Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA INTREPID)
Drug: Riboflavin Placebo
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Investigator
Primary Purpose: Treatment
|Official Title:||CSP #2001 - Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA Intrepid)|
- Amputation-Free Survival [ Time Frame: 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 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.
- Time to Amputation [ Time Frame: Assessed 2 years post intervention ]
Time from randomization to the occurrence of the components of the primary outcome:
- the first occurrence of ipsilateral amputation alone
- the first occurrence of ipsilateral above-ankle amputation
- the first occurrence of ipsilateral through the ankle (e.g. Symes amputation) or below-ankle amputation proximal to the metatarsal-phalangeal joint
- the first occurrence of ipsilateral below-ankle amputation at or distal to the metatarsal-phalangeal joint
- all cause death
Endpoint will be determined by chart review by the Study Coordinator, with confirmation by the Site Investigator, and as needed, by the Study Chair.
- New course of antibacterial therapy for ipsilateral foot infection [ Time Frame: Assessed 2 years post intervention ]
New courses of antibacterial therapy for ipsilateral foot infection during the first year after randomization (yes/no per patient).
Endpoint will be determined by chart review by the Study Coordinator, with consultation with the Site Investigator as needed to confirm that the new course of treatment is directed toward continued or recurrent osteomyelitis of the initially affected lower extremity. The new course will require there be at least a 14 day interval between the end of the initial back-bone antibiotic therapy course.
- Quality of Life [ Time Frame: Assessed 12 months post intervention ]
Quality of life, measured by the 36-Item Short Form Health Survey (SF-36; Ware & Sherbourne, 1992) and its physical and mental health subscales.
This is a widely used self-report instrument that will be administered by the Study Coordinator at baseline, 3-, 6- and 12-months.
- Ambulatory Status [ Time Frame: Assessed 12 months post intervention ]
Ambulatory status, measured by the Study Coordinator, using a modified item from the Amputee Mobility Predictor Questionnaire56.
The patient's "usual method of ambulation within the home" will be assessed by a single self-report item at baseline, 3-, 6- and 12-months using the following response categories:
- No assistive device required to move about
- Bed bound
- Incidence of Falls [ Time Frame: Assessed 12 months post intervention ]Incidence of falls, measured by self-reported frequency of falls and falls that required medical attention in the one-month periods preceding research visits at Baseline, 3-, 6- and 12-months.
- Incidence of adverse events related to direct toxicity of rifampin [ Time Frame: Assessed 3 months post intervention ]
Incidence of adverse events related to direct toxicity of rifampin in active drug vs. placebo groups:
- Nausea requiring dividing the dose to twice a day
- Rash requiring study drug discontinuation
- Nausea requiring study drug discontinuation
- Grade 3 or 4 liver enzyme (ALT) elevations Local Site Investigators, with assistance from their Study Coordinators, will be responsible for reporting adverse events which will be used to analyze these secondary endpoints.
- Incidence of adverse events from drug interactions [ Time Frame: Assessed 3 months post intervention ]
Incidence of adverse events from drug interactions in active drug vs. placebo groups:
- Cardiovascular: Myocardial infarction, cerebrovascular accident, hospitalization for hypertensive emergency
- Glycemic control: Hospitalization for a primary diagnosis of hypoglycemia or uncontrolled diabetes Local Site Investigators, with assistance from their Study Coordinators, will be responsible for reporting adverse events which will be used to analyze these secondary endpoints.
- Comparative dropout [ Time Frame: Assessed 6 weeks post intervention ]
Overall comparative dropout data during the 6-week intervention based on drug intolerance/drug interactions/adverse events in active drug vs. placebo groups.
Dropout endpoint will be determined by chart review by the Study Coordinator and by telephone calls to the subject.
- Remission of osteomyelitis [ Time Frame: Assessed at 1 year post intervention ]
Remission of osteomyelitis at 12 months (yes/no). Remission is defined as epithelialization of any overlying soft tissue defect and the absence of local signs and symptoms of inflammation.
Endpoint will be determined by physical examination by the Site Investigator at the 12 month visit.
- Complete epithelialization of the wound [ Time Frame: Assessed 1 year post intervention ]
Complete epithelialization of the wound at 6 weeks and at 3, 6 and 12 months (yes/no).
Endpoint will be determined by physical examination by the Site Investigator at the 3, 6 and 12 month visits.
|Anticipated Study Start Date:||September 2017|
|Estimated Study Completion Date:||June 2022|
|Estimated Primary Completion Date:||August 2021 (Final data collection date for primary outcome measure)|
Active Comparator: Active drug
Patients receive oral adjunctive rifampin therapy
Subjects who are randomly assigned to adjunctive rifampin will receive a 600 mg oral daily dose targeted for a six-week period. If a subject experiences gastrointestinal intolerance on once daily dosing, the study drug may be administered as rifampin 300 mg twice a day.
Placebo Comparator: Placebo
Patients receive oral riboflavin
Drug: Riboflavin Placebo
A placebo capsule will be administered daily to match frequency and duration of rifampin interventional drug. For the purpose of mimicking urine discoloration when taking rifampin, riboflavin will be added to the placebo to produce a urine discoloration effect.
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 direct examination by the site investigators.
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 three 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT03012529
|Contact: John Hermos, MD||(857) 364-6130 ext firstname.lastname@example.org|
|Contact: Jacqueline DiBella||(617) email@example.com|
|United States, Colorado|
|VA Eastern Colorado Health Care System, Denver, CO||Not yet recruiting|
|Denver, Colorado, United States, 80220|
|Contact: Mary T Bessesen, MD 303-393-2837 firstname.lastname@example.org|
|Contact: Sheldon T Brown (718) 584-9000 ext 5842 Sheldon.Brown@va.gov|
|Study Chair: Mary T Bessesen, MD|
|Study Chair:||Mary T Bessesen, MD||VA Eastern Colorado Health Care System, Denver, CO|