Trimetrexate Plus Leucovorin Calcium Rescue Versus Sulfamethoxazole-Trimethoprim in the Treatment of Pneumocystis Carinii Pneumonia (PCP) in Patients With AIDS
Information source: National Institute of Allergy and Infectious Diseases (NIAID)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pneumonia, Pneumocystis Carinii; HIV Infections
Intervention: Trimetrexate glucuronate (Drug); Sulfamethoxazole-Trimethoprim (Drug); Leucovorin calcium (Drug)
Phase: Phase 3
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. 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.
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: Treatment, Parallel Assignment
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.
Minimum age: 12 Years.
Maximum age: N/A.
- 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
- 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
- Resting alveolar-arterial oxygen differences = or > 30 mm Hg on room air.
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.
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.
Locations and Contacts
San Francisco AIDS Clinic / San Francisco Gen Hosp, San Francisco, California 941102859, United States
Univ of Southern California / LA County USC Med Ctr, Los Angeles, California 900331079, United States
Los Angeles County - USC Med Ctr, Los Angeles, California 90033, United States
Harbor UCLA Med Ctr, Torrance, California 90502, United States
Northwestern Univ Med School, Chicago, Illinois 60611, United States
Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States
Charity Hosp / Tulane Univ Med School, New Orleans, Louisiana 70112, United States
Tulane Univ School of Medicine, New Orleans, Louisiana 70112, United States
SUNY - Stony Brook, Stony Brook, New York 117948153, United States
Mount Sinai Med Ctr, New York, New York 10029, United States
Jack Weiler Hosp / Bronx Municipal Hosp, Bronx, New York 10465, United States
Cornell Univ Med Ctr, New York, New York 10021, United States
Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx, New York 10461, 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
Beth Israel Med Ctr / Peter Krueger Clinic, New York, New York 10003, United States
City Hosp Ctr at Elmhurst / Mount Sinai Hosp, Elmhurst, New York 11373, United States
Univ of North Carolina, Chapel Hill, North Carolina 275997215, United States
Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, 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
Julio Arroyo, West Columbia, South Carolina 29169, United States
Click here for more information about Sulfamethoxazole-Trimethoprim
Click here for more information about Trimetrexate glucuronate
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: June 23, 2005