A Randomized, Non-inferiority, Active Controlled Clinical Trial to Evaluate the Safety and Efficacy of Ciprofloxacin Versus Doxycycline in the Treatment of Plague in Humans
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 5
- 试验地点
- 2
- 主要终点
- all cause mortality
研究概览
简要总结
This study is a randomized, open-label, non-inferiority clinical trial evaluating the safety and efficacy of oral ciprofloxacin compared to oral doxycycline for the treatment of plague in humans. Participants aged 8 years and older with suspected plague presenting to health facilities in Uganda will be enrolled and randomized to receive either ciprofloxacin or doxycycline.
Plague is a severe, potentially fatal infectious disease caused by Yersinia pestis, with high case fatality rates if not promptly treated. Current treatment options include aminoglycosides and tetracyclines such as doxycycline; however, limitations include availability, route of administration, and safety concerns in certain populations. Ciprofloxacin is a widely available fluoroquinolone with favorable pharmacokinetics and demonstrated activity against Y. pestis in vitro and in animal models, but clinical data in humans are limited.
The primary outcome is all-cause mortality within 14 days of enrollment among participants with laboratory-confirmed plague. Secondary outcomes include time to defervescence and antimicrobial-associated adverse events.
This study aims to determine whether ciprofloxacin is non-inferior to doxycycline and to inform treatment guidelines for plague, particularly in resource-limited settings.
详细描述
Plague is a life-threatening disease that requires immediate treatment with effective antimicrobials. Drugs with demonstrated efficacy include streptomycin, doxycycline, and to a lesser extent, gentamicin. Animal and in vitro studies suggest that fluoroquinolones, including ciprofloxacin, may be effective agents for treatment of plague. However, with the exception of a single case report, there are no published instances in which fluoroquinolones have been used successfully to treat plague in humans. There is a critical need to evaluate newer antimicrobials that have been shown to be efficacious in vitro and in animal studies, used extensively in the treatment of other illnesses in humans, work by a separate mechanism than antimicrobials currently used for treatment, and are widely available and affordable.
The objective of this study is to conduct a randomized, open-labeled, non-inferiority study comparing the safety and efficacy of ciprofloxacin to doxycycline, the national treatment standard in Uganda. This study is designed to test the following hypothesis: the safety and efficacy of ciprofloxacin for the treatment of plague in humans is not inferior to doxycycline. This study will result in a better understanding of the safety and efficacy of ciprofloxacin for the treatment of plague in humans. Information from this study will be used to expand the experience and knowledge base for the treatment of plague in humans and guide national and international treatment guidelines. Information from this study also will possibly add to the antiquated list of effective antimicrobials used to treat plague and possibly lead to a reduction in the overall morbidity and mortality caused by plague and its treatment.
The randomized clinical trial provides the best design to distinguish treatment effects from other effects such as bias in allocation, observation, and measurement; spontaneous changes in disease course or healing; and improvement from participating in a study (i.e., placebo effect). An open-labeled design is being used because the opportunities for investigators or patients to bias the outcome are limited (i.e., patient randomized after enrollment and mortality is objective outcome) and a double blind design would greatly increase the complexity and cost of the trial.
The primary outcome for this trial will be patient outcome 14 days from enrollment and initiation of treatment, which includes outcomes of patient recovery without complications, recovery with complications, withdrawal, or death. Patient outcome will be evaluated only for those patients with laboratory-confirmed plague illness. Time to defervesence and occurrence of antimicrobial-associated adverse events will be evaluated as secondary outcomes in patients with laboratory-confirmed plague illness and all enrolled patients, respectively.
When conducting a non-inferiority study, it is important to consider the appropriate selection of a comparator treatment, non-inferiority margin (M), and analysis strategy. For non-inferiority trials, it is critical to select a standard treatment that has proven to be the best historically or been used in prior randomized clinical trials as the comparator treatment. Of the possible options, doxycycline is most optimal choice for this trial because it is the current treatment standard in Uganda (the country location of the proposed study) and its treatment regimen and side effect profile are the similar to that of ciprofloxacin. For this trial, the non-inferiority margin (M) is the acceptable difference between the probability that ciprofloxacin cures plague as compared to the probability that doxycycline cures plague. Because of the severity of illness and high case fatality rate for plague in general, and the potential for pneumonic transmission with pneumonic plague, the choice of an acceptable M should be no more than 10% with a most conservative choice of 2%. If we assume an overall Type I error rate = 0.05, a power (power = 1 - Type II error rate) of 80%, πs = 0.90 and we choose M = 0.10, then the number of patients required for each study arm is well over 1,000 (calculations not shown). From our previous experience with a similar trial (i.e., The safety and efficacy of gentamicin vs. streptomycin in the treatment of plague in humans, CDC IRB #3700) and our current experience with surveillance data in Uganda, we anticipate being able to enroll approximately 100-200 total patients per year. Therefore, we computed the power using different values of M (0.02, 0.05, 0.10; where 0.02 is the most conservative and 0.10 is the most forgiving but still within the accepted non-inferiority margin), to represent a range of reported efficacy of the standards (table not shown). Using the table, we would have approximately 61% power to detect non-inferiority of ciprofloxacin treatment with a non-inferiority margin, M, = 0.10 if the true efficacy of the standard is = 90% and if we were to enroll 148 patients total, for example.
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
- None
入排标准
- 年龄范围
- 8 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Suspect cases of plague will be eligible and will be asked to give consent for study enrollment using the following criteria:
- •any person, including women and persons who are minorities, who;
- •must be aged 8 years or older, and;
- •must have had potential exposure to rodents and/or fleas or contact with a confirmed plague case, and;
- •must have a fever of at least 38ºC that developed rapidly, and have at least one of the following:
- •One or more buboes, defined as a tender lymph node swelling > 1cm in diameter, or;
- •Clinical suspicion of pneumonic plague (e.g. prostration, cough, increased respiratory rate, hemoptysis and/or purulent sputum), or
- •Clinical suspicion of cutaneous plague (lesion)
- •Clinical suspicion of plague and epidemiologic link with other cases
排除标准
- •Patients with suspected plague illness will be considered ineligible for the study and will be excluded from study enrollment using the following criteria:
- •Any women who is pregnant, or;
- •Any woman who is breast-feeding, or;
- •Any person aged < 8 years of age, or;
- •Any patient with:
- •signs of plague meningitis
- •hypotension unresponsive to fluid therapy
- •an illness severity score of > 16 at time of enrollment (see below)
- •known allergy to ciprofloxacin or doxycycline
- •taken tetracyclines, quinolones, gentamicin, streptomycin, trimethoprim-sulfamethoxazole, or chloramphenicol in the 24 hours preceding study enrollment
- •Patients who are pregnant, breast-feeding, or aged < 8 years will be excluded because doxycycline has a relative contraindication for use in these populations due to drug deposition in calcifying areas of bones and teeth, enamel hypoplasia, and decreased linear skeletal growth rate. [22, 23] Please see section 10.2 for additional background describing the reasoning to exclude patients from these populations. Please see section 3.5 for the specifics regarding the timing of urine pregnancy testing.
- •The illness severity score is a composite measure adapted from the APACHE-II and Glasgow Coma scores that estimates the severity of a patient's illness at enrollment. Because most clinic locations are remote with little or no laboratory capacity, the illness severity score utilizes only non-biochemical parameters.
- •Patients will not be tested for Human Immunodeficiency Virus (HIV), and known or suspected HIV-positive patients will not be excluded.
- •Because this study will be conducted in a remote region of Uganda where no prisons are located, the enrollment of prisoners is not applicable to our study. If for some unforeseen reason a prisoner presents to a study clinic location for treatment of suspected plague, the prisoner will be excluded from the trial.
- •All study resources will be available and treatment following the UMOH national plague treatment guidelines will be offered to patients with suspected plague at the UMOH collaborating clinics who are not eligible for enrollment or who declined to consent.
研究组 & 干预措施
doxycycline
Participants with suspected or confirmed plague will receive oral doxycycline, the standard of care in Uganda. Adults and children weighing ≥45 kg will receive a 200 mg oral loading dose followed by 100 mg orally every 12 hours; children weighing <45 kg will receive 4.4 mg/kg oral loading dose followed by 2.2 mg/kg orally every 12 hours. Treatment will be administered for 10 days or until the participant has been afebrile for at least 24 hours, whichever is longer.
干预措施: doxyxcycline (Drug)
ciprofloxacin
Participants with suspected or confirmed plague will receive oral ciprofloxacin. Adults and children weighing ≥50 kg will receive 750 mg orally every 12 hours; children weighing <50 kg will receive 15 mg/kg (maximum 750 mg per dose) orally every 12 hours. Treatment will be administered for 10 days or until the participant has been afebrile for at least 24 hours, whichever is longer.
干预措施: ciprofloxacin (Drug)
结局指标
主要结局
all cause mortality
时间窗: 14 days
Proportion of participants with laboratory-confirmed plague who die from any cause within 14 days of enrollment.
次要结局
- time to defervesence(days to weeks)
- antimicrobial associated adverse events(days to weeks)