Rifampin for Osteomyelitis in Diabetics

(VA INTREPID Trial)

Recruiting at 22 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: VA Office of Research and Development

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

Disqualifiers: Organ transplant, Cancer, HIV, others

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

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.

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 data supports the effectiveness of the drug Rifampin for treating osteomyelitis in diabetics?

Research shows that adding Rifampin to other antibiotic treatments can improve cure rates for osteomyelitis, with one study reporting a cure in 88.2% of diabetic patients with foot osteomyelitis. Additionally, small trials suggest that Rifampin can reduce the rate of amputations and mortality in diabetic foot osteomyelitis patients. ^{1 2 3 4 5}

Is Rifampin generally safe for treating infections?

Rifampin has been associated with some severe side effects, including blood reactions, skin reactions, kidney injuries, low potassium levels, and liver issues. These side effects were observed in a study of patients treated for bone and joint infections, with older age and obesity increasing the risk. ^{6 7 8 9 10}

How is the drug rifampin unique in treating osteomyelitis in diabetics?

Rifampin is unique in treating osteomyelitis in diabetics because it can be added to existing antibiotic regimens to significantly improve cure rates, as shown in small trials, and it has been associated with reduced amputation rates in diabetic foot osteomyelitis. ^{1 2 5 7 11}

Research Team

Mary T Bessesen, MD

Principal Investigator

Rocky Mountain Regional VA Medical Center, Aurora, CO

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Rifampin (Antibiotic)

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.

Participant Groups

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 Canada for the following indications:

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+

Findings from Research

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]

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 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]

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 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 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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Chronic staphylococcal osteomyelitis: treatment with regimens containing rifampin. [2019]

2. England 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). [2022]

3. England pubmed.ncbi.nlm.nih.gov

Rifampicin-ofloxacin oral regimen for the treatment of mild to moderate diabetic foot osteomyelitis. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Adjunctive Rifampin Therapy For Diabetic Foot Osteomyelitis in the Veterans Health Administration. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Adjunctive rifampin therapy for diabetic foot osteomyelitis: A protocol for systematic review and meta-analysis. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Oral rifampin plus azithromycin or clarithromycin to treat osteomyelitis in rabbits. [2019]

7. United States 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. [2021]

8. United States 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. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Antimicrobial-related severe adverse events during treatment of bone and joint infection due to methicillin-susceptible Staphylococcus aureus. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Controversy about the Role of Rifampin in Biofilm Infections: Is It Justified? [2021]

11. United States pubmed.ncbi.nlm.nih.gov

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