Clinical Trial: Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: CSP #2001 - Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA Intrepid)

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 Summary:

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 sys
Sponsor: VA Office of Research and Development

Current Primary Outcome: Amputation-Free Survival [ Time Frame: Assessed 2 years post intervention ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• 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.

• 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.

• 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.

• 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
• 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.
• 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.
• 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.
• 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
  
  

  Original Secondary Outcome:

  • 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.

  • 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.

  • 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.

  • 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
  • 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.
  • 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.
  • 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.
  • Comparative droupout [ Time Frame: Assessed 6 weeks post intervention ]

    Overall comparative dropout data during the 6-week intervention based on drug intolerance/drug interactions/adverse event
    
    Information By: VA Office of Research and Development
    

    Dates:
    Date Received: December 22, 2016
    Date Started: September 2017
    Date Completion: June 2022
    Last Updated: May 9, 2017
    Last Verified: May 2017
    

    

    Join Millions

    Sign Up For One Of Our
    Newsletters

    Email

    Sign Up