Comparison of Three Treatments for Pneumocystis Pneumonia in AIDS Patients
Comparison of Three Treatments for Pneumocystis Pneumonia in AIDS Patients
This study compares three different therapies for treatment of refractory Pneumocystis
 carinii pneumonia (PCP) in patients with AIDS. "Refractory" means that the patient has failed
 to respond to at least 4 days of treatment with either of two standard therapies: (1)
 sulfamethoxazole/trimethoprim (SMX/TMP) or (2) pentamidine (PEN). This study compares therapy
 with trimetrexate (TMTX) and leucovorin (LCV) to standard therapy and standard therapy plus
 high-dose steroids (methylprednisolone). The purpose is to find better and safer forms of
 treatment for PCP in AIDS patients. There is at present no scientific information about the
 best treatment for an AIDS patient with PCP who is not improving while receiving the standard
 therapies (SMX/TMP or PEN). New drug treatments are available, including steroid therapy and
 TMTX, but there is no information proving that these new treatments work better than the
 standard therapies.
There is at present no scientific information about the best treatment for an AIDS patient
 with PCP who is not improving while receiving the standard therapies (SMX/TMP or PEN). New
 drug treatments are available, including steroid therapy and TMTX, but there is no
 information proving that these new treatments work better than the standard therapies.

 Hospitalized patients who have failed to respond to at least 4 full days but no greater than
 14 full days of therapy with SMX/TMP or PEN are randomly placed into one of three study
 groups. Patients are stratified for (1) mechanical ventilation at enrollment, (2) prior
 zidovudine therapy of at least 4 weeks duration, and (3) first versus subsequent episode of
 PCP. One group of patients receives TMTX by intravenous infusion for 21 days and LCV for 24
 days. The second and third group of patients receive either PEN or SMX/TMP depending on which
 therapy they have already received and not improved on. The difference between the second and
 third group is that the second group receives the conventional therapy (PEN or SMX/TMP) and a
 placebo (inactive medication) and the third group receives the conventional therapy and
 prednisolone. Neither investigators nor patients know whether patients receive
 methylprednisolone. Patients continue study treatment until a study end point is reached or
 for a minimum of 21 days (unless there is toxicity).
Inclusion Criteria

 Concurrent Medication:

 Allowed:

 -  physiologic replacement doses of steroids.

 -  Pneumocystis carinii pneumonia (PCP) in patient who is HIV positive by ELISA, HIV
 culture, or p24 antigenemia, or is a member of a risk group for HIV infection.

 -  Failed at least 4 but not > 14 full days' therapy with either
 sulfamethoxazole/trimethoprim (SMX/TMP) or parenteral pentamidine. Patients must have
 received therapy with only one of the two conventional agents prior to enrollment.

 -  Patients in whom an unequivocal diagnosis of this episode of PCP has been or can be
 established by morphologic confirmation of three or more typical Pneumocystis carinii
 organisms in sputum, bronchoalveolar lavage fluid, or lung tissue obtained by
 transbronchial or open lung biopsy within 15 days prior to study entry.

 -  Patients in whom no significant improvement in arterial-alveolar oxygen pressure
 (defined as a decrease of at least 15mm Hg) is observed in the 24 hours prior to
 entry.

 -  Patient is willing to have maximal medical support, including pressors, invasive
 monitoring, and/or mechanical ventilation, during at least the first 7 days of
 protocol therapy if such support is necessary. Continuation of maximal medical support
 beyond 7 days is at discretion of investigator and patient.

 -  Patients with history of hypersensitivity less severe than type I may be enrolled if,
 in opinion of investigator, these adverse effects do not prohibit rechallenge with the
 drug.

 Prior Medication:

 Required:

 -  At least 4 full days but no greater than 14 full days of parenteral and/or oral
 therapy with sulfamethoxazole/trimethoprim (SMX/TMP) or pentamidine.

 Allowed:

 -  Zidovudine (AZT).

 Exclusion Criteria

 Co-existing Condition:

 Excluded:

 -  Patients with history of type I hypersensitivity (urticaria, angioedema, anaphylaxis),
 exfoliative dermatitis, or other life-threatening reaction secondary to trimetrexate,
 sulfamethoxazole/trimethoprim, or pentamidine.

 -  Presence of any process that, in the opinion of investigator, would be adversely and
 seriously affected by steroid therapy.

 -  Failure to meet inclusion criteria.

 Concurrent Medication:

 Excluded:

 -  Zidovudine (AZT).

 -  Myelosuppressive agents.

 -  Nephrotoxic agents.

 -  AZT may be resumed at completion of study.

 Excluded:

 -  Patients with history of type I hypersensitivity (urticaria, angioedema, anaphylaxis),
 exfoliative dermatitis, or other life-threatening reaction secondary to trimetrexate,
 sulfamethoxazole/trimethoprim, or pentamidine.

 -  Presence of any process that, in the opinion of investigator, would be adversely and
 seriously affected by steroid therapy.

 -  Failure to meet inclusion criteria.

 Prior Medication:

 Excluded within 4 days of study entry:

 -  Any other investigational agent.

 -  Excluded within 14 days of study entry:

 -  Steroids (other than physiologic replacement doses).