A Study of Trimetrexate With Leucovorin Rescue for AIDS Patients Who Are Refractory to Standard Therapies for Pneumocystis Carinii Pneumonia

This study has been completed.
Sponsor:
Information provided by:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00000724
First received: November 2, 1999
Last updated: December 18, 2012
Last verified: December 2012
  Purpose

To study the safety and effectiveness of trimetrexate (TMTX) plus leucovorin calcium rescue (LCV) in the treatment of Pneumocystis carinii pneumonia (PCP) in patients who have AIDS, patients who are HIV positive, or those for whom laboratory confirmation of HIV infection has not yet been established if they are at high risk for HIV infection, and who have not responded to standard treatments or who have demonstrated severe or life-threatening intolerance to both conventional therapies for PCP.

The drugs trimethoprim / sulfamethoxazole (TMP / SMX) and pentamidine, usually used to treat PCP in AIDS patients, have proven ineffective in many patients and have had to be discontinued in many other patients because of severe side effects. TMTX was chosen for this trial because it was found to be very active against the PCP organism in laboratory tests and, in a preliminary trial in combination with LCV, there was a high response rate without severe toxicity.


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 Study of Trimetrexate With Leucovorin Rescue for AIDS Patients Who Are Refractory to Standard Therapies for Pneumocystis Carinii Pneumonia

Resource links provided by NLM:


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

Study Completion Date: July 2004
Detailed Description:

The drugs trimethoprim / sulfamethoxazole (TMP / SMX) and pentamidine, usually used to treat PCP in AIDS patients, have proven ineffective in many patients and have had to be discontinued in many other patients because of severe side effects. TMTX was chosen for this trial because it was found to be very active against the PCP organism in laboratory tests and, in a preliminary trial in combination with LCV, there was a high response rate without severe toxicity.

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 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 (> 5 x normal) in 94 patients, anemia (< 7.9 g/dl) in 109, neutropenia (< 750 cells/mm3) in 58, fever (> 40 C) in 37, and thrombocytopenia (< 50000 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 count, 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:

  • Antihypertensive agents.

Concurrent Treatment:

Allowed:

  • Blood products.
  • Ventilatory support.

Prior Medication:

Required:

  • At least 7 days trimethoprim / sulfamethoxazole or parenteral pentamidine.
  • Allowed:
  • Myelosuppressive or nephrotoxic agents including zidovudine, but must be discontinued during trial.

No improvement in ventilatory status, defined as no change or a decrease in arterial or alveolar difference ((A-a) DO2) in the 72 hours prior to entry. (A-a) DO2 should be determined on room air, or receiving an FiO2 of 100 percent for 10 minutes via a tightly fitting non-rebreathing mask, or at an FiO2 of 100 percent for 10 minutes if the patient is being ventilated. Intolerance to TMP / SMX is defined as one or more of the following:

  • Platelets < 50000 platelets/mm3 or absolute neutrophil count (polys + bands) = or < 500 cells/mm3 on at least two occasions = or > 12 hours apart.
  • Blistering rash, mucosal involvement, generalized maculopapular eruption or intolerable pruritus.
  • Transaminase > 5 x ULN or = or > 300 IU if baseline abnormal.
  • Daily temperature = or > 103 degrees F beginning after the 5th day of treatment and persisting for at least 3 days and not responsive to antipyretic therapy, with no other discernible cause.
  • Any other severe or life-threatening adverse reaction to TMP / SMX that, in the investigator's opinion, makes continued or recurrent treatment with TMP / SMX inadvisable (approved on a case-by-case basis by the NIAID clinical monitor).
  • Intolerance to pentamidine is defined as one or more of the following:
  • Platelets < 50000 platelets/mm3 or absolute neutrophil count (polys + bands) < 550 cells/mm3 on at least two occasions = or > 12 hours apart.
  • Serum creatinine > 3.0 mg/dl.
  • Systolic blood pressure < 90 mm requiring supportive therapy.
  • Symptomatic hypoglycemia with blood glucose = or < 40 or hyperglycemia requiring therapy.
  • Pancreatitis with laboratory confirmation (abnormal amylase and/or lipase).
  • Any other severe or life-threatening adverse reaction to pentamidine that, in the investigator's opinion, makes continued or recurrent treatment with pentamidine inadvisable (approved on a case-by-case basis by the NIAID clinical monitor).

Exclusion Criteria

Co-existing Condition:

Patients with the following are excluded:

  • History of Type I hypersensitivity (i.e., urticaria, angioedema, or anaphylaxis), exfoliative dermatitis, or other life-threatening reactions due to trimetrexate.
  • Patients with less severe adverse reactions may be enrolled if, in the opinion of the investigator, they do not prohibit rechallenge with the drug.

Concurrent Medication:

Excluded:

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

Patients with the following are excluded:

  • History of Type I hypersensitivity (i.e., urticaria, angioedema, or anaphylaxis), exfoliative dermatitis, or other life-threatening reactions due to trimetrexate.
  • Patients with less severe adverse reactions may be enrolled if, in the opinion of the investigator, they do not prohibit rechallenge with the drug.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00000724

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

Publications:
Feinberg J, McDermott C, Nutter J. Trimetrexate (TMTX) salvage therapy for PCP in AIDS patients with limited therapeutic options. Int Conf AIDS. 1992 Jul 19-24;8(2):B136 (abstract no PoB 3297)

ClinicalTrials.gov Identifier: NCT00000724     History of Changes
Other Study ID Numbers: NS 401
Study First Received: November 2, 1999
Last Updated: December 18, 2012
Health Authority: United States: Federal Government

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Trimetrexate
Pneumonia, Pneumocystis carinii
Injections, Intravenous
Leucovorin
Drug Evaluation
Drug Therapy, Combination
Folic Acid Antagonists
Acquired Immunodeficiency Syndrome
Antiprotozoal Agents

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
Folic Acid Antagonists
Trimetrexate
Leucovorin
Levoleucovorin
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 16, 2014