Clinical trial NCT00000655: A Randomized, Double-Blind Study of 566C80 Versus Septra (Sulfamethoxazole/Trimethoprim) for the Treatment of Pneumocystis Carinii Pneumonia in AIDS Patients
Official title: A Randomized, Double-Blind Study of 566C80 Versus Septra (Trimethoprim/Sulfamethoxazole) for the Treatment of Pneumocystis Carinii Pneumonia in AIDS Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pneumonia, Pneumocystis Carinii
HIV Infections
Keywords: Trimethoprim-Sulfamethoxazole Combination
AIDS-Related Opportunistic Infections
Pneumonia, Pneumocystis carinii
Naphthoquinones
Antifungal Agents
Acquired Immunodeficiency Syndrome
Sulfamethoxazole-Trimethoprim
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Glaxo Wellcome
First posted: 2001-08-31
Enrollment: 300
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To evaluate the effectiveness of atovaquone (566C80) compared to a standard antipneumocystis agent, (SMX/TMP), for the treatment of mild to moderate Pneumocystis carinii pneumonia (PCP) in AIDS patients. To compare the safety of short-term (21 days) treatment with 566C80 and SMX/TMP in AIDS patients with an acute episode of PCP.

Standard therapies for acute treatment of PCP involve either SMX/TMP or pentamidine isetionate. Although both treatments are equally effective, side effects prevent completion of therapy in 11-55 percent of patients.

Detailed description: Standard therapies for acute treatment of PCP involve either SMX/TMP or pentamidine isetionate. Although both treatments are equally effective, side effects prevent completion of therapy in 11-55 percent of patients.

Patients are randomized into one of two treatment groups to receive either (1) 566C80 for 21 days, or (2) SMX/TMP for 21 days. Patients will be stratified according to severity of PCP. Group A will be those with an arterial-alveolar (A-a) DO2 \< 35 mm Hg. Group B will have an A-a DO2 of 35-45 mm Hg., and will also be required to receive therapy with Corticosteroids. All doses are taken with food. During the 21 days of treatment, patients are examined clinically for adverse effects and have hematology (blood-related) and clinical chemistry studies conducted a minimum of 2 times weekly. More frequent monitoring may be required at the discretion of the investigator. To evaluate the effectiveness of study medication, the clinical status of each patient is evaluated 2 to 3 times per week (e.g., dyspnea score, cough score, chest tightness/pain score, vital signs). Also, on days 7 and 21 of treatment, an arterial blood gas measurement and chest X-ray are performed. Patients who experience severe toxicities will be discontinued from the study and placed on alternative therapy. Patients will also be removed from study if they show significant clinical deterioration within the first 7 days of therapy or if there is no improvement after 10 days of therapy. This study involves a double placebo with one group randomized to receive oral 566C80 and placebo tablets which look like SMX/TMP while the other group will receive SMX/TMP and placebo tablets looking like 566C80.

Eligibility criteria: Inclusion Criteria

Patient must have the following:

* Presumptive diagnosis of AIDS as defined by the CDC.
* Untreated Pneumocystis carinii pneumonia (PCP).
* Willingness and ability to give informed consent.

Prior Medication:

Allowed:

* Prophylactic therapy for Pneumocystis carinii pneumonia (PCP) including aerosolized pentamidine or sulfamethoxazole/trimethoprim (SMX/TMP) (at a dose no greater than two DS tablets twice daily).

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

* Judged by the investigator to be in impending respiratory failure.
* Malabsorption or vomiting that would, in the judgment of investigator, potentially limit the retention and absorption of an oral therapy.
* Concurrent bacterial, fungal, or viral pneumonitis, pulmonary Kaposi's sarcoma or other concurrent illness, or chronic pulmonary disease that, in the investigator's opinion, would make interpretation of drug efficacy difficult.

Concurrent Medication:

Excluded:

* Corticosteroid treatment (except replacement therapy or patients in Group B).
* Ganciclovir.
* Zidovudine (AZT).
* Investigational agents including antiretroviral agents (didanosine (ddI), dideoxycytidine (ddC), etc.).

Drugs likely to have anti-pneumocystis effect such as:

* Sulfonamides.
* Pentamidine.
* Dapsone.
* Trimethoprim.
* Other DHFR inhibitors.
* Primaquine.
* Clindamycin.
* Sulfonylureas.

Patients with the following are excluded:

* Judged by the investigator to be in impending respiratory failure.
* Prior therapy for this episode of PCP or treatment within 4 weeks of entry for a prior episode of PCP.
* Unable to or refuse to discontinue zidovudine, ganciclovir, or other antiretroviral agents during the 21 day treatment period.
* Unable to take medication orally or unwilling or unable to take study medication with food.
* Significant psychosis or emotional disorder such that, in the investigator's opinion, the patient would not be compliant with the study protocol.
* Prior documented glucose-6-phosphate dehydrogenase (G6PD) deficiency.
* Prior history of life-threatening toxicity to SMX/TMP such as severe rash or Stevens-Johnson syndrome.

Prior Medication:

Excluded:

* Prior therapy for this episode of Pneumocystis carinii pneumonia (PCP) or treatment within 4 weeks for a prior episode of PCP.
* Blood transfusions.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham
state: Alabama
city: Harbor City
country: United States
facility: Kaiser Foundation Hosp
state: California
city: Los Angeles
country: United States
facility: USC
state: California
city: Los Angeles
country: United States
facility: Dr Richard Meyer
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Ctr
state: California
city: Oakland
country: United States
facility: Infectious Disease Med Group
state: California
city: San Diego
country: United States
facility: Univ of California / San Diego Treatment Ctr
state: California
city: San Francisco
country: United States
facility: San Francisco Gen Hosp
state: California
city: San Francisco
country: United States
facility: UCSF - San Francisco Gen Hosp
state: California
city: San Francisco
country: United States
facility: Dr Marcus Conant
state: California
city: Washington
country: United States
facility: Georgetown Univ Med Ctr
state: District of Columbia
city: Washington
country: United States
facility: Veterans Administration Med Ctr
state: District of Columbia
city: Roswell
country: United States
facility: Dr Winkler Weinberg
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins Univ School of Medicine
state: Maryland
city: Bethesda
country: United States
facility: Natl Inst of Allergy & Infect Dis / Cln Ctr
state: Maryland
city: St Louis
country: United States
facility: Washington Univ School of Medicine
state: Missouri
city: New York
country: United States
facility: Beth Israel Med Ctr / Peter Krueger Clinic
state: New York
city: New York
country: United States
facility: Saint Vincent's Hosp and Med Ctr
state: New York
city: New York
country: United States
facility: Harlem AIDS Treatment Group / Harlem Hosp Ctr
state: New York
city: Durham
country: United States
facility: Duke Univ Med Ctr
state: North Carolina
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Portland
country: United States
facility: Good Samaritan Hosp
state: Oregon
city: Philadelphia
country: United States
facility: Buckley Braffman Stern Med Associates
state: Pennsylvania
city: Memphis
country: United States
facility: Regional Med Ctr at Memphis
state: Tennessee
city: Memphis
country: United States
facility: The Regional Medical Ctr, Memphis
state: Tennessee
city: Houston
country: United States
facility: Plaza Med Ctr
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Brussels
country: Belgium
facility: CHU Saint Pierre
city: Vancouver
country: Canada
facility: Dr Julio S G Montaner
state: British Columbia
city: Toronto
country: Canada
facility: Wellesley Hosp
state: Ontario
city: Montreal
country: Canada
facility: Montreal Gen Hosp
state: Quebec
city: Paris
country: France
facility: Hopital Bichat - Claude Bernard
city: Berlin 41
country: Germany
facility: August-Viktoria-Krankenhaus Chefarst derII Inneren Abteilung
city: Munich 2
country: Germany
facility: Universitat Munchen / Medizinische Poliklinik
city: Amsterdam
country: Netherlands
facility: Natac Med Centre
city: San Juan
country: Puerto Rico
facility: San Juan Veterans Administration Med Ctr
city: London
country: United Kingdom
facility: Kobler Centre / Saint Stephen's Hosp
city: London
country: United Kingdom
facility: Saint Mary's Hosp
Study officials:
name: Hughes WT
role: STUDY_CHAIR
References:
citation: Hughes W, et al. Comparison of 566C80 & trimethoprim-sulfamethoxazole (TMP-SMZ) for the treatment of P. carinii pneumonitis (PCP). An International Multicenter, CCTG & ACTG Collaboration. Int Conf AIDS. 1992 Jul 19-24;8(1):We48 (abstract no WeB 1019)
citation: Hughes W, Leoung G, Kramer F, Bozzette SA, Safrin S, Frame P, Clumeck N, Masur H, Lancaster D, Chan C, et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med. 1993 May 27;328(21):1521-7. doi: 10.1056/NEJM199305273282103.