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

Condition(s) targeted: Pneumonia, Pneumocystis Carinii; HIV Infections

Intervention: Trimetrexate glucuronate (Drug); Pentamidine isethionate (Drug); Sulfamethoxazole-Trimethoprim (Drug); Leucovorin calcium (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Sattler FR, Study Chair

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.

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

Study design: Intervention Model: Parallel Assignment, Primary Purpose: 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 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.

Minimum age: 12 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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.

Los Angeles County - USC Med Ctr, Los Angeles, California 90033, United States

George Washington Univ Med Ctr, Washington, District of Columbia 20037, United States

Univ of Miami School of Medicine, Miami, Florida 331361013, United States

Northwestern Univ Med School, Chicago, Illinois 60611, United States

Charity Hosp / Tulane Univ Med School, New Orleans, Louisiana 70112, United States

Louisiana State Univ Med Ctr / Tulane Med School, New Orleans, Louisiana 70112, United States

Tulane Univ School of Medicine, New Orleans, Louisiana 70112, United States

Univ of Massachusetts Med Ctr, Worcester, Massachusetts 01655, United States

Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx, New York 10461, United States

Jack Weiler Hosp / Bronx Municipal Hosp, Bronx, New York 10465, United States

Montefiore Med Ctr / Bronx Municipal Hosp, Bronx, New York 10467, United States

SUNY / Erie County Med Ctr at Buffalo, Buffalo, New York 14215, United States

City Hosp Ctr at Elmhurst / Mount Sinai Hosp, Elmhurst, New York 11373, United States

Beth Israel Med Ctr / Peter Krueger Clinic, New York, New York 10003, United States

Mount Sinai Med Ctr, New York, New York 10029, United States

Univ of Rochester Medical Center, Rochester, New York 14642, United States

SUNY - Stony Brook, Stony Brook, New York 117948153, United States

SUNY / State Univ of New York, Syracuse, New York 13210, United States

Holmes Hosp / Univ of Cincinnati Med Ctr, Cincinnati, Ohio 452670405, United States

Univ Hosp of Cleveland / Case Western Reserve Univ, Cleveland, Ohio 44106, United States

Milton S Hershey Med Ctr, Hershey, Pennsylvania 170330850, United States

Thomas Jefferson Med College, Philadelphia, Pennsylvania 19107, United States

Julio Arroyo, West Columbia, South Carolina 29169, United States

Click here for more information about Pentamidine isethionate

Click here for more information about Sulfamethoxazole-Trimethoprim

Related publications:

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.

Last updated: March 15, 2012