Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics

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.

Inclusion Criteria:

1. Age 18 and 89 years

2. 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

3. 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.

4. All planned debridement has been completed prior to randomization.

5. A definitive course of backbone antimicrobial therapy has been selected.

Exclusion Criteria:

1. Patient unable to receive enteral medication.

2. Patient is allergic to or intolerant of rifampin.

3. 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.

4. 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.

5. Patient is receiving antiretroviral therapy for HIV or antiviral medication for
Hepatitis C.

6. Enrollment in another trial of a therapeutic agent with a documented or suspected
interaction with rifampin.

7. 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*,***; OR
patient has Child-Pugh Class C Cirrhosis.

8. Patient has a baseline white blood cell count (WBC) <2000 cells/mm3 OR platelet count
<50,000 cells/mm3** OR hemoglobin <8.0 g/dL.**,***

9. Women of child-bearing potential (those with menses within the last year) with a
positive serum pregnancy test.

10. Patient is believed unlikely to be able to complete the trial due to medical
conditions such as metastatic cancer or end-stage organ failure.

11. 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.

12. Patient refuses or is clinically unable to undergo the recommended level of
debridement.

13. The patient's prescribed backbone antibiotic therapy does not meet standard of care
for either empirical treatment or culture-directed therapy.

14. Indwelling hardware present in the foot, at the site of the index osteomyelitis.

15. Treatment with antibacterial agents for infection at another site, where the duration
of treatment is anticipated to be greater than 14 days.

- 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.