Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics
Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics
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.
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 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; or 3) a medical record diagnosis of diabetes mellitus by a clinician on
 two or more occasions in the previous 10 years

 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 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. Patient is participating in another interventional clinical trial for which a waiver
 of dual enrollment with CSP#2001 has not been obtained.

 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*,***;
 INR > 1.5, 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.

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

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

 15. 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.