora. The collected specimen is then placed in the transport medium and sent to the laboratory for microbiological analysis. The sample is used to detect ESBL-producing Enterobacterales (ESBL-E) and to analyze the intestinal microbiota composition.

Temocillin (NEGABAN®) 2 g intramuscular single dose with lidocaine (3ml)DRUG

patients will receive a single 2 g dose of IM temocillin after reconstitution with 3 mL of lidocaine at 10 mg/mL to prevent pain at the injection site. A single 1 g dose of temocillin has been used for the treatment of N. gonorrhoeae infection (Reimer et al., 1985). We chose to use a single 2 g dose because penicillin MICs are increasing. For bacterial STIs, treatment is currently administered via the intramuscular route, which is the fastest and most practical method of antibiotic administration for outpatients.

Ceftriaxone 1 g intramuscular single dose with lidocaine (3,5ml)DRUG

patients will receive a single 1 g dose of IM ceftriaxone (SOC) after reconstitution with 3,5 mL of lidocaine at 10 mg/mL to prevent pain at the injection site

Rectal, throat, urine/vagina swab (Cobas/Panther and eswab)OTHER

consists of collecting biological specimens from rectal, throat, urine, and vaginal sites using appropriate sterile collection devices, including eSwab systems and sample kits compatible with Cobas or Panther platforms. Samples are collected according to standard clinical procedures and transported to the laboratory for microbiological and molecular analyses. These specimens are analyzed using automated diagnostic platforms (Cobas or Panther) and conventional microbiological methods to detect and identify microorganisms or pathogens present at the sampled sites.

Blood samples: 1 EDTA (Ethylenediaminetetraacetic acid) (7 ml) and 1dry tube (7 ml)OTHER

The blood sample will be performed 15 min after IV administration and 60 min after IM administration.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥ 18 years 2. Positive PCR for Ng (urine/vagina and/or throat and/or anus) 3. Asymptomatic Neisseria gonorrhoeae infection 4. Patient who has understood the entirety of the study and accepts its constraints 5. Women of child-bearing potential (i.e. fertile, following menarche and until becoming post-menopaused unless permanently sterile) who are sexually active have to apply a effective method of birth control\*, throughout the study period and for 90 days following the last dose of study treatment. 6. Signature of the consent form for participation in the trial. 7. Affiliation with a Social Security scheme or State Medical Aid (AME) (waiver to exempt the necessity for patients to be affiliated with a such scheme) 8. French, English or Spanish speaker Exclusion Criteria: 1 - Known allergy to penicillin, temocillin, ceftriaxone or other beta-lactam antibiotics (grade 3 or 4) 2-Known complete heart block 3- Known hypersensitivity to lidocaine or other amide-type anaesthetics 4- Clinical suspicion of hypovolemia 5 - Concomitant antibiotic treatment to be started or in progress for another bacterial infection except for doxycycline as post exposure prophylaxis 6 - BMI (Body Mass Index)\> 35 kg/m2 7 - Another ongoing antibiotic therapy \< 1 month except for doxycycline as post exposure prophylaxis) 8 - Complicated upper genital infection 9 - Pregnant or breastfeeding woman (urinary βHCG (Beta Human Chorionic Gonadotropin) at baseline for patients with childbearing potential\*) 10 - Known renal or hepatic dysfunction 11 - Patient on curative anticoagulation or known haemostasis disorder (contraindication for the IM route) 12- Prior participation in this study 13 - Patient under legal guardianship 14 - Participation in another randomized trial or trial concerning a medicinal product or clinical investigation protocol concerning a medical device (\<3 months) 15- patients deprived of liberty by judicial or administrative decision 16- Patients who are the investigator or any other member of the study team, or close relatives of the investigator or persons involved in the study (e.g., assistant physicians, pharmacists, nurses…)\*A woman is considered of childbearing potential (WOCBP), i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

Outcomes

Primary Outcomes

Proportion of participants with a negative PCR for NG at urine/vagina site

Proportion of participants with a negative PCR for NG at urine/vagina site in order to determine the therapeutic success at day 21. PCR for NG at all three sites (urine/vagina, throat and anus) needs to be negative.

Time frame: Day 21

Secondary Outcomes

Proportion of participants with a negative PCR for NG at throat site

Proportion of participants with a negative PCR for NG at throat site in order to determine the therapeutic success at day 21. PCR for NG at all three sites (urine/vagina, throat and anus) needs to be negative.

Time frame: Day 21

Proportion of participants with a negative PCR for NG at anus site

Proportion of participants with a negative PCR for NG at anus site in order to determine the therapeutic success at day 21. PCR for NG at all three sites (urine/vagina, throat and anus) needs to be negative.

Time frame: Day 21

Proportion of participants with therapeutic success at day 21 for urine/vagina infection.

The proportion of participants with a negative PCR for the infection site at day 21 of treatment.

Time frame: Day 21

Proportion of participants with therapeutic success at day 21 for throat infection.

The proportion of participants with a negative PCR for the infection site at day 21 of treatment.

Time frame: Day 21

Proportion of participants with therapeutic success at day 21 for anus infection.

The proportion of participants with a negative PCR for the infection site at day 21 of treatment.

Time frame: at Day 21

Number of clinical AE (adverse effects)

the number of clinical adverse effects that are observed or felt by the patient within 90 days

Time frame: Day 1 to Day 90

Number of biological adverse effects

The number of biological adverse effects identified through laboratory test or biological measurements within 90 days

Time frame: Day 1 to Day 90

Number of grade 3 or 4 AE

the number of severe and life threatening adverse events within 90 days

Time frame: Day 1 to Day 90

Number of all grade AEs

the number of all grade adverse events within 90 days

Time frame: Day 1 to Day 90

Number of treatment-related adverse events (all grade)

the number of side effects judged by investigator to be caused by or linked to the experimental treatment within 90 days

Time frame: Day 1 to Day 90

Number of study discontinuations due to AEs

the number of patients who stop the study due to an adverse event within 90 days

Time frame: Day 1 to Day 90

Number of serious adverse events

the number of serious adverse events developped by patients within 90 days

Time frame: Day 1 to Day 90

score of pain felt during the injection according to the Numerical Scale from 0 to 10

Score of pain felt during the injection, evaluated by the patient in order to evaluate the patient satisfaction and perception

Time frame: Day 1 and Day 21

Lickert score result regarding the speed of injection management

Likert score result regarding the speed of injection management (Lickert scale scored from 1 to 5)in order to evaluate the patient satisfaction and perception

Time frame: Day 1 and Day 21

Lickert score result regarding the invasive perception of the management of the infection

Lickert score result regarding the invasive perception of the management of the infection (Lickert scale scored from 1 to 5) in order to evaluate the patient satisfaction and perception

Time frame: Day 1 and Day 21

Lickert score result regarding the comprehension of the patient that the antibiotic can only be administered by injection

Lickert score result regarding the comprehension of the patient that the antibiotic can only be administered by injection (Lickert scale scored from 1 to 5) in order to evaluate the patient satisfaction and perception

Time frame: Day 1 and Day 21

Lickert score result regarding the perception of the patient that the injection was painful

Lickert score result regarding the comprehension of the patient that the antibiotic can only be administered by injection (Lickert scale scored from 1 to 5)in order to evaluate the patient satisfaction and perception

Time frame: Day 1 and Day 21

Proportion of participants of ESBL-E rectal colonization

Proportion of participants with rectal colonization by ESBL-producing Enterobacterales

Time frame: Day 1, Day 21, and day 90

Composition of the throat microbiota

Analysis of the composition of the microbiota from throat samples at D1, D21, and D90 to assess changes over the study period.

Time frame: Day 1, Day 21, and Day 90

Composition of the anal microbiota

Analysis of the composition of the microbiota from anal samples at D1, D21, and D90 to assess changes over the study period.

Time frame: Day 1, Day 21, and Day 90

Composition of the urine/vagina microbiota

Analysis of the composition of the microbiota from urine/vagina samples at D1, D21, and D90 to assess changes over the study period.

Time frame: Day 1, Day 21, and Day 90

Neisseria gonorrhoeae populations

Analysis of Neisseria gonorrhoeae populations at D1 and D21.

Time frame: Day 1 and Day 21

Neisseria gonorrhoeae clonality

Analysis of Neisseria gonorrhoeae clonality at D1 and D21.

Time frame: Day 1 and Day 21

Neisseria gonorrhoeae strains and resistance determinants

Analysis of Neisseria gonorrhoeae resistance determinants, including minimum inhibitory concentrations (MIC), sequence types (ST), and resistance genes at D1 and D21.

Time frame: Day 1 and Day 21

Efficacy of Temocillin Compared to Standard of Care in the Treatment of Neisseria Gonorrhoeae Infections

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts