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A Controlled Comparative Trial of Sulfamethoxazole-Trimethoprim Versus Aerosolized Pentamidine for Secondary Prophylaxis of Pneumocystis Carinii Pneumonia in AIDS Patients Receiving Azidothymidine (AZT)

Primary Purpose

Pneumonia, Pneumocystis Carinii, HIV Infections

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Pentamidine isethionate
Pyrimethamine
Sulfamethoxazole/Trimethoprim
Sulfadoxine/Pyrimethamine
Zidovudine
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pneumonia, Pneumocystis Carinii focused on measuring Sulfadoxine, Trimethoprim-Sulfamethoxazole Combination, AIDS-Related Opportunistic Infections, Pneumonia, Pneumocystis carinii, Pentamidine, Pyrimethamine, Drug Evaluation, Administration, Inhalation, Administration, Oral, Aerosols, Acquired Immunodeficiency Syndrome, Zidovudine

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria Patients must fulfill the following criteria: Randomization within 10 weeks of completing therapy for Pneumocystis carinii pneumonia (PCP). Ability to tolerate oral and aerosolized therapy at the time of randomization. Life expectancy > 4 months. Concurrent Medication: Allowed: Inhaled bronchodilators for cough and bronchospasm related to aerosolized pentamidine treatment. Aspirin at modest doses. Ibuprofen at modest doses. Acetaminophen at modest doses. Erythropoietin for management of anemia. Allowed to treat opportunistic infections while on study: Acyclovir. Ketoconazole. Amphotericin B. Nystatin. Clotrimazole. Also allowed: Ganciclovir (DHPG) for maintenance therapy of life-threatening or sight-threatening cytomegalovirus retinitis (CMV retinitis) infection only. Zidovudine (AZT) must be discontinued during the acute induction phase of treatment and will be restarted when maintenance therapy is introduced. Concurrent Treatment: Allowed: Local radiation therapy for Kaposi's sarcoma. Prior Medication: Allowed: Primary prophylactic therapy prior to Pneumocystis carinii pneumonia (PCP) episode. Risk Behavior: Allowed: Patients maintained in a methadone maintenance program per local investigator's judgment. Exclusion Criteria Active drug or alcohol abuse which would impair performance as a study subject. Concurrent Medication: Excluded: Famotidine. Any medications suspected of interference with the metabolism of zidovudine. Flurazepam. Chronic probenecid. Phenobarbital. Phenytoin. Experimental therapies, except as noted. Chronic oral bronchodilators should not be started in patients in order to maintain them on aerosolized pentamidine after they have exhibited pulmonary toxicity. Prior Medication: Excluded for the 30 patients who will undergo pharmacokinetic studies: Zidovudine (AZT) at any time. Excluded within 7 days of study entry for the 30 patients who will undergo pharmacokinetic studies: Trimethoprim / sulfamethoxazole. Pyrimethamine / sulfadoxine. Aerosolized pentamidine. Excluded: Pentamidine by any route for the original infection. Prophylactic therapy for Pneumocystis carinii pneumonia (PCP) between the discontinuation of acute treatment and study entry. Prior Treatment: Excluded within 2 weeks of study entry: Transfusions of blood or red blood cells. Patients may not have any of the following symptoms or diseases: Known treatment-limiting hypersensitivity to sulfonamides, trimethoprim, pyrimethamine, pentamidine, or zidovudine (AZT), especially but not limited to, exfoliative dermatitis, erythema multiforme, and Stevens-Johnson syndrome. Development of severe hypoglycemia (serum glucose < 50 mg/dl with pentamidine therapy). History of neoplasms other than basal cell carcinoma of the skin or carcinoma in situ of the cervix, or mucocutaneous Kaposi's sarcoma. Known visceral Kaposi's sarcoma. Known glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Sites / Locations

  • USC CRS
  • Ucsd, Avrc Crs
  • Ucsf Aids Crs
  • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
  • Bmc Actg Crs
  • University of Minnesota, ACTU
  • Memorial Sloan-Kettering Cancer Ctr.
  • Case CRS
  • University of Washington AIDS CRS

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

First Posted
November 2, 1999
Last Updated
October 27, 2021
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT00000727
Brief Title
A Controlled Comparative Trial of Sulfamethoxazole-Trimethoprim Versus Aerosolized Pentamidine for Secondary Prophylaxis of Pneumocystis Carinii Pneumonia in AIDS Patients Receiving Azidothymidine (AZT)
Official Title
A Controlled Comparative Trial of Trimethoprim - Sulfamethoxazole Versus Aerosolized Pentamidine for Secondary Prophylaxis of Pneumocystis Carinii Pneumonia in AIDS Patients Receiving Azidothymidine (AZT)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
undefined (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
August 1991 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

5. Study Description

Brief Summary
To determine if the drug combination sulfamethoxazole-trimethoprim (SMX-TMP), given by mouth, and the drug pentamidine (PEN), given by inhaled aerosol, are effective in preventing a relapse of Pneumocystis carinii pneumonia (PCP) when they are given to patients who have recovered from a first episode of PCP and are being given zidovudine (AZT) to treat primary HIV infection. AZT prolongs survival in patients with AIDS and decreases the occurrence of opportunistic infections such as PCP. However, PCP recurs in about 43 percent of patients receiving AZT, indicating a need for other treatments to reduce the relapse rate. The two medications to be tested in this study, SMX/TMP and aerosolized PEN, have also been partially effective in preventing recurrence of PCP. It is hoped that the combination of AZT with these medications will be more effective than AZT or one of the medications alone.
Detailed Description
AZT prolongs survival in patients with AIDS and decreases the occurrence of opportunistic infections such as PCP. However, PCP recurs in about 43 percent of patients receiving AZT, indicating a need for other treatments to reduce the relapse rate. The two medications to be tested in this study, SMX/TMP and aerosolized PEN, have also been partially effective in preventing recurrence of PCP. It is hoped that the combination of AZT with these medications will be more effective than AZT or one of the medications alone. Patients receive the standard dose of AZT at study entry. Low body weight patients receive AZT at a lower dose. Patients are randomly assigned to one of two medications intended to prevent the recurrence of PCP. Patients assigned to SMX/TMP will take 1 capsule which contains both drugs once a day for 1 year. Patients assigned to PEN will have 1 aerosol treatment every 4 weeks for 1 year. Blood will be drawn at intervals in order to estimate blood levels of the drugs and to detect any adverse effects from the drugs. Note: Earlier versions of this protocol reflect its original design as a 3-arm study comparing aerosolized PEN, SMX/TMP, and pyrimethamine-sulfadoxine as secondary prophylaxis of PCP in AIDS patients receiving AZT. In order to reduce the effective sample size and permit the completion of accrual in a reasonable period of time, the pyrimethamine - sulfadoxine arm of this study has been discontinued. Patients randomized to this arm will be continued in this study on the original randomized therapy. Management of these patients will follow that described for SMX/TMP in the latest protocol version. AMENDED: Lower dose of AZT allowed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pneumonia, Pneumocystis Carinii, HIV Infections
Keywords
Sulfadoxine, Trimethoprim-Sulfamethoxazole Combination, AIDS-Related Opportunistic Infections, Pneumonia, Pneumocystis carinii, Pentamidine, Pyrimethamine, Drug Evaluation, Administration, Inhalation, Administration, Oral, Aerosols, Acquired Immunodeficiency Syndrome, Zidovudine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Enrollment
322 (false)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Pentamidine isethionate
Intervention Type
Drug
Intervention Name(s)
Pyrimethamine
Intervention Type
Drug
Intervention Name(s)
Sulfamethoxazole/Trimethoprim
Intervention Type
Drug
Intervention Name(s)
Sulfadoxine/Pyrimethamine
Intervention Type
Drug
Intervention Name(s)
Zidovudine

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria Patients must fulfill the following criteria: Randomization within 10 weeks of completing therapy for Pneumocystis carinii pneumonia (PCP). Ability to tolerate oral and aerosolized therapy at the time of randomization. Life expectancy > 4 months. Concurrent Medication: Allowed: Inhaled bronchodilators for cough and bronchospasm related to aerosolized pentamidine treatment. Aspirin at modest doses. Ibuprofen at modest doses. Acetaminophen at modest doses. Erythropoietin for management of anemia. Allowed to treat opportunistic infections while on study: Acyclovir. Ketoconazole. Amphotericin B. Nystatin. Clotrimazole. Also allowed: Ganciclovir (DHPG) for maintenance therapy of life-threatening or sight-threatening cytomegalovirus retinitis (CMV retinitis) infection only. Zidovudine (AZT) must be discontinued during the acute induction phase of treatment and will be restarted when maintenance therapy is introduced. Concurrent Treatment: Allowed: Local radiation therapy for Kaposi's sarcoma. Prior Medication: Allowed: Primary prophylactic therapy prior to Pneumocystis carinii pneumonia (PCP) episode. Risk Behavior: Allowed: Patients maintained in a methadone maintenance program per local investigator's judgment. Exclusion Criteria Active drug or alcohol abuse which would impair performance as a study subject. Concurrent Medication: Excluded: Famotidine. Any medications suspected of interference with the metabolism of zidovudine. Flurazepam. Chronic probenecid. Phenobarbital. Phenytoin. Experimental therapies, except as noted. Chronic oral bronchodilators should not be started in patients in order to maintain them on aerosolized pentamidine after they have exhibited pulmonary toxicity. Prior Medication: Excluded for the 30 patients who will undergo pharmacokinetic studies: Zidovudine (AZT) at any time. Excluded within 7 days of study entry for the 30 patients who will undergo pharmacokinetic studies: Trimethoprim / sulfamethoxazole. Pyrimethamine / sulfadoxine. Aerosolized pentamidine. Excluded: Pentamidine by any route for the original infection. Prophylactic therapy for Pneumocystis carinii pneumonia (PCP) between the discontinuation of acute treatment and study entry. Prior Treatment: Excluded within 2 weeks of study entry: Transfusions of blood or red blood cells. Patients may not have any of the following symptoms or diseases: Known treatment-limiting hypersensitivity to sulfonamides, trimethoprim, pyrimethamine, pentamidine, or zidovudine (AZT), especially but not limited to, exfoliative dermatitis, erythema multiforme, and Stevens-Johnson syndrome. Development of severe hypoglycemia (serum glucose < 50 mg/dl with pentamidine therapy). History of neoplasms other than basal cell carcinoma of the skin or carcinoma in situ of the cervix, or mucocutaneous Kaposi's sarcoma. Known visceral Kaposi's sarcoma. Known glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Holzman R
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Hardy WD
Official's Role
Study Chair
Facility Information:
Facility Name
USC CRS
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Ucsd, Avrc Crs
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
Ucsf Aids Crs
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Facility Name
Indiana Univ. School of Medicine, Infectious Disease Research Clinic
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Bmc Actg Crs
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
University of Minnesota, ACTU
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Ctr.
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Case CRS
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
University of Washington AIDS CRS
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
8717596
Citation
Freedberg KA, Hardy WD, Holzman RS, Tosteson AN, Craven DE. Validating literature-based models with direct clinical trial results: the cost-effectiveness of secondary prophylaxis for PCP in AIDS patients. Med Decis Making. 1996 Jan-Mar;16(1):29-35. doi: 10.1177/0272989X9601600110.
Results Reference
background
PubMed Identifier
1448121
Citation
Hardy WD, Feinberg J, Finkelstein DM, Power ME, He W, Kaczka C, Frame PT, Holmes M, Waskin H, Fass RJ, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021. N Engl J Med. 1992 Dec 24;327(26):1842-8. doi: 10.1056/NEJM199212243272604.
Results Reference
background
Citation
Hardy WD, Holzman RS, Avramis V, Bawdon R, Fall H, Feinberg J. Clinical and pharmacokinetic interactions of combined zidovudine (ZDV) therapy and sulfadoxine-pyrimethamine (fansidar) prophylaxis in post-PCP AIDS patients (ACTG 021). Int Conf AIDS. 1989 Jun 4-9;5:294 (abstract no TBP46)
Results Reference
background
PubMed Identifier
10985216
Citation
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an AIDS Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank tests. Biometrics. 2000 Sep;56(3):779-88. doi: 10.1111/j.0006-341x.2000.00779.x.
Results Reference
background

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A Controlled Comparative Trial of Sulfamethoxazole-Trimethoprim Versus Aerosolized Pentamidine for Secondary Prophylaxis of Pneumocystis Carinii Pneumonia in AIDS Patients Receiving Azidothymidine (AZT)

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