Pneumonia, Pneumocystis CariniiPhase 3NCT00000724
A Study of Trimetrexate With Leucovorin Rescue for AIDS Patients Who Are Refractory to Standard Therapies for Pneumocystis Carinii Pneumonia
A Phase 3 study testing Trimetrexate glucuronate and Leucovorin calcium in people with Pneumonia, Pneumocystis Carinii and HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Pneumonia, Pneumocystis Carinii, HIV Infections
- What is being tested?
- Trimetrexate glucuronate and Leucovorin calcium
- How many people
- Not given
- Where
- 1 siteUnited States
- Study dates
- Start not givento Jul 2004
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Concurrent Medication:
- Allowed:
- Antihypertensive agents.
- Concurrent Treatment:
- Allowed:
- Blood products.
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- 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).
Who cannot join
- 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:
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Warner-Lambert Parke-Davis
Morris Plains, New Jersey, 07950
About this study
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.
Read the 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.
- Conditions
- Pneumonia, Pneumocystis Carinii, HIV Infections
- Being tested
- Trimetrexate glucuronate, Leucovorin calcium
- Keywords
- Trimetrexate, Pneumonia, Pneumocystis carinii, Injections, Intravenous, Leucovorin, Drug Evaluation, Drug Therapy, Combination, Folic Acid Antagonists, Acquired Immunodeficiency Syndrome, Antiprotozoal Agents
- Medical subject headings
- Pneumonia, Pneumocystis, HIV Infections, Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Trimetrexate glucuronateDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Aug 2001 (estimated)
- Study completionJul 2004
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Pneumonia, Pneumocystis CariniiStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Masking
- None (open label)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Investigators
- Feinberg J, Study chair
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00000724
- Sponsor's protocol ID
- NS 401
- Status last verified
- Dec 2012
- First submitted
- 2 Nov 1999
- Last updated
- 19 Dec 2012
- Results posted
- No
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)
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Study of Trimetrexate With Leucovorin Rescue for AIDS Patients Who Are Refractory to Standard Therapies for Pneumocystis Carinii Pneumonia
- ClinicalTrials.gov ID
- NCT00000724
- Acronym / sponsor ID
- NS 401
- Conditions
- Pneumonia, Pneumocystis Carinii, HIV Infections
- Keywords
- Trimetrexate, Pneumonia, Pneumocystis carinii, Injections, Intravenous, Leucovorin, Drug Evaluation, Drug Therapy, Combination, Folic Acid Antagonists, Acquired Immunodeficiency Syndrome
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study completion
- Jul 2004 (actual)
- First posted
- 31 Aug 2001 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Masking
- None (open label)
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (25 listed)
- Antihypertensive agents.
- Blood products.
- Ventilatory support.
- At least 7 days trimethoprim / sulfamethoxazole or parenteral pentamidine.
- Allowed:
Key exclusion criteria (11 listed)
- 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.
- Myelosuppressive or nephrotoxic agents.
- Other investigational drugs including high-dose steroids (exceeding physiologic replacement doses).
- History of Type I hypersensitivity (i.e., urticaria, angioedema, or anaphylaxis), exfoliative dermatitis, or other life-threatening reactions due to trimetrexate.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Trimetrexate glucuronate | Drug | – |
| Leucovorin calcium | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2012.
- BackgroundFeinberg 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)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Feinberg J study chair
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Trimetrexate glucuronate and Leucovorin calcium in people with Pneumonia, Pneumocystis Carinii and HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Dec 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00000724, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2012.