A Phase 4 interventional study of Rifampin and Riboflavin Placebo in Osteomyelitis, Diabetes and Amputation, sponsored by VA Office of Research and Development. Completed at 30 sites in United States. Open to participants aged 18 Years to 89 Years. Per ClinicalTrials.gov, last updated 2026-04-20.
Sponsored by VA Office of Research and Development · Phase 4, Interventional, and Treatment
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 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.
105 studies on the registry are indexed under Osteomyelitis; 30 are open to participants now.
This study's enrollment of 843 is above the median of 74 across 60 interventional studies indexed under Osteomyelitis.
Browse Osteomyelitis studies →VA Office of Research and Development is the lead sponsor of 1,771 studies on the registry; 392 are open to participants now.
Of its 213 completed or terminated interventional studies of FDA-regulated products, 185 (87%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
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.
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Blood tests of how long blood takes to clot. The INR is the prothrombin time (PT) put on a common scale; about 1 is usual for someone not taking a blood thinner.
Criteria often make an exception for people on a blood thinner such as warfarin, whose INR is raised on purpose.
A score of how well the liver works in people with liver disease such as cirrhosis: class A is mild, B moderate and C severe.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
HbA1c
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hepatitis C tests
Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.
After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
INR, PT and aPTT (clotting tests)
Blood tests of how long blood takes to clot. The INR is the prothrombin time (PT) put on a common scale; about 1 is usual for someone not taking a blood thinner.
Criteria often make an exception for people on a blood thinner such as warfarin, whose INR is raised on purpose.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Child-Pugh class
A score of how well the liver works in people with liver disease such as cirrhosis: class A is mild, B moderate and C severe.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hemoglobin (Hb)
The protein in red blood cells that carries oxygen. A low level is anaemia, which can cause tiredness and breathlessness. Measured in g/dL or g/L (9 g/dL is 90 g/L).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients receive oral adjunctive rifampin therapy
Drug: Rifampin
Patients receive oral riboflavin
Drug: Riboflavin Placebo
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.
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.
Amputation-Free Survival
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.
Time frame: Assessed 2 years post intervention
Time to Amputation
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.
Time frame: Assessed 2 years post intervention
New course of antibacterial therapy for ipsilateral foot infection
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.
Time frame: Assessed 2 years post intervention
Quality of Life - SF-36
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.
Time frame: Assessed 12 months post intervention
Ambulatory Status
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
Time frame: Assessed 12 months post intervention
Incidence of Falls
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.
Time frame: Assessed 12 months post intervention
Incidence of adverse events related to direct toxicity of rifampin
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.
Time frame: Assessed 3 months post intervention
Incidence of adverse events from drug interactions
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.
Time frame: Assessed 3 months post intervention
Comparative dropout
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.
Time frame: Assessed 6 weeks post intervention
Remission of osteomyelitis
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.
Time frame: Assessed at 1 year post intervention
Complete epithelialization of the wound
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.
Time frame: Assessed 1 year post intervention
First occurrence of ipsilateral amputation related to index osteomyelitis
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.
Time frame: Assessed 2 years post intervention
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from Jan 2018 to primary completion in Nov 2025, 93 months.
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Studies of the drug tested here: Rifampin
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