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

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Primary Purpose

Status

Terminated

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Pafuramidine maleate (DB289)

Trimethoprim-Sulfamethoxazole (TMP-SMX)

About this trial

This is an interventional treatment trial for Pneumonia, Interstitial Plasma Cell focused on measuring Pulmonary disease, Dyspnea, Hypoxemia, AIDS, Pneumocystis jiroveci

Eligibility Criteria

13 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

University of California
The University of Chicago
Henry Ford Health System
NYU School of Medicine
UNC AIDS Clinical Trials
University of Cincinnati
Medical University of SC

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

1

2

Arm Description

pafuramidine maleate, oral tablet, 100 mg bid X 14 days

TMP/SMX oral tablet, 15 mg/kg, split tid X 21 days

Outcomes

Primary Outcome Measures

The primary efficacy endpoint will be the proportion of subjects with clinical success at the End of Treatment (Day 22) for the Modified Intent-to-Treat population (mITT).

Secondary Outcome Measures

The secondary efficacy endpoints will be the proportion of subjects with clinical success at the End of Treatment (Day 22)for the Per Protocol population and sustained clinical success at the End of Study (Day 42)in the Per Protocol and mITT populations.

Full Information

NCT ID

NCT00302341

First Posted

March 10, 2006

Last Updated

March 6, 2013

Sponsor

Immtech Pharmaceuticals, Inc

1. Study Identification

Unique Protocol Identification Number

NCT00302341

Brief Title

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

Official Title

International Randomized, Controlled Phase 3 Trial of DB289 Versus Trimethoprim-sulfamethoxazole for the Treatment of Acute Pneumocystis Jiroveci Pneumonia (PCP) in Patients With HIV/AIDS

Study Type

Interventional

2. Study Status

Record Verification Date

March 2013

Overall Recruitment Status

Terminated

Why Stopped

FDA Clinical Hold as of 12/21/07 due to safety concerns

Study Start Date

May 2006 (undefined)

Primary Completion Date

December 2008 (Actual)

Study Completion Date

December 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Immtech Pharmaceuticals, Inc

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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).

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pneumonia, Interstitial Plasma Cell, Pneumocystis Carinii Pneumonia, Pneumonia, Pneumocystis Carinii, HIV Infections

Keywords

Pulmonary disease, Dyspnea, Hypoxemia, AIDS, Pneumocystis jiroveci

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

48 (Actual)

8. Arms, Groups, and Interventions

Arm Title

1

Arm Type

Experimental

Arm Description

pafuramidine maleate, oral tablet, 100 mg bid X 14 days

Arm Title

2

Arm Type

Active Comparator

Arm Description

TMP/SMX oral tablet, 15 mg/kg, split tid X 21 days

Intervention Type

Drug

Intervention Name(s)

Pafuramidine maleate (DB289)

Intervention Description

Oral tablet, 100 mg bid, 14 days

Intervention Type

Drug

Intervention Name(s)

Trimethoprim-Sulfamethoxazole (TMP-SMX)

Other Intervention Name(s)

Bactrim

Intervention Description

15 mg/kg, oral tablet split tid X 21 days

Primary Outcome Measure Information:

Title

The primary efficacy endpoint will be the proportion of subjects with clinical success at the End of Treatment (Day 22) for the Modified Intent-to-Treat population (mITT).

Time Frame

Day 22

Secondary Outcome Measure Information:

Title

The secondary efficacy endpoints will be the proportion of subjects with clinical success at the End of Treatment (Day 22)for the Per Protocol population and sustained clinical success at the End of Study (Day 42)in the Per Protocol and mITT populations.

Time Frame

Day 22

10. Eligibility

Sex

All

Minimum Age & Unit of Time

13 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

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

Overall Study Officials: