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An Open, Prospective, Multicenter Study of Trimetrexate With Leucovorin Rescue for AIDS Patients With Pneumocystis Carinii Pneumonia (PCP) and Serious Intolerance to Approved Therapies

Primary Purpose

Pneumonia, Pneumocystis Carinii, HIV Infections

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Trimetrexate glucuronate
Leucovorin calcium
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pneumonia, Pneumocystis Carinii focused on measuring Trimetrexate, AIDS-Related Opportunistic Infections, Pneumonia, Pneumocystis carinii, Leucovorin, Drug Evaluation, Drug Therapy, Combination, Acquired Immunodeficiency Syndrome, Antiprotozoal Agents

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria Concurrent Medication: Allowed: Noninvestigational therapies as needed. Maintenance therapy with investigational triazoles such as itraconazole and SCH 39304. High-dose corticosteroids (exceed physiologic replacement doses) including oral prednisone 40 mg bid for 5 days, 40 mg daily for 5 days and then 20 mg daily for the remainder of PCP therapy. Same dose for methylprednisolone. Concurrent Treatment: Allowed: Any ventilatory support, antihypertensive agents, invasive monitoring, and other necessary medical intervention, according to his/her medical status, personal wishes, and the judgment of his/her physician. Patients must have: HIV seropositivity. Diagnosis of Pneumocystis carinii pneumonia (PCP). Serious intolerance to trimethoprim / sulfamethoxazole (TMP / SMX) therapy defined as follows: Platelets < 50000 platelets/mm3. Neutrophil count (polys plus bands) = or < 500 cells/mm3 on at least two occasions = or > 12 hours apart. Mucocutaneous reaction - blistering rash, mucosal involvement, generalized maculopapular eruption, or intolerable pruritus. Hepatitis demonstrated by transaminase elevation > 5 times the upper limit of normal, or = or > 300 IU if baseline is abnormal. Drug fever with daily temperature = or > 103 degrees F beginning after the 5th day of treatment 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 which, in the investigator's opinion, makes continued or recurrent treatment with TMP / SMX inadvisable as determined on a case-by-case basis. Serious intolerance to pentamidine therapy defined as follows: Platelets < 50000 platelets/mm3. Neutrophil count (polys plus bands) = or < 500 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 < 40, or hyperglycemia requiring therapy. Pancreatitis with laboratory confirmation (abnormal amylase and/or lipase). Any other severe or life-threatening adverse reaction to pentamidine, which, in the investigator's opinion, makes continued or recurrent treatment with pentamidine inadvisable as determined on a case-by-case basis. Informed consent by patient or legal guardian. Prior Medication: Required: Trimethoprim / sulfamethoxazole and pentamidine therapies. Prior Medication: Allowed: Myelosuppressive or nephrotoxic agents including zidovudine. History of high-risk behavior for HIV infection - homosexual or bisexual men, intravenous drug abusers, recipients of HIV-infected blood products, or sexual partners of persons in these groups may be admitted without proof of HIV infection. Exclusion Criteria Co-existing Condition: Patients with the following conditions or symptoms 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 a less severe adverse reaction may be enrolled if, in the opinion of the investigator, these adverse effects do not prohibit rechallenge with the drug. Concurrent Medication: Excluded: Myelosuppressive or nephrotoxic agents including zidovudine and ganciclovir. Investigational therapies. 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 a less severe adverse reaction may be enrolled if, in the opinion of the investigator, these adverse effects do not prohibit rechallenge with the drug.

Sites / Locations

  • Univ of Miami School of Medicine
  • Northwestern Univ Med School
  • Indiana Univ Hosp
  • Tulane Univ School of Medicine
  • Johns Hopkins Hosp
  • Beth Israel Deaconess - West Campus
  • Univ of Massachusetts Med Ctr
  • Warner-Lambert Parke-Davis
  • Bronx Municipal Hosp Ctr/Jacobi Med Ctr
  • Montefiore Med Ctr / Bronx Municipal Hosp
  • SUNY / Erie County Med Ctr at Buffalo
  • City Hosp Ctr at Elmhurst / Mount Sinai Hosp
  • Beth Israel Med Ctr
  • Bellevue Hosp / New York Univ Med Ctr
  • Mount Sinai Med Ctr
  • Univ of Rochester Medical Center
  • SUNY - Stony Brook
  • Duke Univ Med Ctr
  • Case Western Reserve Univ
  • Julio Arroyo
  • Univ of Washington

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
November 2, 1999
Last Updated
October 27, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00000714
Brief Title
An Open, Prospective, Multicenter Study of Trimetrexate With Leucovorin Rescue for AIDS Patients With Pneumocystis Carinii Pneumonia (PCP) and Serious Intolerance to Approved Therapies
Official Title
An Open, Prospective, Multicenter Study of Trimetrexate With Leucovorin Rescue for AIDS Patients With Pneumocystis Carinii Pneumonia (PCP) and Serious Intolerance to Approved Therapies
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
undefined (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
July 2004 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
To determine the safety and effectiveness of an investigational drug therapy (trimetrexate plus leucovorin calcium (TMTX / 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 suffered severe or life-threatening ill effects from both conventional therapies for PCP. 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 (> 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: 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 side effects. Currently there are no proven alternatives to these drugs. TMTX was chosen for this trial because it was found to be very active against the PCP organism in laboratory tests. Also TMTX, in combination with LCV, had a high response rate and did not cause severe toxicity in a preliminary trial.
Detailed Description
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 (> 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: 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 side effects. Currently there are no proven alternatives to these drugs. TMTX was chosen for this trial because it was found to be very active against the PCP organism in laboratory tests. Also TMTX, in combination with LCV, had a high response rate and did not cause severe toxicity in a preliminary trial. Patients entered in the study are given TMTX for 21 days and LCV 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. It is essential to ensure that patients receive each and every dose of LCV and that LCV therapy is continued for a full 3 days after TMTX therapy has been completed or discontinued. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pneumonia, Pneumocystis Carinii, HIV Infections
Keywords
Trimetrexate, AIDS-Related Opportunistic Infections, Pneumonia, Pneumocystis carinii, Leucovorin, Drug Evaluation, Drug Therapy, Combination, Acquired Immunodeficiency Syndrome, Antiprotozoal Agents

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Masking
None (Open Label)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Trimetrexate glucuronate
Intervention Type
Drug
Intervention Name(s)
Leucovorin calcium

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Concurrent Medication: Allowed: Noninvestigational therapies as needed. Maintenance therapy with investigational triazoles such as itraconazole and SCH 39304. High-dose corticosteroids (exceed physiologic replacement doses) including oral prednisone 40 mg bid for 5 days, 40 mg daily for 5 days and then 20 mg daily for the remainder of PCP therapy. Same dose for methylprednisolone. Concurrent Treatment: Allowed: Any ventilatory support, antihypertensive agents, invasive monitoring, and other necessary medical intervention, according to his/her medical status, personal wishes, and the judgment of his/her physician. Patients must have: HIV seropositivity. Diagnosis of Pneumocystis carinii pneumonia (PCP). Serious intolerance to trimethoprim / sulfamethoxazole (TMP / SMX) therapy defined as follows: Platelets < 50000 platelets/mm3. Neutrophil count (polys plus bands) = or < 500 cells/mm3 on at least two occasions = or > 12 hours apart. Mucocutaneous reaction - blistering rash, mucosal involvement, generalized maculopapular eruption, or intolerable pruritus. Hepatitis demonstrated by transaminase elevation > 5 times the upper limit of normal, or = or > 300 IU if baseline is abnormal. Drug fever with daily temperature = or > 103 degrees F beginning after the 5th day of treatment 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 which, in the investigator's opinion, makes continued or recurrent treatment with TMP / SMX inadvisable as determined on a case-by-case basis. Serious intolerance to pentamidine therapy defined as follows: Platelets < 50000 platelets/mm3. Neutrophil count (polys plus bands) = or < 500 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 < 40, or hyperglycemia requiring therapy. Pancreatitis with laboratory confirmation (abnormal amylase and/or lipase). Any other severe or life-threatening adverse reaction to pentamidine, which, in the investigator's opinion, makes continued or recurrent treatment with pentamidine inadvisable as determined on a case-by-case basis. Informed consent by patient or legal guardian. Prior Medication: Required: Trimethoprim / sulfamethoxazole and pentamidine therapies. Prior Medication: Allowed: Myelosuppressive or nephrotoxic agents including zidovudine. History of high-risk behavior for HIV infection - homosexual or bisexual men, intravenous drug abusers, recipients of HIV-infected blood products, or sexual partners of persons in these groups may be admitted without proof of HIV infection. Exclusion Criteria Co-existing Condition: Patients with the following conditions or symptoms 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 a less severe adverse reaction may be enrolled if, in the opinion of the investigator, these adverse effects do not prohibit rechallenge with the drug. Concurrent Medication: Excluded: Myelosuppressive or nephrotoxic agents including zidovudine and ganciclovir. Investigational therapies. 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 a less severe adverse reaction may be enrolled if, in the opinion of the investigator, these adverse effects do not prohibit rechallenge with the drug.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Feinberg J
Official's Role
Study Chair
Facility Information:
Facility Name
Univ of Miami School of Medicine
City
Miami
State/Province
Florida
ZIP/Postal Code
331361013
Country
United States
Facility Name
Northwestern Univ Med School
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Indiana Univ Hosp
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
462025250
Country
United States
Facility Name
Tulane Univ School of Medicine
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
Johns Hopkins Hosp
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Beth Israel Deaconess - West Campus
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Univ of Massachusetts Med Ctr
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01655
Country
United States
Facility Name
Warner-Lambert Parke-Davis
City
Morris Plains
State/Province
New Jersey
ZIP/Postal Code
07950
Country
United States
Facility Name
Bronx Municipal Hosp Ctr/Jacobi Med Ctr
City
Bronx
State/Province
New York
ZIP/Postal Code
10461
Country
United States
Facility Name
Montefiore Med Ctr / Bronx Municipal Hosp
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
SUNY / Erie County Med Ctr at Buffalo
City
Buffalo
State/Province
New York
ZIP/Postal Code
14215
Country
United States
Facility Name
City Hosp Ctr at Elmhurst / Mount Sinai Hosp
City
Elmhurst
State/Province
New York
ZIP/Postal Code
11373
Country
United States
Facility Name
Beth Israel Med Ctr
City
New York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
Facility Name
Bellevue Hosp / New York Univ Med Ctr
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Mount Sinai Med Ctr
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Univ of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
SUNY - Stony Brook
City
Stony Brook
State/Province
New York
ZIP/Postal Code
117948153
Country
United States
Facility Name
Duke Univ Med Ctr
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Case Western Reserve Univ
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Julio Arroyo
City
West Columbia
State/Province
South Carolina
ZIP/Postal Code
29169
Country
United States
Facility Name
Univ of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
981224304
Country
United States

12. IPD Sharing Statement

Citations:
Citation
Katz D, Feinberg J, Myers M, Gubish E, Hoth D. Providing access to promising investigational drugs for AIDS: A management model for "treatment INDs". Int Conf AIDS. 1989 Jun 4-9;5:855 (abstract no TEP51)
Results Reference
background
Citation
Feinberg J, Katz D, McDermott C, Myers M, Hoth D. Trimetrexate (TMTX) salvage therapy of PCP in AIDS patients without any therapeutic options: interim results of the 1st AIDS "treatment IND" protocol. Int Conf AIDS. 1989 Jun 4-9;5:201 (abstract no TBO28)
Results Reference
background

Learn more about this trial

An Open, Prospective, Multicenter Study of Trimetrexate With Leucovorin Rescue for AIDS Patients With Pneumocystis Carinii Pneumonia (PCP) and Serious Intolerance to Approved Therapies

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