Antibiotic Therapy for Mycobacterium Avium Complex Infection

(MAC2v3 Trial)

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

474 Participants Needed

Trial Summary

What is the purpose of this trial?

NTM therapy consists of a multi-drug macrolide based regimen for 18-24 months. Treated patients frequently experience debilitating side effects, and many patients delay the start of antibiotic treatment due to these risks. Common side effects include nausea, diarrhea, and fatigue, and rare but serious toxicities include ocular toxicity, hearing loss, and hematologic toxicity. To date, most of the evidence underlying the current treatment recommendations has come from observational studies in which either a macrolide has been combined with rifampin and ethambutol, or in some cases combined with ethambutol alone. The proposed study will answer whether a third drug is necessary or whether taking two drugs can increase tolerability without a substantial loss of efficacy.

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.

What data supports the effectiveness of the drug Azithromycin for Mycobacterium Avium Complex infection?

Azithromycin has shown effectiveness in reducing Mycobacterium avium complex bacteria in patients with AIDS, with a significant decrease in bacterial levels and improvement in symptoms like fever and night sweats in about 75% of patients treated for at least 20 days. ^{1 2 3 4 5}

Is the antibiotic therapy for Mycobacterium Avium Complex infection generally safe for humans?

The treatment for Mycobacterium Avium Complex infection, which includes drugs like azithromycin, ethambutol, and rifampin, can have significant side effects. Common issues include gastrointestinal problems, changes in white blood cell counts, and liver enzyme abnormalities. Some patients may find the side effects difficult to tolerate, and adjustments in medication may be necessary. ^{1 4 6 7 8}

How is the drug Azithromycin, Ethambutol, Rifampin unique for treating Mycobacterium Avium Complex infection?

This drug combination is unique because Azithromycin, a macrolide antibiotic, can reach high concentrations inside cells, making it effective against Mycobacterium avium complex, especially in patients with AIDS, where traditional tuberculosis drugs are less effective. ^{1 5 9 10 11}

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

The potential role of drug transporters and amikacin modifying enzymes in M. avium. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Azithromycin for treatment of Mycobacterium avium-intracellulare complex infection in patients with AIDS. [2019]

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

Mycobacterium avium complex develop resistance to synergistically active drug combinations during infection. [2013]

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

Efficacy of clarithromycin and ethambutol for Mycobacterium avium complex pulmonary disease. A preliminary study. [2014]

5. England pubmed.ncbi.nlm.nih.gov

Comparative activity of azithromycin against clinical isolates of mycobacteria. [2019]

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

In vitro susceptibility of Mycobacterium avium complex to antibacterial agents. [2019]

7. United States 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. [2019]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Risk-benefit assessment of therapies for Mycobacterium avium complex infections. [2018]

9. France pubmed.ncbi.nlm.nih.gov

[Azithromycin and Mycobacterium avium infection]. [2020]

10. England pubmed.ncbi.nlm.nih.gov

In vitro activity of aminoglycosides, clofazimine, d-cycloserine and dapsone against 83 Mycobacterium avium complex clinical isolates. [2022]

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

Medical management of pulmonary disease caused by Mycobacterium avium complex. [2019]