Clinical trial NCT00001014: Trimetrexate Plus Leucovorin Calcium Rescue Versus Sulfamethoxazole-Trimethoprim in the Treatment of Pneumocystis Carinii Pneumonia (PCP) in Patients With AIDS
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pneumonia, Pneumocystis Carinii
HIV Infections
Keywords: Trimethoprim-Sulfamethoxazole Combination
Trimetrexate
AIDS-Related Opportunistic Infections
Pneumonia, Pneumocystis carinii
Infusions, Intravenous
Leucovorin
Drug Therapy, Combination
Administration, Oral
Acquired Immunodeficiency Syndrome
Antiprotozoal Agents
AIDS-Related Complex
Sulfamethoxazole-Trimethoprim
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 302
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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. 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.

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.

Eligibility criteria: 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: New Orleans
country: United States
facility: Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
state: Louisiana
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Buffalo
country: United States
facility: SUNY - Buffalo, Erie County Medical Ctr.
state: New York
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
Study officials:
name: Sattler FR
role: STUDY_CHAIR
References:
citation: 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. doi: 10.1093/infdis/170.1.165.