Pivmecillinam as Oral Step-Down Treatment for Escherichia Coli Febrile Urinary Tract Infection Versus Standard of Care: A Randomized Controlled Non-Inferiority Multicenter Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 560
- 试验地点
- 13
- 主要终点
- Clinical response (primary endpoint).
研究概览
简要总结
The goal of this clinical trial is to learn if oral treatment with pivmecillinam is effective to treat febrile urinary tract infections in adult patients. Hospitalized patients who have received 2-4 days of intravenous antibiotic therapy for febrile urinary tract infections, and have responded to treatment, will be randomized to either pivmecillinam or standard treatment (other oral or intravenous antibiotics).
The main question the study aims to answer is if oral follow-up with pivmecillinam is as effective as standard treatment. Patients will be evaluated for clinical response (resolution of fever and urinary tract symptoms) and microbiological response (no growth of bacteria in urine) 7 and 28 days after the end of treatment. Patients will also be asked about side effects. Some of the participants will also be examined for changes in the gut microbiome and drug exposures in blood and urine.
Participants will:
- Keep a patient diary to record antibiotic intake, body temperature, urinary tract symptoms, and suspected side effects until 7 days after end of treatment.
- Participate in phone interviews 7 and 28 days after end of treatment to assess clinical response.
- Provide urine samples 7 and 28 days after end of treatment to evaluate microbiological response.
- A subgroup (60 patients) will provide fecal samples at five time-points over three months to assess antibiotic-induced changes in the gut microbiome.
- A subgroup (30 patients) treated with to pivmecillinam will provide blood and urine samples to determine the pharmacokinetics of mecillinam during one dosing interval.
详细描述
Background:
Escherichia coli is the predominant uropathogen and the most common cause of bloodstream infections. In the hospital setting, patients with febrile UTI (fUTI) are normally treated with intravenous antibiotics for 2-4 days until clinical improvement followed by oral step-down treatment guided by microbiological antibiotic susceptibility testing results. However, oral treatment options are increasingly limited due to emerging resistance in uropathogens and the lack of new antibiotics.
This non-inferiority, open label, randomized clinical trial (RCT), conducted in Sweden and Norway, will evaluate the efficacy of an oral narrow-spectrum penicillin (pivmecillinam) as oral step-down for patients with fUTI caused by Escherichia coli. Pivmecillinam is a first line antibiotic for acute cystitis and is sometimes used also for fUTI in Denmark and Norway although no previous RCT has evaluated its efficacy for this indication. Pivmecillinam will be compared to standard of care, i.e. step-down treatment with other orally administered antibiotics, such as ciprofloxacin or trimethoprim-sulfamethoxazole, or continued intravenous antibiotic treatment. The target sample size is 560 participants, to be enrolled over a three-year period.
Patient population:
The following PICO (Population/Intervention/Control/Outcome) applies: Population - Patients with E. coli fUTI receiving initial intravenous antibiotic treatment; Intervention - Oral follow-up treatment with pivmecillinam; Control - Standard of care; Outcome - Clinical response (primary endpoint).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •≥18 years of age.
- •Diagnosis of fUTI, defined as i) fever ≥ 38°C and ii) at least one of the following: flank pain or pelvic pain, nausea or vomiting, dysuria, urinary frequency or urgency, and costovertebral angle tenderness on physical examination.
- •Growth of E. coli in urine with antimicrobial susceptibility to mecillinam.
- •Adequate intravenous antibiotic treatment for fUTI (defined below) for 2 days to which the isolated E. coli is determined susceptible.
- •Defervescence and hemodynamic stability for at least 24 hours, according to the responsible physician.
- •Planned treatment with one of the following antibiotics, should the patient be randomized to the standard-of-care arm. Intravenous antibiotics: 1) Penicillins; ampicillin, piperacillin/tazobactam, ≥2) cephalosporins; cefotaxime, cefuroxime, ceftriaxone, 3) carbapenems; ertapenem, imipenem, meropenem, 4) monobactams; aztreonam, 5) aminoglycosides; amikacin, gentamicin, tobramycin, 6) other; fosfomycin. Oral antibiotics: 1) ciprofloxacin, 2) trimethoprim-sulfamethoxazole, 3) amoxicillin or amoxicillin/clavulanic acid provided that the isolated E. coli is determined susceptible according to the EUCAST-breakpoint for systemic infections, i.e., MIC ≤ 8 mg/l, and high dosing is used (≥750 mg amoxicillin x 3 and ≥750 mg amoxicillin/125 mg clavulanic acid x 3, respectively) and 4) tebipenem (if approved by the EMA).
- •Signed informed consent.
排除标准
- •Adequate intravenous antibiotic treatment for > 4 days prior to randomization or other adequate (microbiologically active) oral antibiotic treatment for the same fUTI episode prior to recruitment.
- •Growth of other bacterial species than E. coli, or fungi, in urine.
- •Contraindication for pivmecillinam (e.g. allergy).
- •Clinical suspicion of bacterial prostatitis.
- •Renal abscess.
- •Kidney transplant.
- •Myelosuppressive disorder with neutrophil count < 0.5 x 10(9)/L at randomization.
- •Planned antibiotic treatment for fUTI > 14 days.
- •Likely to be prescribed antibiotic prophylaxis after treatment.
- •Other intravenous or oral antibiotic treatment; ongoing or planned during the follow-up period (i.e. until 28 days after EOT for fUTI).
- •Severe renal impairment (eGFR < 20 mL/min) at randomization.
- •Morbid obesity (BMI > 40 kg/m2).
- •Pregnancy or breastfeeding.
- •Unlikely to follow instructions or the study protocol.
- •Previous participation in the study.
- •If consenting to microbiome analysis: i) contraindication for ciprofloxacin (e.g. allergy), ii) unlikely to be able to provide fecal samples per protocol, iii) treatment with antibiotics in the past 3 months before the current fUTI episode, iv) chronic intestinal disease or previous surgery in the gastrointestinal tract.
- •If consenting to pharmacokinetic analysis: expected difficulties in providing blood and urine samples per protocol.
研究组 & 干预措施
Standard of care
The control group will receive standard of care treatment at the discretion of the responsible physician and according to existing treatment guidelines.
干预措施: Standard of Care (Investigator Choice) (Drug)
Pivmecillinam
Pivmecillinam (high dose, 400 mg four times daily).
干预措施: Pivmecillinam (Drug)
结局指标
主要结局
Clinical response (primary endpoint).
时间窗: 7 (+/-2) days after EOT
Clinical response: i) no new healthcare contacts or antibiotic treatments for suspected or proven UTI, ii) sustained defervescence (\< 38°C), and iii) patient-documented resolution of fUTI symptoms that were present and recorded in the eCRF at trial entry (and no new fUTI symptoms) at test of cure (TOC), which will be performed 7 (+/-2) days after end of treatment (EOT). The evaluation of clinical response (primary endpoint) will be performed by blinded assessors.
次要结局
- Sustained clinical response(28 (+/- 2) days after EOT)
- Microbiological response(7 (+/-2) days after EOT)
- Sustained microbiological response(28 (+/- 2) days after EOT)
- Occurrence and severity of adverse events(From start of study treatment until test of cure 7 (+/-2) days after EOT)