CSP #2001 - Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA Intrepid)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 843
- 试验地点
- 60
- 主要终点
- Amputation-Free Survival
研究概览
简要总结
The purpose of this research study is to determine if rifampin, an antibiotic (a medicine that treats infections), is effective in treating osteomyelitis (infection of the bone) of the foot in diabetic patients. Despite use of powerful antibiotics prescribed over a long period of time, many diabetic patients remain at a high risk for needing an amputation of part of the foot or lower leg because the osteomyelitis is not cured. Some small research studies have shown that addition of rifampin to other antibiotics is effective in treating osteomyelitis in both diabetics and non-diabetics. However, because few diabetics with osteomyelitis have been studied, there is no definite proof that it is better than the usual treatments for diabetic patients. If this study finds that adding rifampin to the usual antibiotics prescribed for osteomyelitis reduces the risk for amputations, doctors will be able to more effectively treat many Veteran patients with this serious infection. Improving treatment outcomes is an important healthcare goal of the VA.
详细描述
This is a prospective, randomized, double-blind, placebo-controlled, investigation of a six week course of adjunctive rifampin vs. adjunctive matched placebo (riboflavin) added to backbone antibacterial therapy for the treatment of diabetic foot osteomyelitis. Backbone antibacterial therapy will be with single or multiple agents selected by the clinical treatment team based either on culture results or standard empiric therapy, and which can be administered either intravenously or orally. Rifampin will be dosed at 600 mg daily. The primary outcome measure is amputation-free survival. Amputation events include both below- and above-ankle amputations. Primary outcomes will be determined by systematic medical record review and through confirmatory research visits, phone calls and, as needed, information from non-VA providers. The results for amputation-free survival will be analyzed by means of a two-sided log-rank test. The secondary outcomes of complete wound epithelialization and remission of osteomyelitis will be determined by the research team through VA record review and/or direct examination.
The study will initially enroll and randomize a total of 880 study participants to receive either rifampin or placebo (riboflavin) in addition to backbone antibiotic therapy prescribed by their clinician. Investigators expect to enroll, on average, close to one subject per month per site (10-12 per year/site) at 28 VA medical centers to achieve total randomization of 880 subjects over seven years. In meeting this average site enrollment projection, Investigators anticipate variation in enrollment between larger and smaller sites, and between high-performing and low-performing sites. Subjects will be followed through the end of the second year after randomization or until a study primary endpoint event (amputation or death) occurs. On average, study participants will be followed for 1.8 years through systematic review of medical records, and by study visits and phone calls.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 89 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18 and 89 years
- •Diagnosis of diabetes mellitus, either by: 1) use of oral hypoglycemic agents or insulin at the time of enrollment; 2) a hemoglobin A1c (HgA1c) level within the past 90 days > 6.5; or 3) a medical record diagnosis of diabetes mellitus by a clinician on two or more occasions in the previous 10 years
- •Definite or probable osteomyelitis in the diabetic foot, as defined by the International Working Group on the Diabetic Foot (Table 1). Criteria must be present at some point within 90 days prior to enrollment.
- •All planned debridement has been completed prior to randomization.
- •A course of backbone antimicrobial therapy has been selected.
排除标准
- •Patient unable to receive enteral medication.
- •Patient is allergic to or intolerant of rifampin.
- •Patient is taking a drug that has interactions with rifampin that would require either stoppage, substitution or an empiric dose modification that may place the patient at medical risk.
- •Within 30 days of enrollment, patient is taking immunosuppressive medications to prevent rejection of an organ transplant or is receiving chemotherapy for cancer or molecularly targeted therapies for cancer.
- •Patient is receiving antiretroviral therapy for HIV or antiviral medication for Hepatitis C.
- •Patient is participating in another interventional clinical trial for which a waiver of dual enrollment with CSP#2001 has not been obtained.
- •Patient has an ALT > 3 times the upper limit of normal for the site laboratory, or total bilirubin > 2.5 times the upper limit of normal for the site laboratory*,***; INR > 1.5, OR patient has Child-Pugh Class C Cirrhosis.
- •Patient has a baseline white blood cell count (WBC) <2000 cells/mm3*** OR absolute neutrophil count (ANC) <1000 cells/mm3*** OR platelet count <50,000 cells/mm3**,*** OR hemoglobin <8.0 g/dL.**,***.
- •Women of child-bearing potential (those with menses within the last year) with a positive serum pregnancy test.
- •Patient is believed unlikely to be able to complete the trial due to medical conditions.
- •Patient is believed unlikely to complete the trial due to neurologic and psycho-behavioral disorders such as active substance abuse or dependence, disabling dementias or psychoses.
- •Patient refuses or is clinically unable to undergo the recommended level of debridement.
- •Indwelling hardware present in the foot, at the site of the index osteomyelitis.
- •Treatment with antibacterial agents for infection at another site, where the duration of treatment is anticipated to be greater than 14 days.
- •Patient is receiving therapy for COVID-19 that interacts with rifampin.
- •Patients with total bilirubin > 2 times the ULN who have Gilbert's Disease or any other inherited disease affecting bilirubin metabolism without meeting other exclusionary criteria, may be considered for inclusion in the study.
- •Patients with platelet count <50,000 cells/mm3 due only to hypersplenism and meeting no other exclusionary criteria may be considered for inclusion in the study.
- •If multiple laboratory values are available, the most recent value will be applied for eligibility.
研究组 & 干预措施
Active drug
Patients receive oral adjunctive rifampin therapy
干预措施: Rifampin (Drug)
Placebo
Patients receive oral riboflavin
干预措施: Riboflavin Placebo (Drug)
结局指标
主要结局
Amputation-Free Survival
时间窗: Assessed 2 years post intervention
The primary endpoint is amputation-free survival, ending with amputation or death from any cause. Amputation is defined as surgical treatment of osteomyelitis by removal or debridement of necrotic/infected bone (all or part of a bone) from a lower extremity limb or digit on the ipsilateral side of the protocol-treated osteomyelitis. Debridement prior to randomization may include removal of bone. Because this debridement occurs early, prior to exposure to study drug or placebo, removal of bone at that time is not a study endpoint.
次要结局
- Incidence of adverse events related to direct toxicity of rifampin(Assessed 3 months post intervention)
- New course of antibacterial therapy for ipsilateral foot infection(Assessed 2 years post intervention)
- Time to Amputation(Assessed 2 years post intervention)
- Ambulatory Status(Assessed 12 months post intervention)
- Incidence of Falls(Assessed 12 months post intervention)
- First occurrence of ipsilateral amputation related to index osteomyelitis(Assessed 2 years post intervention)
- Quality of Life - SF-36(Assessed 12 months post intervention)
- Remission of osteomyelitis(Assessed at 1 year post intervention)
- Incidence of adverse events from drug interactions(Assessed 3 months post intervention)
- Comparative dropout(Assessed 6 weeks post intervention)
- Complete epithelialization of the wound(Assessed 1 year post intervention)