Trimetrexate Plus Leucovorin Calcium Rescue Versus Sulfamethoxazole-Trimethoprim in the Treatment of Pneumocystis Carinii Pneumonia (PCP) in Patients With AIDS

October 28, 2021 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

A Randomized, Comparative, Double-Blind Trial of Trimetrexate (CI-898) With Leucovorin Calcium Rescue Versus Trimethoprim / Sulfamethoxazole for Moderately Severe Pneumocystis Carinii Pneumonia in Patients With AIDS

To compare the safety and effectiveness of an investigational drug therapy (trimetrexate plus leucovorin calcium) with that of conventional therapy (sulfamethoxazole-trimethoprim) in the treatment of moderately severe Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, are HIV positive, or are at high risk for HIV infection. New treatments are needed to reduce the mortality rate from PCP in AIDS patients and to reduce the high relapse rate found after conventional therapy. Trimetrexate (TMTX) was chosen for this trial because it was found to be much more potent than sulfamethoxazole/trimethoprim (SMX/TMP) against the PCP organism in laboratory tests. Also TMTX, in combination with leucovorin (LCV), did not cause severe toxicity in a preliminary trial. It is believed that TMTX will be more effective in treating PCP and in preventing a recurrence of PCP.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

New treatments are needed to reduce the mortality rate from PCP in AIDS patients and to reduce the high relapse rate found after conventional therapy. Trimetrexate (TMTX) was chosen for this trial because it was found to be much more potent than sulfamethoxazole/trimethoprim (SMX/TMP) against the PCP organism in laboratory tests. Also TMTX, in combination with leucovorin (LCV), did not cause severe toxicity in a preliminary trial. It is believed that TMTX will be more effective in treating PCP and in preventing a recurrence of PCP.

Patients entered in the study are randomly assigned to trimetrexate / leucovorin (TMTX / LCV) or to sulfamethoxazole/trimethoprim (SMX/TMP) for a 21-day trial. For the first 10 days, the trial is double-blind (neither patient nor physician knows which drugs the patient is receiving), and drugs are given by intravenous infusion. TMTX is given once every 24 hours and LCV every 6 hours; SMX/TMP is given every 6 hours. Doses are determined by body size. After the first 10 days, LCV and SMX/TMP may be given orally. Doses are adjusted or treatment is changed to intravenous pentamidine if side effects are too severe. During the 21-day trial, zidovudine (AZT) may not be used because of possible increased bone marrow toxicity. AZT may be resumed as soon as the patient's white cell count is acceptable. Drug therapy aimed at preventing recurrence of PCP is not allowed for a minimum of 4 weeks after the completion of study therapy.

Study Type

Interventional

Enrollment

302

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94110
        • Ucsf Aids Crs
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Rush Univ. Med. Ctr. ACTG CRS
    • Louisiana
      • New Orleans, Louisiana, United States, 70112
        • Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
    • Missouri
      • Saint Louis, Missouri, United States
        • Washington U CRS
    • New York
      • Buffalo, New York, United States, 14215
        • SUNY - Buffalo, Erie County Medical Ctr.
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Case CRS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria

Concurrent Medication:

Allowed:

  • Acetaminophen 650 mg prescribed as necessary for temperature > 38.7 degrees C. Acetaminophen q4h should not be prescribed as a standing order for more than 48 hours.

Prior Medication:

Allowed:

  • Zidovudine as long as such therapy is suspended prior to randomization and not reinstituted until therapy for the acute episode is completed.
  • Prophylaxis for Pneumocystis carinii pneumonia (PCP).
  • Unequivocal diagnosis of Pneumocystis carinii pneumonia (PCP) by morphologic confirmation of three or more typical P. carinii organisms in sputum, bronchoalveolar lavage fluid, or lung tissue obtained by transbronchial or open-lung biopsy within 3 days before or after randomization. If morphologic confirmation is not possible prior to therapy, patients may be randomized if the investigator believes there is a high suspicion of PCP based on clinical presentation. If morphologic diagnosis cannot be established within 6 days of randomization, the patient will be withdrawn from study therapy.
  • Resting alveolar-arterial oxygen differences = or > 30 mm Hg on room air.

Exclusion Criteria

Patients with the following are excluded:

  • Inability to have alveolar blood gas analysis on room air.
  • Medically unable to receive a liter of intravenous fluid (5 percent dextrose in water) per 24 hours. This procedure is required in order to maintain blinding.

Prior Medication:

Excluded within 14 days of study entry:

  • Systemic steroids exceeding physiological replacement.
  • Other investigational drugs.
  • Excluded within 6 weeks of study entry:
  • Antiprotozoal regimen for this episode consisting of pentamidine, eflornithine, DFMO, or dapsone, for therapy of active Pneumocystis carinii pneumonia (PCP)
  • History of Type I hypersensitivity (i.e., urticaria, angioedema, or anaphylaxis), exfoliative dermatitis, or other life-threatening reaction secondary to antibiotics containing sulfa, trimethoprim, or trimetrexate.
  • History of life-threatening pentamidine toxicity.
  • Requirement for treatment with agents that are known to be myelosuppressive or nephrotoxic during the period of acute Pneumocystis carinii pneumonia (PCP) therapy.
  • Other drugs for the treatment or prevention of AIDS or Pneumocystis carinii pneumonia (PCP); disulcid; aspirin; acetaminophen q4h for more than 48 hours.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Interventional Model: Parallel Assignment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

  • Study Chair: Sattler FR

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Completion (Actual)

September 1, 1991

Study Registration Dates

First Submitted

November 2, 1999

First Submitted That Met QC Criteria

August 30, 2001

First Posted (Estimate)

August 31, 2001

Study Record Updates

Last Update Posted (Actual)

November 4, 2021

Last Update Submitted That Met QC Criteria

October 28, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ACTG 031
  • 11007 (DAIDS ES Registry Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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