Clinical trial NCT03012529: Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics
Official title: CSP #2001 - Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA Intrepid)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Osteomyelitis
Diabetes
Amputation
Keywords: Rifampin
Double-blind
Clinical Trial
Veterans
Diabetes
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2017-01-06
Enrollment: 880
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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 absolute neutrophil count (ANC) \<1000 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.

Primary outcomes:
measure: Amputation-Free Survival
timeFrame: Assessed 2 years post intervention
Secondary outcomes:
measure: Time to Amputation
timeFrame: Assessed 2 years post intervention
measure: New course of antibacterial therapy for ipsilateral foot infection
timeFrame: Assessed 2 years post intervention
measure: Quality of Life - SF-36
timeFrame: Assessed 12 months post intervention
measure: Ambulatory Status
timeFrame: Assessed 12 months post intervention
measure: Incidence of Falls
timeFrame: Assessed 12 months post intervention
measure: Incidence of adverse events related to direct toxicity of rifampin
timeFrame: Assessed 3 months post intervention
measure: Incidence of adverse events from drug interactions
timeFrame: Assessed 3 months post intervention
measure: Comparative dropout
timeFrame: Assessed 6 weeks post intervention
measure: Remission of osteomyelitis
timeFrame: Assessed at 1 year post intervention
measure: Complete epithelialization of the wound
timeFrame: Assessed 1 year post intervention
measure: First occurrence of ipsilateral amputation related to index osteomyelitis
timeFrame: Assessed 2 years post intervention
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix VA Health Care System, Phoenix, AZ
state: Arizona
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System, Loma Linda, CA
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System, Long Beach, CA
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: Sacramento
country: United States
facility: VA Northern California Health Care System, Mather, CA
state: California
city: West Los Angeles
country: United States
facility: VA Greater Los Angeles Healthcare System, West Los Angeles, CA
state: California
city: Aurora
country: United States
facility: Rocky Mountain Regional VA Medical Center, Aurora, CO
state: Colorado
city: Washington
country: United States
facility: Washington DC VA Medical Center, Washington, DC
state: District of Columbia
city: Bay Pines
country: United States
facility: Bay Pines VA Healthcare System, Pay Pines, FL
state: Florida
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System, Gainesville, FL
state: Florida
city: Miami
country: United States
facility: Miami VA Healthcare System, Miami, FL
state: Florida
city: Tampa
country: United States
facility: James A. Haley Veterans' Hospital, Tampa, FL
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur, GA
state: Georgia
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System, Ann Arbor, MI
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis VA Medical Center John Cochran Division, St. Louis, MO
state: Missouri
city: Bronx
country: United States
facility: James J. Peters VA Medical Center, Bronx, NY
state: New York
city: Salisbury
country: United States
facility: Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center, Cincinnati, OH
state: Ohio
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center, Cleveland, OH
state: Ohio
city: Dayton
country: United States
facility: Dayton VA Medical Center, Dayton, OH
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma City VA Medical Center, Oklahoma City, OK
state: Oklahoma
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Nashville
country: United States
facility: Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
state: Tennessee
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: San Antonio
country: United States
facility: South Texas Health Care System, San Antonio, TX
state: Texas
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
city: Salem
country: United States
facility: Salem VA Medical Center, Salem, VA
state: Virginia
city: Madison
country: United States
facility: William S. Middleton Memorial Veterans Hospital, Madison, WI
state: Wisconsin
Study officials:
affiliation: Rocky Mountain Regional VA Medical Center, Aurora, CO
name: Mary T Bessesen, MD
role: STUDY_CHAIR
References:
citation: Bessesen MT, Doros G, Henrie AM, Harrington KM, Hermos JA, Bonomo RA, Ferguson RE, Huang GD, Brown ST. A multicenter randomized placebo controlled trial of rifampin to reduce pedal amputations for osteomyelitis in veterans with diabetes (VA INTREPID). BMC Infect Dis. 2020 Jan 8;20(1):23. doi: 10.1186/s12879-019-4751-3.