Rifampin for Osteomyelitis in Diabetics

(VA INTREPID Trial)

Not currently recruiting at 32 trial locations

Overseen By Paul A Monach, MD PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: VA Office of Research and Development

Must not be taking: Immunosuppressants, Antiretrovirals, Antivirals, others

Disqualifiers: Organ transplant, Cancer, HIV, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding rifampin, an antibiotic, to usual treatments can better address osteomyelitis (a bone infection) in the feet of people with diabetes. Many diabetics risk amputation because current antibiotics often fall short. The study aims to determine if rifampin can reduce this risk by improving treatment outcomes. People with diabetes who have a diagnosed foot bone infection and have completed any necessary cleaning of the infection site may qualify for this trial. As a Phase 4 trial, this research seeks to understand how the already FDA-approved and effective treatment can benefit more patients.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but if you are taking drugs that interact with rifampin, you may need to stop, substitute, or adjust the dose. It's best to discuss your specific medications with the trial team.

What is the safety track record for rifampin?

Research shows that rifampin is generally safe for treating infections. One study found that patients with diabetic foot infections who took rifampin had lower rates of death and amputation compared to those who did not. This suggests it might be a safer choice than some other treatments. Other studies have found that adding rifampin to standard antibiotics can improve recovery in bone infections for both diabetics and non-diabetics.

Although data specifically for diabetic foot infections is limited, existing research is promising. Rifampin has been successfully used to treat other bone infections without major safety issues. Overall, the treatment is well-tolerated, and serious side effects are rare. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Rifampin is unique because it offers a new approach to treating osteomyelitis in diabetics by potentially enhancing the effectiveness of existing antibiotic therapies. Unlike traditional treatments that mainly focus on a range of antibiotics like vancomycin or cefazolin, rifampin works by inhibiting bacterial RNA synthesis, which can help in tackling persistent infections that are hard to treat. Researchers are excited about rifampin because it might reduce the duration and severity of infections in diabetic patients, offering a more efficient and potentially faster recovery option.

What evidence suggests that rifampin might be an effective treatment for osteomyelitis in diabetics?

Research has shown that rifampin might help treat osteomyelitis, a bone infection. In some studies, patients who took rifampin had lower chances of dying or needing an amputation, resulting in fewer people requiring part of their foot or leg to be removed. This trial will evaluate rifampin as an active treatment option for diabetic patients with osteomyelitis. Other studies have found that rifampin improved recovery in bone infections not related to diabetes, suggesting it could also be a good option for people with diabetes who have foot infections. However, more research is needed to confirm its effectiveness specifically for diabetic patients. ^{1 3 4 5 6}

Who Is on the Research Team?

Mary T Bessesen, MD

Principal Investigator

Rocky Mountain Regional VA Medical Center, Aurora, CO

Are You a Good Fit for This Trial?

Adults aged 18-89 with diabetes and foot osteomyelitis, who've completed debridement and selected a backbone antimicrobial therapy. Excluded are those unable to take oral meds, allergic to rifampin, at medical risk due to drug interactions, on immunosuppressants or certain cancer therapies, pregnant women, unlikely to complete the trial due to health/behavioral issues, with specific low blood counts or liver function abnormalities.

Inclusion Criteria

I have been diagnosed with a bone infection in my foot due to diabetes within the last 90 days.

I have diabetes as shown by my medication, recent HgA1c levels, or past diagnoses.

All my scheduled tissue removal surgeries are done.

Exclusion Criteria

I am currently on immunosuppressants for an organ transplant or receiving cancer treatment.

My liver tests are significantly abnormal, or I have severe liver disease.

I cannot take medicine by mouth.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a six-week course of adjunctive rifampin or placebo added to backbone antibacterial therapy

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including amputation-free survival and quality of life

2 years

Regular visits and phone calls

Long-term follow-up

Participants are followed for additional outcomes such as remission of osteomyelitis and incidence of adverse events

1.8 years

What Are the Treatments Tested in This Trial?

Interventions

• Rifampin

Trial Overview The study is testing whether adding rifampin to standard antibiotics can reduce the need for amputations in diabetic patients with foot osteomyelitis. Participants will either receive rifampin or a placebo alongside their regular antibiotic treatment.

How Is the Trial Designed?

Group I: Active drug Active Control 1 Intervention

Patients receive oral adjunctive rifampin therapy

Group II: Placebo Placebo Group 1 Intervention

Patients receive oral riboflavin

Rifampin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Rifampin for:

• Tuberculosis
• Meningitis
• Osteomyelitis
• Brucellosis
• Legionnaires' disease

Approved in European Union as Rifampicin for:

• Tuberculosis
• Meningitis
• Osteomyelitis
• Brucellosis
• Legionnaires' disease

Approved in Canada as Rifampin for:

• Tuberculosis
• Meningitis
• Osteomyelitis
• Brucellosis
• Legionnaires' disease

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

Azithromycin alone was ineffective in treating staphylococcal osteomyelitis in rats, despite achieving very high concentrations in bone, as it did not significantly reduce bacterial levels compared to controls.

Combining azithromycin with rifampin showed promising results, significantly reducing bacterial counts and achieving sterilization in 80% of cases, suggesting that azithromycin could be beneficial as a partner drug in combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relationship between antibiotic concentration in bone and efficacy of treatment of staphylococcal osteomyelitis in rats: azithromycin compared with clindamycin and rifampin. O'Reilly, T., Kunz, S., Sande, E., et al.[2021]

This study is investigating whether adding rifampin to standard antibiotic treatment can improve amputation-free survival in patients with diabetic foot osteomyelitis (DFO), involving 880 participants followed for an average of 1.8 years.

The primary goal is to determine if rifampin can significantly lower the risk of amputation compared to a placebo, which could lead to better treatment practices and reduced complications for patients with diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter randomized placebo controlled trial of rifampin to reduce pedal amputations for osteomyelitis in veterans with diabetes (VA INTREPID). Bessesen, MT., Doros, G., Henrie, AM., et al.[2022]

In a review of 28 patients with chronic staphylococcal osteomyelitis, 70% of those treated with regimens including rifampin showed an apparent cure of their infection, indicating its potential efficacy when used in combination therapy.

Staphylococcus aureus was successfully eradicated from the sinus drainage in nearly all patients, suggesting that rifampin can effectively target this bacteria; however, further studies with more patients and longer follow-up are needed to fully assess its role in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic staphylococcal osteomyelitis: treatment with regimens containing rifampin. Norden, CW., Fierer, J., Bryant, RE.[2019]

In a rabbit model of Staphylococcus aureus osteomyelitis, combination therapy with oral rifampin and either azithromycin or clarithromycin significantly reduced bacterial infection rates compared to untreated controls, with infection rates of 13.3% and 20%, respectively.

The combination of rifampin and nafcillin resulted in complete sterilization of the infection, indicating that this regimen may be highly effective for treating severe osteomyelitis caused by Staphylococcus aureus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral rifampin plus azithromycin or clarithromycin to treat osteomyelitis in rabbits. Shirtliff, ME., Mader, JT., Calhoun, J.[2019]

In a study of 6174 patients with diabetic foot osteomyelitis (DFO), those treated with rifampin showed a lower rate of death or amputation (26.9%) compared to those not treated with rifampin (37.2%), indicating that rifampin may improve clinical outcomes.

The study suggests that adding rifampin to standard antibiotic regimens for DFO could be beneficial, as the association remained significant even after adjusting for other health factors and comorbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive Rifampin Therapy For Diabetic Foot Osteomyelitis in the Veterans Health Administration. Wilson, BM., Bessesen, MT., Doros, G., et al.[2022]

This meta-analysis aims to evaluate the efficacy and safety of rifampicin as an adjuvant treatment for diabetic foot osteomyelitis (DFO), a condition that significantly increases the risk of amputation and mortality in diabetic patients.

By systematically reviewing various studies, the research seeks to provide high-quality evidence that could support the clinical use of rifampicin, potentially reducing amputation rates and improving patient outcomes in DFO treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjunctive rifampin therapy for diabetic foot osteomyelitis: A protocol for systematic review and meta-analysis. Zhang, Y., Wang, S., Liu, M., et al.[2023]

In a study involving rabbits with chronic osteomyelitis caused by Staphylococcus aureus, rifampin alone was only moderately effective, achieving a bone sterilization rate of 5%-55% over 28 days, while combinations with other antibiotics significantly improved efficacy, reaching sterilization rates of 75%-100%.

The most effective combination was rifampin with sisomicin and cephalothin, which completely sterilized the bones of all treated rabbits in just 14 days, suggesting that this combination could be a promising treatment for osteomyelitis in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experimental chronic staphylococcal osteomyelitis in rabbits: treatment with rifampin alone and in combination with other antimicrobial agents. Norden, CW.[2019]

In a rat model of staphylococcal periprosthetic joint infection, rifabutin and rifapentine, when combined with vancomycin, were found to be as effective as rifampin with vancomycin in reducing MRSA levels in infected bones.

Both rifabutin and rifapentine showed significantly lower bacterial counts in bone and on K-wires compared to no treatment or vancomycin alone, indicating their potential as alternative treatments for patients who cannot tolerate rifampin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Use of Rifabutin and Rifapentine to Treat Methicillin-Resistant Staphylococcus aureus in a Rat Model of Foreign Body Osteomyelitis. Karau, MJ., Schmidt-Malan, SM., Albano, M., et al.[2021]

In a study of 200 patients with methicillin-susceptible Staphylococcus aureus (MSSA) bone and joint infections, 15% experienced severe adverse events (SAE) related to prolonged antimicrobial therapy, highlighting the need for careful monitoring during treatment.

Age was identified as a significant independent risk factor for SAE, with older patients being more susceptible, while higher daily doses of antistaphylococcal penicillins and obesity also increased the risk, emphasizing the importance of tailored dosing and management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antimicrobial-related severe adverse events during treatment of bone and joint infection due to methicillin-susceptible Staphylococcus aureus. Valour, F., Karsenty, J., Bouaziz, A., et al.[2021]

In a study involving 17 diabetic patients with osteomyelitic foot lesions, a combination treatment of rifampicin and ofloxacin resulted in an 88.2% cure rate after 6 months, indicating high efficacy for this antibiotic regimen.

The treatment was well-tolerated, with no serious drug-related side effects reported, suggesting it is a safe option for managing infections in diabetic patients with foot lesions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rifampicin-ofloxacin oral regimen for the treatment of mild to moderate diabetic foot osteomyelitis. Senneville, E., Yazdanpanah, Y., Cazaubiel, M., et al.[2019]

Rifampin is highly effective against staphylococcal infections associated with implants, but its use in non-implant infections is not recommended based on current data.

A recent randomized controlled trial found no benefit of rifampin for treating acute staphylococcal periprosthetic joint infections with retained prostheses, raising concerns about its efficacy in certain clinical scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controversy about the Role of Rifampin in Biofilm Infections: Is It Justified? Renz, N., Trampuz, A., Zimmerli, W.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6902814/

Adjunctive Rifampin Therapy For Diabetic Foot ... In this cohort study, patients administered rifampin experienced lower rates of death and amputation than patients not treated with rifampin, ...

2. bmcinfectdis.biomedcentral.com bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-4751-3

A multicenter randomized placebo controlled trial of rifampin ... Adjunctive rifampin therapy has improved outcomes in several studies of osteomyelitis outside the setting of the diabetic foot [13, 14]. There ...

3. journals.lww.com journals.lww.com/md-journal/fulltext/2020/05290/adjunctive_rifampin_therapy_for_diabetic_foot.67.aspx

Adjunctive rifampin therapy for diabetic foot osteomyelitis Adjunctive rifampin therapy has improved outcomes in several studies of osteomyelitis outside the setting of the diabetic foot.

4. jwatch.org jwatch.org/fw116073/2019/11/25/rifampin-tied-better-outcomes-diabetic-foot-osteomyelitis

Rifampin Tied to Better Outcomes in Diabetic Foot ... Rifampin might be a more effective treatment for diabetic foot osteomyelitis than other antibiotics, suggests an observational study in JAMA ...

5. academic.oup.com academic.oup.com/ofid/article/11/11/ofae582/7818262

Should Rifabutin Be Included in Clinical Trials for Adjunctive ... Rifampin may improve diabetic foot osteomyelitis outcomes, but its extensive drug–drug interactions could hamper its use.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6950878/

A multicenter randomized placebo controlled trial of rifampin ... There are limited comparative data available on the impact of rifampin therapy of osteomyelitis in the setting of the diabetic foot. Effect ...