Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics

Time from randomization to the occurrence of the components of the primary outcome:

1. the first occurrence of ipsilateral amputation alone
2. the first occurrence of ipsilateral above-ankle amputation
3. the first occurrence of ipsilateral through the ankle (e.g. Symes amputation) or below-ankle amputation proximal to the metatarsal-phalangeal joint
4. the first occurrence of ipsilateral below-ankle amputation at or distal to the metatarsal-phalangeal joint
5. 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 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, 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, 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:

1. No assistive device required to move about
2. Cane
3. Crutches
4. Walker
5. Wheelchair
6. Bed bound

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 in active drug vs. placebo groups:

1. Nausea requiring dividing the dose to twice a day
2. Rash requiring study drug discontinuation
3. Nausea requiring study drug discontinuation
4. 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 in active drug vs. placebo groups:

1. Cardiovascular: Myocardial infarction, cerebrovascular accident, hospitalization for hypertensive emergency
2. 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.

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 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 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.

Time from randomization to the first occurrence of ipsilateral amputation for the treatment of osteomyelitis related to the index osteomyelitis.

Relatedness will be determined by the LSI or qualified Co-investigator on thePrimary Outcome case report form. An episode of ipsilateral osteomyelitis is considered related to the index osteomyelitis if it involves the same bone or a contiguous bone.