Antibiotic Therapy for Mycobacterium Avium Complex Infection

(MAC2v3 Trial)

Not currently recruiting at 25 trial locations

Overseen By Daniel Salerno, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Kevin Winthrop

Must be taking: Macrolides

Disqualifiers: Fibrocavitary disease, Cystic fibrosis, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests different antibiotic combinations to improve treatment for lung infections caused by Mycobacterium Avium Complex (MAC). The current treatment often leads to side effects like nausea and fatigue. The study aims to determine if using two drugs instead of three can reduce these side effects without compromising effectiveness. Participants will receive either a two-drug regimen or a three-drug regimen. Suitable candidates for this trial are those with a confirmed MAC lung infection who have not undergone extensive antibiotic treatments. As a Phase 2, Phase 3 trial, this study measures treatment effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes those who have taken certain antibiotics recently. If you have a significant drug interaction that can't be managed, you might not be eligible.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that taking azithromycin and ethambutol together is usually well-tolerated, though they can cause some side effects. Common side effects include nausea, diarrhea, and fatigue. Rare but serious side effects may affect vision, hearing, or blood.

Adding rifampin to this treatment can increase the risk of these side effects. Studies have found that while this three-drug combination can be effective, it may also cause more severe side effects, leading some individuals to stop treatment.

In summary, both the two-drug and three-drug treatments are used for Mycobacterium avium complex infections. The two-drug treatment might be easier to tolerate, but it may not be as effective. Consulting a healthcare provider is essential to determine the best option. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Mycobacterium Avium Complex (MAC) infection because they explore the effectiveness of different antibiotic combinations. The 2-drug regimen includes azithromycin and ethambutol, offering a potentially simpler treatment option with fewer drugs to manage, which could be beneficial for patients who struggle with more complex medication schedules. The 3-drug regimen adds rifampin to the mix, which may boost treatment effectiveness by attacking the bacteria with an additional mechanism, potentially leading to better outcomes. Both regimens are administered three times a week, which could improve patient adherence compared to daily treatments. These approaches aim to balance effectiveness with patient convenience, potentially improving the management of MAC infections.

What evidence suggests that this trial's treatments could be effective for Mycobacterium Avium Complex infection?

This trial will compare two treatment regimens for Mycobacterium avium complex infections. One arm involves a 2-drug regimen with azithromycin and ethambutol, which studies have shown to achieve moderate success over a year. The other arm includes a 3-drug regimen that adds rifampin to azithromycin and ethambutol. Some research suggests that adding rifampin might not significantly enhance treatment, while other studies recommend its inclusion. Patients have experienced symptom relief with these treatments, but side effects are common and can be serious. ^{2 4 6 7 8}

Who Is on the Research Team?

Kevin L Winthrop, MD, MPH

Principal Investigator

Oregon Health and Science University

Emily Henkle, PhD, MPH

Principal Investigator

Oregon Health and Science University

Are You a Good Fit for This Trial?

This trial is for adults over 18 who can consent and have a confirmed pulmonary Mycobacterium Avium Complex (MAC) infection. It's not for those with severe lung damage, planned lung surgery, extensive prior MAC treatment, cystic fibrosis, organ transplants, unmanageable drug interactions, or HIV.

Inclusion Criteria

I am over 18 years old.

I have a confirmed lung infection caused by MAC bacteria.

Ability to provide informed consent

Exclusion Criteria

I am allergic or cannot tolerate one of the medications in this study.

I have been diagnosed with HIV.

The study drug may interact with other medications you are taking in a way that could be harmful, and the doctor thinks it cannot be managed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a 2-drug or 3-drug regimen for pulmonary MAC disease, with treatment changes at the discretion of the treating physician and patient.

12 months

Routine visits for therapy changes and adverse event monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including culture conversion and tolerability assessments.

12 months post randomization

What Are the Treatments Tested in This Trial?

Interventions

• Azithromycin
• Ethambutol
• Rifampin

Trial Overview The study tests if two antibiotics (Azithromycin and Ethambutol) are as effective as three by adding Rifampin in treating pulmonary MAC disease. The goal is to see if fewer drugs reduce side effects without losing benefits during the usual 18-24 month treatment period.

How Is the Trial Designed?

Group I: 2-drug regimen Active Control 2 Interventions

This arm is a 3 time per week (TIW) treatment regimen that includes azithromycin 500 mg po + ethambutol 25 mg/kg Treatment changes are at the discretion of the treating physician and patient. Where possible, changes in dosing or frequency that allow the patient to continue taking the assigned drugs during the 12 months study period are preferred.

Group II: 3-drug regimen Active Control 3 Interventions

This arm is a 3 time per week (TIW) treatment regimen that includes azithromycin 500 mg po + ethambutol 25 mg/kg + rifampin 600 mg Treatment changes are at the discretion of the treating physician and patient. Where possible, changes in dosing or frequency that allow the patient to continue taking the assigned drugs during the 12 months study period are preferred.

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

Approved in European Union as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in United States as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in Canada as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Who Is Running the Clinical Trial?

Kevin Winthrop

Lead Sponsor

Trials

4

Recruited

760+

Kaiser Permanente Hawaii

Collaborator

Trials

1

Recruited

470+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

University of Iowa

Collaborator

Trials

486

Recruited

934,000+

University of North Carolina

Collaborator

Trials

174

Recruited

1,457,000+

Columbia University

Collaborator

Trials

1,529

Recruited

2,832,000+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

Temple University

Collaborator

Trials

321

Recruited

89,100+

University of California, San Diego

Collaborator

Trials

1,215

Recruited

1,593,000+

Loma Linda University

Collaborator

Trials

322

Recruited

267,000+

Published Research Related to This Trial

Azithromycin demonstrated effective in-vitro activity against Mycobacterium avium complex, with a minimum inhibitory concentration (MIC90) of 32 mg/L, suggesting its potential use in treating infections caused by this non-tuberculous mycobacterium.

The drug showed no effectiveness against Mycobacterium tuberculosis and Mycobacterium marinum, indicating that its therapeutic benefits may be limited to specific types of mycobacterial infections, particularly in patients with AIDS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative activity of azithromycin against clinical isolates of mycobacteria. Watt, B., Rayner, A., Harris, G.[2019]

In a trial involving 26 patients with pulmonary Mycobacterium avium complex (MAC) disease, high-dose rifabutin (600 mg/d) led to adverse events in 77% of participants, with 58% needing dosage adjustments or discontinuation due to side effects.

The most significant adverse effects included a substantial drop in white blood cell counts and gastrointestinal symptoms, prompting a recommendation to lower the rifabutin dose to 300 mg/d when used with macrolides for safer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with high-dose rifabutin in macrolide-containing regimens for the treatment of Mycobacterium avium complex lung disease. Griffith, DE., Brown, BA., Girard, WM., et al.[2019]

In a study of 119 patients with Mycobacterium avium complex lung disease, the two-drug regimen of clarithromycin and ethambutol resulted in a higher rate of sputum culture conversion (55.0%) compared to the three-drug regimen that included rifampicin (40.6%).

The incidence of adverse events leading to treatment discontinuation was higher in the three-drug group (37.2%) compared to the two-drug group (26.6%), suggesting that the simpler regimen may be safer and equally effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of clarithromycin and ethambutol for Mycobacterium avium complex pulmonary disease. A preliminary study. Miwa, S., Shirai, M., Toyoshima, M., et al.[2014]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/9827282/

Randomized, open-label trial of azithromycin plus ... Thirty-seven patients were evaluable for determination of quantitative bacteremia and clinical outcomes. Clearance of bacteremia was seen at the final visit in ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1876034125000607

Two-drug versus three-drug regimens for treating ... This meta-analysis compared the efficacy of 2-drug regimens with that of 3-drug regimens in bacteriological responses, acquired macrolide resistance (AMR), and ...

3. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT00002140?term=Ethambutol&draw=1&rank=7

A Randomized, Double-Blind, Comparative Study of ... To evaluate the efficacy and safety of two different doses of azithromycin in combination with ethambutol for the treatment of patients with Mycobacterium avium ...

4. academic.oup.com academic.oup.com/ofid/article/12/6/ofaf292/8129731

Treatment Outcomes of Mycobacterium avium Complex ... The 2-drug daily regimen of macrolides and ethambutol showed moderate efficacy in treating MAC-PD when used for >12 months.

5. amj.amegroups.org amj.amegroups.org/article/view/5726/html

Effective treatment with macrolide and ethambutol for ... Kim et al. described that maintenance therapy for MAC-PD with ethambutol was more strongly associated with the microbiological cure than that with rifampicin ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6304322/

Treatment of Mycobacterium avium Complex Pulmonary ... A regimen consisting of macrolides (clarithromycin or azithromycin) with rifampin and ethambutol has been recommended; this regimen significantly improves the ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03672630

Study Details | NCT03672630 | Comparison of Two- ... The study is a multicenter randomized pragmatic clinical trial to compare azithromycin + ethambutol (2-drug therapy) vs. azithromycin + ethambutol + rifampin (3 ...

8. clinicalinfo.hiv.gov clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/disseminated

Disseminated Mycobacterium avium Complex: Adult and ... One randomized clinical trial demonstrated that adding rifabutin to the combination of clarithromycin and ethambutol improved survival, and in ...