A Treatment Protocol for the Use of Trimetrexate With Leucovorin Rescue for AIDS Patients With Pneumocystis Carinii Pneumonia and Serious Intolerance to Approved Therapies

This study has been completed.
Sponsor:
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00001016
First received: November 2, 1999
Last updated: September 26, 2008
Last verified: July 1993
  Purpose

To determine the safety and effectiveness of an investigational drug trimetrexate (TMTX) with leucovorin rescue (LCV) in the treatment of Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, are HIV positive, or are at high risk for HIV infection, and who have demonstrated serious adverse effects from the conventional therapies for PCP.

The drugs usually used to treat PCP in AIDS patients (trimethoprim / sulfamethoxazole and pentamidine) have had to be discontinued in many patients because of severe adverse effects. Currently there are no proven alternatives to these drugs. TMTX was chosen for this trial because it has been found to be very active against the PCP organism in laboratory tests. In a preliminary trial, TMTX in combination with LCV has been effective against PCP with fewer and less severe adverse effects.


Condition Intervention Phase
Pneumonia, Pneumocystis Carinii
HIV Infections
Drug: Trimetrexate glucuronate
Drug: Leucovorin calcium
Phase 3

Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
Official Title: A Treatment Protocol for the Use of Trimetrexate With Leucovorin Rescue for AIDS Patients With Pneumocystis Carinii Pneumonia and Serious Intolerance to Approved Therapies

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Completion Date: August 2007
Detailed Description:

The drugs usually used to treat PCP in AIDS patients (trimethoprim / sulfamethoxazole and pentamidine) have had to be discontinued in many patients because of severe adverse effects. Currently there are no proven alternatives to these drugs. TMTX was chosen for this trial because it has been found to be very active against the PCP organism in laboratory tests. In a preliminary trial, TMTX in combination with LCV has been effective against PCP with fewer and less severe adverse effects.

AMENDED: 08/01/90. As of August 31, 1989, 437 patients were enrolled into uncontrolled studies of trimetrexate for PCP:214 in TX 301/ACTG 0=039 (trimetrexate for patients intolerant of approved therapies) and 223 in NS 401 (trimetrexate for patients refractory to approved therapies). The analysis of overall response rate, stringently defined as having received at least 14 days of trimetrexate and being alive at follow-up 1 month after the completion of therapy, reveals 84/159 intolerant patients and 48/160 refractory patients had responded, for rates of 53 percent and 30 percent, respectively. These response rates include all individuals who received at least one dose of trimetrexate. Of the 111 patients who were ventilator-dependent at study entry, 18 completed a course of therapy and were alive a month later, for a response rate of 16 percent. All other ventilated patients died. The most common severe (grades 3 and 4) toxicities were: transaminase elevation (greater than 5 x normal) in 94 patients, anemia (less than 7.9 g/dl) in 109, neutropenia (less than 750 cells/mm3) in 58, fever (greater than 40 degrees C) in 37, and thrombocytopenia (less than 50,000 platelets/mm3) in 27.

Toxicity required discontinuation of therapy in approximately 5 percent of all patients. Original design: Patients entered in the study are given TMTX once a day for 21 days and LCV 4 times a day (every 6 hours) for 24 days. Doses are determined by body size. Both drugs are given by intravenous infusion, but LCV may be given orally after the first 10 days. Doses are adjusted if side effects, such as low white blood cell counts, 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 administration of TMTX and LCV has been completed. After treatment with TMTX, the patient may be treated with other drugs to prevent the recurrence of PCP at the discretion of his/her physician.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Concurrent Medication:

Allowed:

  • Blood pressure medication.

Concurrent Treatment:

Allowed:

  • Blood products.
  • Ventilatory support.

Patients must have the following:

  • Diagnosis of Pneumocystis carinii pneumonia (PCP).
  • Be HIV positive by ELISA, HIV culture, or p24 antigenemia; or be a member of an identified risk group.
  • Intolerant to trimethoprim / sulfamethoxazole (TMP / SMX).
  • Intolerant to pentamidine.

Prior Medication:

Allowed:

  • Trimethoprim / sulfamethoxazole trials.
  • Pentamidine trials.
  • Myelosuppressive agents.
  • Nephrotoxic agents.
  • Zidovudine (AZT).

Exclusion Criteria

Co-existing Condition:

Patients who do not meet the inclusion criteria are excluded.

Concurrent Medication:

Excluded:

  • Myelosuppressive agents.
  • Nephrotoxic agents.
  • Other investigational drugs including high-dose steroids (exceeding physiologic replacement doses).

Patients who do not meet the inclusion criteria are excluded.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00001016

Locations
United States, New Jersey
Warner-Lambert Parke-Davis
Morris Plains, New Jersey, United States, 07950
Sponsors and Collaborators
Investigators
Study Chair: Feinberg J
  More Information

No publications provided

ClinicalTrials.gov Identifier: NCT00001016     History of Changes
Other Study ID Numbers: TX 301
Study First Received: November 2, 1999
Last Updated: September 26, 2008
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Trimetrexate
Pneumonia, Pneumocystis carinii
Quinazolines
Infusions, Intravenous
Injections, Intravenous
Leucovorin
Drug Evaluation
Drug Therapy, Combination
Administration, Oral
Acquired Immunodeficiency Syndrome
Antiprotozoal Agents
AIDS-Related Complex

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Pneumonia
Pneumonia, Pneumocystis
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Lung Diseases, Fungal
Mycoses
Pneumocystis Infections
Antiprotozoal Agents
Leucovorin
Levoleucovorin
Trimetrexate
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Vitamin B Complex
Vitamins
Micronutrients

ClinicalTrials.gov processed this record on August 21, 2014