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

HIV Infections Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00001013
• Other study ID #: ACTG 029
• Secondary ID: 11005
• Status: Completed
• Phase: Phase 3
• Est. completion date: September 1991

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 than SMX/TMP in treating PCP and in preventing a recurrence of PCP. Preliminary studies suggest that aerosolized pentamidine (PEN) is likely to be effective in preventing a recurrence of PCP.

Patients entered in the study are randomly assigned to TMTX / LCV or to 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 PEN 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. Aerosolized PEN therapy is begun 7 - 10 days after completion of therapy for the acute episode. PEN is inhaled once weekly for 4 weeks, then every 2 weeks for 48 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 364
• Est. completion date: September 1991
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria

Concurrent Medication:

Allowed:

• Acetaminophen:

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

Prior Medication:

Allowed:

• Zidovudine (AZT) as long as such therapy is suspended prior to randomization and not reinstituted until therapy for the acute episode is completed and the patient's white blood cell count is acceptable.

• Other myelosuppressive therapies which may be handled in the same manner as AZT.

• 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 (A-a) DO2 < 30 torr on room air. Patient, parent, guardian, or person with power of attorney gives informed consent.

Exclusion Criteria

Co-existing Condition:

Patients will be excluded for the following reasons:

• 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.

Concurrent Medication:

Excluded:

• Other drugs for the treatment or prevention of AIDS or Pneumocystis carinii pneumonia (PCP).

• Disalcid.

• Aspirin.

• Acetaminophen q4h as a standing order for more than 48 hours.

Prior Medication:

Excluded within 14 days of study entry:

• Systemic steroids exceeding physiological replacement.

• Other investigational drugs including ganciclovir.

• Excluded within 6 weeks of study entry:

• Another antiprotozoal regimen for this episode for therapy of active Pneumocystis carinii pneumonia (PCP).

• Patients who are unable to have arterial blood gas analysis (ABG's) on room air.

• Patients for whom a liter of intravenous fluid (5 percent dextrose in water) per 24 hours, which is required to maintain blinding, would be medically inadvisable.

Related Conditions & MeSH terms

• HIV Infections
• Pneumonia
• Pneumonia, Pneumocystis
• Pneumonia, Pneumocystis Carinii

Intervention

Drug:
• Trimetrexate glucuronate

• Pentamidine isethionate

• Sulfamethoxazole-Trimethoprim

• Leucovorin calcium

Locations

Country	Name	City	State
United States	Bronx Municipal Hosp Ctr/Jacobi Med Ctr	Bronx	New York
United States	Jack Weiler Hosp / Bronx Municipal Hosp	Bronx	New York
United States	Montefiore Med Ctr / Bronx Municipal Hosp	Bronx	New York
United States	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York
United States	Northwestern Univ Med School	Chicago	Illinois
United States	Holmes Hosp / Univ of Cincinnati Med Ctr	Cincinnati	Ohio
United States	Univ Hosp of Cleveland / Case Western Reserve Univ	Cleveland	Ohio
United States	City Hosp Ctr at Elmhurst / Mount Sinai Hosp	Elmhurst	New York
United States	Milton S Hershey Med Ctr	Hershey	Pennsylvania
United States	Los Angeles County - USC Med Ctr	Los Angeles	California
United States	Univ of Miami School of Medicine	Miami	Florida
United States	Charity Hosp / Tulane Univ Med School	New Orleans	Louisiana
United States	Louisiana State Univ Med Ctr / Tulane Med School	New Orleans	Louisiana
United States	Tulane Univ School of Medicine	New Orleans	Louisiana
United States	Beth Israel Med Ctr / Peter Krueger Clinic	New York	New York
United States	Mount Sinai Med Ctr	New York	New York
United States	Thomas Jefferson Med College	Philadelphia	Pennsylvania
United States	Univ of Rochester Medical Center	Rochester	New York
United States	SUNY - Stony Brook	Stony Brook	New York
United States	SUNY / State Univ of New York	Syracuse	New York
United States	George Washington Univ Med Ctr	Washington	District of Columbia
United States	Julio Arroyo	West Columbia	South Carolina
United States	Univ of Massachusetts Med Ctr	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Sattler FR, Frame P, Davis R, Nichols L, Shelton B, Akil B, Baughman R, Hughlett C, Weiss W, Boylen CT, et al. Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031. J Infect Dis. 1994 Jul;170(1):165-72. — View Citation