DB289 Versus TMP-SMX for the Treatment of Acute Pneumocystis Jiroveci Pneumonia (PCP)

Immtech Pharmaceuticals

Status and phase

Terminated

Phase 3

Conditions

Pneumonia, Interstitial Plasma Cell

Pneumonia, Pneumocystis Carinii

Pneumocystis Carinii Pneumonia

HIV Infections

Treatments

Drug: Pafuramidine maleate (DB289)

Drug: Trimethoprim-Sulfamethoxazole (TMP-SMX)

Study type

Interventional

Funder types

Industry

Identifiers

NCT00302341

C05-009

Details and patient eligibility

About

The purpose of this study is to demonstrate the non-inferiority of pafuramidine maleate (DB289)versus trimethoprim-sulfamethoxazole (TMP-SMX)for the treatment of mild to moderately severe Pneumocystis pneumonia (PCP).

Full description

The gold standard treatment for PCP is trimethoprim-sulfamethoxazole (TMP-SMX). This drug is highly effective; however, a significant number of patients are unable to complete a course of therapy due to adverse events, some of which can be life-threatening. In addition, mutations that confer resistance to sulfa-based drugs in other microorganisms are increasingly being reported in P. jiroveci. A potential role of these mutations in conferring clinical resistance to PCP and in breakthroughs to prophylaxis regimens based on sulfa drugs is being actively studied. Second and third line agents or combinations for PCP treatment are also limited in efficacy and/or by adverse events.

A new agent such as pafuramidine maleate (DB289), which has well documented activity against P. carinii in animal models, documented efficacy in a preliminary study trial in HIV-infected patients with PCP that were intolerant or resistant to TMP-SMX, was well tolerated in this trial and demonstrated a low toxicity profile in Phase 1 studies, would meet a significant medical need. Furthermore, pafuramidine maleate is active against other pathogens responsible for significant morbidity and mortality in patients with AIDS in the developing world, like different strains of Plasmodium (malaria) and Cryptosporidium parvum. The decrease in the rate of PCP in countries where patients with AIDS have access to HAART will present a significant challenge to the completion of this development program. The last published trial of PCP treatment was conducted by the ACTG in 24 U.S. sites between May 1991 and june 1993. That study needed to decrease the planned sample size to 195 due to low enrollment. This represents an important challenge for our program.

Enrollment

48 patients

Sex

All

Ages

13 to 65 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Documented or presumptive HIV infection
Signs and symptoms of PCP present for at least 5 days
Pneumocystis jiroveci confirmed in BAL fluid or induced sputum sample
Suitable candidate for oral therapy
Alveolar-arterial oxygen (A-a) gradient < or = 45 mm Hg on room air and partial pressure of oxygen (pO2) > or = 60 mm Hg
No more than 48 hours of prior treatment in the preceding 7 days for PCP treatment at full doses; failure of Pneumocystis prophylaxis or use of medications recommended for treatment of PCP at doses less than recommended by the CDC Guidelines is acceptable.

Exclusion criteria

Unwilling or unable to discontinue use of other medications with anti-PCP activity
AIDS related cachexia (weight loss that is more than 10% of ideal body weight)
Severe diarrhea and/or vomiting
History of hypersensitivity or severe or life threatening toxicity to TMP-SMX, other sulfonamides or pentamidine
Active illicit drug use
Impending respiratory failure or need for intubation
AST and ALT levels > 3 times the upper limit of normal
History of pancreatitis
Severe PCP
Karnofsky score < or = 20
Terminal HIV disease or life expectancy of less than 6 months
Acute concurrent pulmonary pathological condition that would obscure the evaluation of response to therapy
Concomitant use of amphotericin B, gangciclovir, cyclosporine, warfarin, thiazide diuretics, phenytoin, methotrexate, leucovorin
Receipt of systemic corticosteroids (except replacement therapy) within 14 days of study entry at high doses for 3 or more consecutive days. Concomitant use of corticosteroids, other than replacement doses for adrenal insufficiency, is also excluded unless the patient meets the CDC criteria for use of corticosteroids for treatment of PCP
Pregnant or lactating women
The subject has been previously enrolled in the study