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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00001013

Collaborator

(none)

364

Enrollment

Locations

15.8

Patients Per Site

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia, Pneumocystis Carinii HIV Infections	Drug: Trimetrexate glucuronate Drug: Pentamidine isethionate Drug: Sulfamethoxazole-Trimethoprim Drug: Leucovorin calcium	Phase 3

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.

Study Design

Study Type:

Interventional

Intervention Model:

Parallel Assignment

Primary Purpose:

Treatment

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

Actual Study Completion Date :

Sep 1, 1991

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Los Angeles County - USC Med Ctr	Los Angeles	California	United States	90033
2	George Washington Univ Med Ctr	Washington	District of Columbia	United States	20037
3	Univ of Miami School of Medicine	Miami	Florida	United States	331361013
4	Northwestern Univ Med School	Chicago	Illinois	United States	60611
5	Charity Hosp / Tulane Univ Med School	New Orleans	Louisiana	United States	70112
6	Louisiana State Univ Med Ctr / Tulane Med School	New Orleans	Louisiana	United States	70112
7	Tulane Univ School of Medicine	New Orleans	Louisiana	United States	70112
8	Univ of Massachusetts Med Ctr	Worcester	Massachusetts	United States	01655
9	Bronx Municipal Hosp Ctr/Jacobi Med Ctr	Bronx	New York	United States	10461
10	Jack Weiler Hosp / Bronx Municipal Hosp	Bronx	New York	United States	10465
11	Montefiore Med Ctr / Bronx Municipal Hosp	Bronx	New York	United States	10467
12	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York	United States	14215
13	City Hosp Ctr at Elmhurst / Mount Sinai Hosp	Elmhurst	New York	United States	11373
14	Beth Israel Med Ctr / Peter Krueger Clinic	New York	New York	United States	10003
15	Mount Sinai Med Ctr	New York	New York	United States	10029
16	Univ of Rochester Medical Center	Rochester	New York	United States	14642
17	SUNY - Stony Brook	Stony Brook	New York	United States	117948153
18	SUNY / State Univ of New York	Syracuse	New York	United States	13210
19	Holmes Hosp / Univ of Cincinnati Med Ctr	Cincinnati	Ohio	United States	452670405
20	Univ Hosp of Cleveland / Case Western Reserve Univ	Cleveland	Ohio	United States	44106
21	Milton S Hershey Med Ctr	Hershey	Pennsylvania	United States	170330850
22	Thomas Jefferson Med College	Philadelphia	Pennsylvania	United States	19107
23	Julio Arroyo	West Columbia	South Carolina	United States	29169