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