<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03012529</url>
  </required_header>
  <id_info>
    <org_study_id>2001</org_study_id>
    <nct_id>NCT03012529</nct_id>
  </id_info>
  <brief_title>Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics</brief_title>
  <acronym>VA INTREPID</acronym>
  <official_title>CSP #2001 - Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA Intrepid)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research study is to determine if rifampin, an antibiotic (a medicine&#xD;
      that treats infections), is effective in treating osteomyelitis (infection of the bone) of&#xD;
      the foot in diabetic patients. Despite use of powerful antibiotics prescribed over a long&#xD;
      period of time, many diabetic patients remain at a high risk for needing an amputation of&#xD;
      part of the foot or lower leg because the osteomyelitis is not cured. Some small research&#xD;
      studies have shown that addition of rifampin to other antibiotics is effective in treating&#xD;
      osteomyelitis in both diabetics and non-diabetics. However, because few diabetics with&#xD;
      osteomyelitis have been studied, there is no definite proof that it is better than the usual&#xD;
      treatments for diabetic patients. If this study finds that adding rifampin to the usual&#xD;
      antibiotics prescribed for osteomyelitis reduces the risk for amputations, doctors will be&#xD;
      able to more effectively treat many Veteran patients with this serious infection. Improving&#xD;
      treatment outcomes is an important healthcare goal of the VA.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a prospective, randomized, double-blind, placebo-controlled, investigation of a six&#xD;
      week course of adjunctive rifampin vs. adjunctive matched placebo (riboflavin) added to&#xD;
      backbone antibacterial therapy for the treatment of diabetic foot osteomyelitis. Backbone&#xD;
      antibacterial therapy will be with single or multiple agents selected by the clinical&#xD;
      treatment team based either on culture results or standard empiric therapy, and which can be&#xD;
      administered either intravenously or orally. Rifampin will be dosed at 600 mg daily. The&#xD;
      primary outcome measure is amputation-free survival. Amputation events include both below-&#xD;
      and above-ankle amputations. Primary outcomes will be determined by systematic medical record&#xD;
      review and through confirmatory research visits, phone calls and, as needed, information from&#xD;
      non-VA providers. The results for amputation-free survival will be analyzed by means of a&#xD;
      two-sided log-rank test. The secondary outcomes of complete wound epithelialization and&#xD;
      remission of osteomyelitis will be determined by the research team through VA record review&#xD;
      and/or direct examination.&#xD;
&#xD;
      The study will initially enroll and randomize a total of 880 study participants to receive&#xD;
      either rifampin or placebo (riboflavin) in addition to backbone antibiotic therapy prescribed&#xD;
      by their clinician. Investigators expect to enroll, on average, close to one subject per&#xD;
      month per site (10-12 per year/site) at 28 VA medical centers to achieve total randomization&#xD;
      of 880 subjects over three years. In meeting this average site enrollment projection,&#xD;
      Investigators anticipate variation in enrollment between larger and smaller sites, and&#xD;
      between high-performing and low-performing sites. Subjects will be followed through the end&#xD;
      of the second year after randomization or until a study primary endpoint event (amputation or&#xD;
      death) occurs. On average, study participants will be followed for 1.8 years through&#xD;
      systematic review of medical records, and by study visits and phone calls.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 22, 2018</start_date>
  <completion_date type="Anticipated">January 22, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 22, 2024</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Amputation-Free Survival</measure>
    <time_frame>Assessed 2 years post intervention</time_frame>
    <description>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/infected 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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Amputation</measure>
    <time_frame>Assessed 2 years post intervention</time_frame>
    <description>Time from randomization to the occurrence of the components of the primary outcome:&#xD;
the first occurrence of ipsilateral amputation alone&#xD;
the first occurrence of ipsilateral above-ankle amputation&#xD;
the first occurrence of ipsilateral through the ankle (e.g. Symes amputation) or below-ankle amputation proximal to the metatarsal-phalangeal joint&#xD;
the first occurrence of ipsilateral below-ankle amputation at or distal to the metatarsal-phalangeal joint&#xD;
all cause death&#xD;
Endpoint will be determined by chart review by the Study Coordinator, with confirmation by the Site Investigator, and as needed, by the Study Chair.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New course of antibacterial therapy for ipsilateral foot infection</measure>
    <time_frame>Assessed 2 years post intervention</time_frame>
    <description>New courses of antibacterial therapy for ipsilateral foot infection during the first year after randomization (yes/no per patient).&#xD;
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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life - SF-36</measure>
    <time_frame>Assessed 12 months post intervention</time_frame>
    <description>Quality of life, measured by the 36-Item Short Form Health Survey (SF-36; Ware &amp; Sherbourne, 1992) and its physical and mental health subscales.&#xD;
This is a widely used self-report instrument that will be administered by the Study Coordinator at baseline, 3-, 6- and 12-months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ambulatory Status</measure>
    <time_frame>Assessed 12 months post intervention</time_frame>
    <description>Ambulatory status, measured by the Study Coordinator, using a modified item from the Amputee Mobility Predictor Questionnaire56.&#xD;
The patient's &quot;usual method of ambulation within the home&quot; will be assessed by a single self-report item at baseline, 3-, 6- and 12-months using the following response categories:&#xD;
No assistive device required to move about&#xD;
Cane&#xD;
Crutches&#xD;
Walker&#xD;
Wheelchair&#xD;
Bed bound</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Falls</measure>
    <time_frame>Assessed 12 months post intervention</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events related to direct toxicity of rifampin</measure>
    <time_frame>Assessed 3 months post intervention</time_frame>
    <description>Incidence of adverse events related to direct toxicity of rifampin in active drug vs. placebo groups:&#xD;
Nausea requiring dividing the dose to twice a day&#xD;
Rash requiring study drug discontinuation&#xD;
Nausea requiring study drug discontinuation&#xD;
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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events from drug interactions</measure>
    <time_frame>Assessed 3 months post intervention</time_frame>
    <description>Incidence of adverse events from drug interactions in active drug vs. placebo groups:&#xD;
Cardiovascular: Myocardial infarction, cerebrovascular accident, hospitalization for hypertensive emergency&#xD;
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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparative dropout</measure>
    <time_frame>Assessed 6 weeks post intervention</time_frame>
    <description>Overall comparative dropout data during the 6-week intervention based on drug intolerance/drug interactions/adverse events in active drug vs. placebo groups.&#xD;
Dropout endpoint will be determined by chart review by the Study Coordinator and by telephone calls to the subject.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Remission of osteomyelitis</measure>
    <time_frame>Assessed at 1 year post intervention</time_frame>
    <description>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.&#xD;
Endpoint will be determined by physical examination by the Site Investigator at the 12 month visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete epithelialization of the wound</measure>
    <time_frame>Assessed 1 year post intervention</time_frame>
    <description>Complete epithelialization of the wound at 6 weeks and at 3, 6 and 12 months (yes/no).&#xD;
Endpoint will be determined by physical examination by the Site Investigator at the 3, 6 and 12 month visits.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>First occurrence of ipsilateral amputation related to index osteomyelitis</measure>
    <time_frame>Assessed 2 years post intervention</time_frame>
    <description>Time from randomization to the first occurrence of ipsilateral amputation for the treatment of osteomyelitis related to the index osteomyelitis.&#xD;
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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">880</enrollment>
  <condition>Osteomyelitis</condition>
  <condition>Diabetes</condition>
  <condition>Amputation</condition>
  <arm_group>
    <arm_group_label>Active drug</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients receive oral adjunctive rifampin therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients receive oral riboflavin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifampin</intervention_name>
    <description>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.</description>
    <arm_group_label>Active drug</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Riboflavin Placebo</intervention_name>
    <description>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.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 18 and 89 years&#xD;
&#xD;
          2. Diagnosis of diabetes mellitus, either by: 1) use of oral hypoglycemic agents or&#xD;
             insulin at the time of enrollment; 2) a hemoglobin A1c (HgA1c) level within the past&#xD;
             90 days &gt; 6.5; or 3) a medical record diagnosis of diabetes mellitus by a clinician on&#xD;
             two or more occasions in the previous 10 years&#xD;
&#xD;
          3. Definite or probable osteomyelitis in the diabetic foot, as defined by the&#xD;
             International Working Group on the Diabetic Foot (Table 1). Criteria must be present&#xD;
             at some point within 90 days prior to enrollment.&#xD;
&#xD;
          4. All planned debridement has been completed prior to randomization.&#xD;
&#xD;
          5. A course of backbone antimicrobial therapy has been selected.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient unable to receive enteral medication.&#xD;
&#xD;
          2. Patient is allergic to or intolerant of rifampin.&#xD;
&#xD;
          3. Patient is taking a drug that has interactions with rifampin that would require either&#xD;
             stoppage, substitution or an empiric dose modification that may place the patient at&#xD;
             medical risk.&#xD;
&#xD;
          4. Within 30 days of enrollment, patient is taking immunosuppressive medications to&#xD;
             prevent rejection of an organ transplant or is receiving chemotherapy for cancer or&#xD;
             molecularly targeted therapies for cancer.&#xD;
&#xD;
          5. Patient is receiving antiretroviral therapy for HIV or antiviral medication for&#xD;
             Hepatitis C.&#xD;
&#xD;
          6. Patient is participating in another interventional clinical trial for which a waiver&#xD;
             of dual enrollment with CSP#2001 has not been obtained.&#xD;
&#xD;
          7. Patient has an ALT &gt; 3 times the upper limit of normal for the site laboratory, or&#xD;
             total bilirubin &gt; 2.5 times the upper limit of normal for the site laboratory*,***;&#xD;
             INR &gt; 1.5, OR patient has Child-Pugh Class C Cirrhosis.&#xD;
&#xD;
          8. Patient has a baseline white blood cell count (WBC) &lt;2000 cells/mm3*** OR absolute&#xD;
             neutrophil count (ANC) &lt;1000 cells/mm3*** OR platelet count &lt;50,000 cells/mm3**,*** OR&#xD;
             hemoglobin &lt;8.0 g/dL.**,***.&#xD;
&#xD;
          9. Women of child-bearing potential (those with menses within the last year) with a&#xD;
             positive serum pregnancy test.&#xD;
&#xD;
         10. Patient is believed unlikely to be able to complete the trial due to medical&#xD;
             conditions.&#xD;
&#xD;
         11. Patient is believed unlikely to complete the trial due to neurologic and&#xD;
             psycho-behavioral disorders such as active substance abuse or dependence, disabling&#xD;
             dementias or psychoses.&#xD;
&#xD;
         12. Patient refuses or is clinically unable to undergo the recommended level of&#xD;
             debridement.&#xD;
&#xD;
         13. Indwelling hardware present in the foot, at the site of the index osteomyelitis.&#xD;
&#xD;
         14. Treatment with antibacterial agents for infection at another site, where the duration&#xD;
             of treatment is anticipated to be greater than 14 days.&#xD;
&#xD;
         15. Patient is receiving therapy for COVID-19 that interacts with rifampin.&#xD;
&#xD;
               -  Patients with total bilirubin &gt; 2 times the ULN who have Gilbert's Disease or any&#xD;
                  other inherited disease affecting bilirubin metabolism without meeting other&#xD;
                  exclusionary criteria, may be considered for inclusion in the study.&#xD;
&#xD;
                    -  Patients with platelet count &lt;50,000 cells/mm3 due only to hypersplenism and&#xD;
                       meeting no other exclusionary criteria may be considered for inclusion in&#xD;
                       the study.&#xD;
&#xD;
                         -  If multiple laboratory values are available, the most recent value will&#xD;
                            be applied for eligibility.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>89 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mary T Bessesen, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Rocky Mountain Regional VA Medical Center, Aurora, CO</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Paul A Monach, MD PhD</last_name>
    <phone>(857) 364-6662</phone>
    <email>Paul.Monach@va.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Kayla R Morrison</last_name>
    <phone>(617) 435-6375</phone>
    <email>Kayla.Morrison@va.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Phoenix VA Health Care System, Phoenix, AZ</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85012</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>VA Loma Linda Healthcare System, Loma Linda, CA</name>
      <address>
        <city>Loma Linda</city>
        <state>California</state>
        <zip>92357</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ronald Fernando, MD</last_name>
      <phone>909-583-6361</phone>
      <email>ronald.fernando@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Agnes Lee, LVN</last_name>
      <email>Agnes.Lee2@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>VA Long Beach Healthcare System, Long Beach, CA</name>
      <address>
        <city>Long Beach</city>
        <state>California</state>
        <zip>90822</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ian Gordon, MD</last_name>
      <phone>562-826-8000</phone>
      <phone_ext>24409</phone_ext>
      <email>ian.gordon@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Christine Ma, MPH</last_name>
      <email>christine.ma@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>VA Palo Alto Health Care System, Palo Alto, CA</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304-1207</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mark Holodniy, MD</last_name>
      <phone>650-852-3408</phone>
      <email>mark.holodniy@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Leonor Lopez, RN</last_name>
      <email>Leonor.Lopez@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>VA Northern California Health Care System, Mather, CA</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95655</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hien Nguyen, MD</last_name>
      <phone>916-843-9242</phone>
      <email>hien.nguyen6@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Lam Nguyen, BA</last_name>
      <email>Lam.Nguyen3@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>VA Greater Los Angeles Healthcare System, West Los Angeles, CA</name>
      <address>
        <city>West Los Angeles</city>
        <state>California</state>
        <zip>90073</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Rocky Mountain Regional VA Medical Center, Aurora, CO</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lindsay Nicholson, MD</last_name>
      <phone>720-723-6772</phone>
    </contact>
    <contact_backup>
      <last_name>Anna Wyrwa, BSN</last_name>
      <phone>(720) 857-5117</phone>
      <email>Anna.Wyrwa@va.gov</email>
    </contact_backup>
    <investigator>
      <last_name>Mary T Bessesen, MD</last_name>
      <role>Study Chair</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Washington DC VA Medical Center, Washington, DC</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20422</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Angelike Liappis, MD</last_name>
      <phone>202-745-8000</phone>
      <phone_ext>58301</phone_ext>
      <email>angelike.liappis@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Shirley Cummins, CCRC</last_name>
      <email>shirley.cummins@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Bay Pines VA Healthcare System, Pay Pines, FL</name>
      <address>
        <city>Bay Pines</city>
        <state>Florida</state>
        <zip>33744</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melissa Abercrombie, DPM</last_name>
      <phone>727-398-6661</phone>
      <phone_ext>17379</phone_ext>
      <email>Melissa.Abercrombie@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Cortny Withee, BS</last_name>
      <email>Cortny.Withee@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>North Florida/South Georgia Veterans Health System, Gainesville, FL</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32608</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gary Wang, MD</last_name>
      <phone>352-548-6483</phone>
      <email>Gary.Wang@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Leslie Brown, BA</last_name>
      <email>leslie.brown1@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Miami VA Healthcare System, Miami, FL</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33125</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>James A. Haley Veterans' Hospital, Tampa, FL</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>John Toney, MD</last_name>
      <phone>813-972-2000</phone>
      <phone_ext>6697</phone_ext>
      <email>John.Toney@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Natalie Veling, BSN</last_name>
      <email>Natalie.Veling@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Atlanta VA Medical and Rehab Center, Decatur, GA</name>
      <address>
        <city>Decatur</city>
        <state>Georgia</state>
        <zip>30033</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>VA Ann Arbor Healthcare System, Ann Arbor, MI</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48105</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kathleen Linder, MD</last_name>
      <phone>734-222-7598</phone>
      <email>Kathleen.Linder2@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Kimberly Nofz, BSN</last_name>
      <email>Kimberly.Nofz@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Minneapolis VA Health Care System, Minneapolis, MN</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55417</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Derrick Green, MD</last_name>
      <phone>612-467-7275</phone>
      <email>derrick.green@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Aigerim Toleuova, MN</last_name>
      <email>aigerim.toleuova@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>St. Louis VA Medical Center John Cochran Division, St. Louis, MO</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63106</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>James J. Peters VA Medical Center, Bronx, NY</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10468</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Gelman, MD</last_name>
      <phone>718-584-9000</phone>
      <phone_ext>6680</phone_ext>
      <email>michael.gelman@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Kathleen Escoto, MPH</last_name>
      <email>Kathleen.Escoto@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Salisbury W.G. (Bill) Hefner VA Medical Center, Salisbury, NC</name>
      <address>
        <city>Salisbury</city>
        <state>North Carolina</state>
        <zip>28144</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Luis Barroso, MD</last_name>
      <phone>704-638-9000</phone>
      <phone_ext>13570</phone_ext>
      <email>Luis.Barroso@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Ashly Hinson, LPN</last_name>
      <email>Ashly.Hinson@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Cincinnati VA Medical Center, Cincinnati, OH</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45220</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>George Smulian, MD</last_name>
      <phone>513-348-6804</phone>
      <email>george.smulian@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Laura Lach, BS</last_name>
      <email>Laura.Lach@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Louis Stokes VA Medical Center, Cleveland, OH</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Usha Stiefel, MD</last_name>
      <phone>216-791-3800</phone>
      <phone_ext>64788</phone_ext>
      <email>Usha.Stiefel@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Karly Tarase, BSN</last_name>
      <email>Karly.Tarase@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Dayton VA Medical Center, Dayton, OH</name>
      <address>
        <city>Dayton</city>
        <state>Ohio</state>
        <zip>45428</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hari Polenakovik, MD</last_name>
      <phone>937-268-6511</phone>
      <phone_ext>2630</phone_ext>
      <email>hari.polenakovik@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Barbara Lane, MSN</last_name>
      <email>Barbara.Lane@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Oklahoma City VA Medical Center, Oklahoma City, OK</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>George Kurdgelashvili, MD</last_name>
      <phone>405-456-2544</phone>
      <email>George.Kurdgelashvili@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Seerat Moutassam, MPH</last_name>
      <email>Seerat.Moutassam@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>VA Portland Health Care System, Portland, OR</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97207-2964</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marissa Maier, MD</last_name>
      <phone>503-220-8262</phone>
      <phone_ext>52363</phone_ext>
      <email>Marissa.Maier@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Erik Mauk, BS</last_name>
      <email>Erik.Mauk@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Tennessee Valley Healthcare System Nashville Campus, Nashville, TN</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37212-2637</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Todd Hulgan, MD</last_name>
      <phone>615-835-5082</phone>
      <email>Todd.Hulgan@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Rachel Turgeon, MS</last_name>
      <email>Rachel.Turgeon@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75216</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David Truong, DPM</last_name>
      <phone>214-857-0039</phone>
      <email>David.Truong1@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Sarah Balogun, BS</last_name>
      <email>Sarah.Balogun@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Michael E. DeBakey VA Medical Center, Houston, TX</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Neal Barshes, MD</last_name>
      <phone>713-791-1414</phone>
      <phone_ext>25188</phone_ext>
      <email>neal.barshes@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Alexander Uribe-Gomez, MD</last_name>
      <email>Alexander.Uribe-Gomez@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>South Texas Health Care System, San Antonio, TX</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jose Cadena Zuluaga, MD</last_name>
      <phone>210-617-5300</phone>
      <phone_ext>14793</phone_ext>
      <email>jose.cadena-zuluaga@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Michele Paprocki, MSN</last_name>
      <email>Michele.Paprocki@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>VA Salt Lake City Health Care System, Salt Lake City, UT</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84148</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Clint Larsen, DPM</last_name>
      <phone>801-582-1565</phone>
      <phone_ext>4826</phone_ext>
      <email>clint.larsen@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Cicilia Velarde, BS</last_name>
      <email>Cicilia.Velarde@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>Salem VA Medical Center, Salem, VA</name>
      <address>
        <city>Salem</city>
        <state>Virginia</state>
        <zip>24153-6404</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Shikha Vasudeva, MD</last_name>
      <phone>540-982-2463</phone>
      <phone_ext>3843</phone_ext>
      <email>shikha.vasudeva@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Brooke Fuhrey, BS</last_name>
      <email>Brooke.Fuhrey@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>William S. Middleton Memorial Veterans Hospital, Madison, WI</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53705</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christopher Crnich, MD</last_name>
      <phone>608-843-0438</phone>
      <email>christopher.crnich@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Kenneth Wagman, BSN</last_name>
      <email>Kenneth.Wagman@va.gov</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>January 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 6, 2017</study_first_posted>
  <last_update_submitted>August 21, 2023</last_update_submitted>
  <last_update_submitted_qc>August 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Rifampin</keyword>
  <keyword>Double-blind</keyword>
  <keyword>Clinical Trial</keyword>
  <keyword>Veterans</keyword>
  <keyword>Diabetes</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteomyelitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Riboflavin</mesh_term>
    <mesh_term>Rifampin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03012529
org study id: 2001
nct id: NCT03012529
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Amputation-Free Survival
time frame: Assessed 2 years post intervention
description: 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/infected 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.
measure: Time to Amputation
time frame: Assessed 2 years post intervention
description: Time from randomization to the occurrence of the components of the primary outcome:
the first occurrence of ipsilateral amputation alone
the first occurrence of ipsilateral above-ankle amputation
the first occurrence of ipsilateral through the ankle (e.g. Symes amputation) or below-ankle amputation proximal to the metatarsal-phalangeal joint
the first occurrence of ipsilateral below-ankle amputation at or distal to the metatarsal-phalangeal joint
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.
measure: New course of antibacterial therapy for ipsilateral foot infection
time frame: Assessed 2 years post intervention
description: 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.
measure: Quality of Life - SF-36
time frame: Assessed 12 months post intervention
description: 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.
measure: Ambulatory Status
time frame: Assessed 12 months post intervention
description: 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:
No assistive device required to move about
Cane
Crutches
Walker
Wheelchair
Bed bound
measure: Incidence of Falls
time frame: Assessed 12 months post intervention
description: 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.
measure: Incidence of adverse events related to direct toxicity of rifampin
time frame: Assessed 3 months post intervention
description: Incidence of adverse events related to direct toxicity of rifampin in active drug vs. placebo groups:
Nausea requiring dividing the dose to twice a day
Rash requiring study drug discontinuation
Nausea requiring study drug discontinuation
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.
measure: Incidence of adverse events from drug interactions
time frame: Assessed 3 months post intervention
description: Incidence of adverse events from drug interactions in active drug vs. placebo groups:
Cardiovascular: Myocardial infarction, cerebrovascular accident, hospitalization for hypertensive emergency
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.
measure: Comparative dropout
time frame: Assessed 6 weeks post intervention
description: 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.
measure: Remission of osteomyelitis
time frame: Assessed at 1 year post intervention
description: 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.
measure: Complete epithelialization of the wound
time frame: Assessed 1 year post intervention
description: 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.
measure: First occurrence of ipsilateral amputation related to index osteomyelitis
time frame: Assessed 2 years post intervention
description: 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.
arm group label: Active drug
arm group type: Active Comparator
description: Patients receive oral adjunctive rifampin therapy
arm group label: Placebo
arm group type: Placebo Comparator
description: Patients receive oral riboflavin
intervention type: Drug
intervention name: Rifampin
description: 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.
arm group label: Active drug
intervention type: Drug
intervention name: Riboflavin Placebo
description: 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.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 89 Years
healthy volunteers: No
last name: Mary T Bessesen, MD
role: Study Chair
affiliation: Rocky Mountain Regional VA Medical Center, Aurora, CO
last name: Paul A Monach, MD PhD
phone: (857) 364-6662
email: Paul.Monach@va.gov
last name: Kayla R Morrison
phone: (617) 435-6375
email: Kayla.Morrison@va.gov
facility: 
status: Terminated
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Terminated
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Terminated
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Terminated
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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country: United States
responsible party type: Sponsor
mesh term: Osteomyelitis
mesh term: Riboflavin
mesh term: Rifampin
sharing ipd: No