Low-Dose Trimethoprim-Sulfamethoxazole for Pneumocystis Pneumonia

(LOW-TMP Trial)

Overseen By Kristen Moran

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre

Must not be taking: Sulfa drugs

Disqualifiers: Hepatic impairment, G6PD deficiency, pregnancy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days

300 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Trimethoprim-Sulfamethoxazole for treating Pneumocystis pneumonia?

Research shows that low-dose Trimethoprim-Sulfamethoxazole is effective for treating Pneumocystis pneumonia in patients without HIV, with similar survival rates to conventional doses but fewer side effects. ^{1 2 3 4 5}

Is trimethoprim-sulfamethoxazole generally safe for humans?

Trimethoprim-sulfamethoxazole can cause side effects, especially in people with weakened immune systems, such as those with HIV/AIDS. Common side effects include changes in blood cell counts, liver function issues, skin reactions, and stomach problems. Despite these side effects, it is often used because alternative treatments may not be better. ^{2 4 6 7 8}

How is low-dose trimethoprim-sulfamethoxazole different from other drugs for Pneumocystis pneumonia?

Low-dose trimethoprim-sulfamethoxazole is unique because it may be effective for treating Pneumocystis pneumonia in patients who are not infected with HIV, with fewer side effects compared to the standard dose. This makes it a potentially safer option for certain patients who are immunocompromised but not HIV-positive. ^{1 2 3 9 10}

What is the purpose of this trial?

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection of immunocompromised hosts which causes in significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15-20 mg/kg/day of TMP, is associated with serious adverse events, including hypersensitivity reactions, drug-induced liver injury, cytopenia, and renal failure occurring among 20-60% of patients. The frequency of adverse events increases in a dose dependent manner and commonly limits the use of TMP-SMX. Reduced treatment doses of TMP-SMX for PJP reduced ADEs without mortality differences in a recent meta-analysis of observational studies. We therefore propose a Phase III randomized, placebo-controlled trial to directly compare the efficacy and safety of low dose (10 mg/kg/day of TMP) compared to the standard-of-care (15 mg/kg/day) among patients with PJP for the primary outcome of death, new mechanical ventilation, and change of treatment.

Research Team

Todd C Lee, MD MPH

Principal Investigator

Research Institute of the McGill University Health Centre

Emily G McDonald, MD MSc

Principal Investigator

Research Institute of the McGill University Health Centre

Zahra N Sohani, MD PhD

Principal Investigator

Research Institute of the McGill University Health Centre

Eligibility Criteria

This trial is for immunocompromised individuals, including those with HIV, organ transplants, cancers, or on long-term steroids. They must have a proven or probable PJP diagnosis and can be in the hospital or just visiting. People who've had bad reactions to TMP-SMX/sulfa drugs, certain liver issues, started other PJP treatments over 72 hours ago, pregnant/breastfeeding women, or unable to consent are excluded.

Inclusion Criteria

I have recently visited a hospital for my condition.

I have a weakened immune system due to a condition or treatment.

You have been diagnosed with a lung infection called PJP using specific medical criteria.

Exclusion Criteria

You had a bad reaction to TMP-SMX or any sulfa drugs before.

I have been diagnosed with porphyria.

I have received treatment for PJP for more than 72 hours.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either reduced-dose (10 mg/kg/day) or standard-dose (15 mg/kg/day) TMP-SMX for the treatment of Pneumocystis jirovecii pneumonia

21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and quality of life

90 days

Treatment Details

Interventions

• Trimethoprim-Sulfamethoxazole

Trial Overview The study tests if a lower dose of Trimethoprim-Sulfamethoxazole (10 mg/kg/day) is as effective and safer than the standard dose (15 mg/kg/day) for treating Pneumocystis jirovecii pneumonia. It's a Phase III trial where patients are randomly assigned to receive either the low dose or standard treatment.

Participant Groups

Group I: Reduced dose TMP-SMX Experimental Treatment 1 Intervention

Trimethoprim-Sulfamethoxazole at a total dose of 10mg/kg/day. Oral or intravenous drug will be administered at discretion of treating team. This will be given as a dose of 10mg/kg/day open label with additional placebo tablets or intravenous placebo solution given to simulate 15mg/kg/day. All doses will be adjusted for obesity and renal function.

Group II: Standard dose TMP-SMX Active Control 1 Intervention

Trimethoprim-Sulfamethoxazole at a total dose of 15mg/kg/day. Oral or intravenous drug will be administered at discretion of treating team. This will be given as 10mg/kg/day open label plus an extra masked 5mg/kg/day of tablets or intravenous solution. All doses will be adjusted for obesity and renal function.

Who Is Running the Clinical Trial?

McGill University Health Centre/Research Institute of the McGill University Health Centre

Lead Sponsor

Trials

476

Recruited

170,000+

References

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

Failure of trimethoprim-sulfamethoxazole in the therapy of recurrent Pneumocystis carinii pneumonia. [2015]

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

Management of adverse reactions to trimethoprim-sulfamethoxazole in human immunodeficiency virus-infected patients. [2015]

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

Low-dose trimethoprim-sulfamethoxazole treatment for pneumocystis pneumonia in non-human immunodeficiency virus-infected immunocompromised patients: A single-center retrospective observational cohort study. [2019]

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

Efficacy and safety of trimethoprim-sulfamethoxazole for the prevention of pneumocystis pneumonia in human immunodeficiency virus-negative immunodeficient patients: A systematic review and meta-analysis. [2021]

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

A Four-Center Retrospective Study of the Efficacy and Toxicity of Low-Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Pneumonia in Patients without HIV Infection. [2018]

6. Spain pubmed.ncbi.nlm.nih.gov

[Adverse reactions to trimethoprim-sulfamethoxazole in AIDS patients]. [2015]

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

Efficacy and toxicity of two doses of trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus. Dutch AIDS Treatment Group. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

[Side effects of trimethoprim-sulfamethoxazole in patients with AIDS]. [2015]

9. England pubmed.ncbi.nlm.nih.gov

Risk factors associated with increased discontinuation rate of trimethoprim-sulfamethoxazole used as a primary prophylaxis for Pneumocystis pneumonia: A retrospective cohort study. [2021]

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

Quantification of co-trimoxazole in serum and plasma using MS/MS. [2015]