Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA INTREPID)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03012529
Recruitment Status : Recruiting
First Posted : January 6, 2017
Last Update Posted : January 16, 2019
Information provided by (Responsible Party):
VA Office of Research and Development

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.

Condition or disease Intervention/treatment Phase
Osteomyelitis Diabetes Amputation Drug: Rifampin Drug: Riboflavin Placebo Phase 4

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 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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 880 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: CSP #2001 - Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA Intrepid)
Actual Study Start Date : November 21, 2017
Estimated Primary Completion Date : October 1, 2021
Estimated Study Completion Date : July 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Foot Health

Arm Intervention/treatment
Active Comparator: Active drug
Patients receive oral adjunctive rifampin therapy
Drug: Rifampin
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.

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Time to Amputation [ Time Frame: Assessed 2 years post intervention ]

    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.

  2. 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.

  3. 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.

  4. 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:

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

  5. 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.

  6. 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:

    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.

  7. 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:

    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.

  8. 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.

  9. 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.

  10. 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.

  11. First occurrence of ipsilateral amputation related to index osteomyelitis [ Time Frame: Assessed 2 years post intervention ]

    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years to 89 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03012529

Contact: Kelly Harrington, PhD
Contact: Jacqueline DiBella (617) 232-9500

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United States, Arizona
Phoenix VA Health Care System, Phoenix, AZ Recruiting
Phoenix, Arizona, United States, 85012
Contact: Negin Blattman, MD   
Contact: Lisa Orozco, RN   
United States, California
VA Loma Linda Healthcare System, Loma Linda, CA Recruiting
Loma Linda, California, United States, 92357
Contact: Ronald Fernando, MD   
Contact: Agnes Lee, LVN   
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Long Beach, California, United States, 90822
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VA Palo Alto Health Care System, Palo Alto, CA Recruiting
Palo Alto, California, United States, 94304-1290
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VA Northern California Health Care System, Mather, CA Recruiting
Sacramento, California, United States, 95655
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West Los Angeles, California, United States, 90073
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United States, Colorado
Rocky Mountain Regional VA Medical Center, Aurora, CO Recruiting
Aurora, Colorado, United States, 80045
Contact: Mary T Bessesen, MD    303-393-2837   
Contact: Sheldon T Brown    (718) 584-9000 ext 5842   
Study Chair: Mary T Bessesen, MD         
United States, District of Columbia
Washington DC VA Medical Center, Washington, DC Recruiting
Washington, District of Columbia, United States, 20422
Contact: Angelike Liappis, MD   
Contact: Shirley Cummins, CCRC   
United States, Florida
Bay Pines VA Healthcare System, Pay Pines, FL Recruiting
Bay Pines, Florida, United States, 33744
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North Florida/South Georgia Veterans Health System, Gainesville, FL Recruiting
Gainesville, Florida, United States, 32608
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Miami VA Healthcare System, Miami, FL Recruiting
Miami, Florida, United States, 33125
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Tampa, Florida, United States, 33612
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Decatur, Georgia, United States, 30033
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United States, Michigan
VA Ann Arbor Healthcare System, Ann Arbor, MI Recruiting
Ann Arbor, Michigan, United States, 48105
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United States, Minnesota
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Minneapolis, Minnesota, United States, 55417
Contact: Anjum Kaka, MD   
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United States, Missouri
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Saint Louis, Missouri, United States, 63106
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United States, New York
James J. Peters VA Medical Center, Bronx, NY Recruiting
Bronx, New York, United States, 10468
Contact: Michael Gelman, MD   
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United States, North Carolina
Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC Recruiting
Salisbury, North Carolina, United States, 28144
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United States, Ohio
Cincinnati VA Medical Center, Cincinnati, OH Recruiting
Cincinnati, Ohio, United States, 45220
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Cleveland, Ohio, United States, 44106
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Dayton, Ohio, United States, 45428
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VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX Recruiting
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VA Salt Lake City Health Care System, Salt Lake City, UT Recruiting
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Salem VA Medical Center, Salem, VA Recruiting
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Contact: Suzanne West, RN   
United States, Wisconsin
William S. Middleton Memorial Veterans Hospital, Madison, WI Recruiting
Madison, Wisconsin, United States, 53705
Contact: Christopher Crnich, MD   
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Sponsors and Collaborators
VA Office of Research and Development
Study Chair: Mary T Bessesen, MD Rocky Mountain Regional VA Medical Center, Aurora, CO

Responsible Party: VA Office of Research and Development Identifier: NCT03012529     History of Changes
Other Study ID Numbers: 2001
First Posted: January 6, 2017    Key Record Dates
Last Update Posted: January 16, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:
Clinical Trial

Additional relevant MeSH terms:
Bone Diseases, Infectious
Bone Diseases
Musculoskeletal Diseases
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
Vitamin B Complex
Growth Substances
Physiological Effects of Drugs
Photosensitizing Agents
Dermatologic Agents