Clinical trial NCT00000892: A Study of Several Anti-HIV Drug Combinations in HIV-Infected Patients Who Have Used Indinavir
Official title: Activity of the Soft Gelatin Capsule of Saquinavir (SQVsgc) in Combination With Ritonavir or Nelfinavir and Combinations of Delavirdine and/or Adefovir Dipivoxil in HIV-Infected Subjects With Prior Indinavir Use and Viral Loads From 2,000 to 200,000 Copies HIV RNA/ml
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Keywords: HIV-1
Drug Therapy, Combination
HIV Protease Inhibitors
Ritonavir
Indinavir
RNA, Viral
Saquinavir
Delavirdine
Nelfinavir
Adenine
Anti-HIV Agents
Viral Load
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 300
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To compare the proportion of patients whose plasma HIV-1 RNA is below 500 copies/ml after 16 weeks of treatment. To assess the safety, toxicity, and tolerance of each treatment arm.

While indinavir is currently the most commonly prescribed protease inhibitor, the optimal therapy for a person on an indinavir-containing regimen who experiences a rebound in viral load or never experiences a decrease in viral load below 500 copies per milliliter is unknown. Current clinical practice for such patients typically involves empiric use of a combination of other protease inhibitors (saquinavir/nelfinavir or saquinavir/ritonavir) and at least 1 other antiretroviral agent to which the patient has had little or no prior exposure. This may involve the use of 1 or more reverse transcriptase inhibitors (RTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). This study attempts to formally evaluate some of these options in indinavir-experienced patients.

Detailed description: While indinavir is currently the most commonly prescribed protease inhibitor, the optimal therapy for a person on an indinavir-containing regimen who experiences a rebound in viral load or never experiences a decrease in viral load below 500 copies per milliliter is unknown. Current clinical practice for such patients typically involves empiric use of a combination of other protease inhibitors (saquinavir/nelfinavir or saquinavir/ritonavir) and at least 1 other antiretroviral agent to which the patient has had little or no prior exposure. This may involve the use of 1 or more reverse transcriptase inhibitors (RTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). This study attempts to formally evaluate some of these options in indinavir-experienced patients.

Patients are stratified by HIV RNA (2,000 - 20,000 copies/ml versus 20,000 - 200,000 copies/ml), and randomized to 1 of 6 treatment arms as follows:

Arm A: Saquinavir (SQV) plus ritonavir (RTV) plus delavirdine (DLV) plus adefovir dipivoxil placebo.

Arm B: SQV plus RTV plus DLV placebo plus adefovir dipivoxil. Arm C: SQV plus RTV plus DLV plus adefovir dipivoxil. Arm D: SQV plus nelfinavir (NFV) plus DLV plus adefovir dipivoxil placebo. Arm E: SQV plus NFV plus DLV placebo plus adefovir dipivoxil. Arm F: SQV plus NFV plus DLV plus adefovir dipivoxil. In addition to assigned study treatment patients receive an L-carnitine supplement.

Therapy is administered for 24 weeks. Patients who have an average HIV RNA value for Weeks 12 and 16 that is less than 5,000 copies or a least 1 log below their baseline value may continue their assigned study treatment for an additional 24 weeks. \[AS PER AMENDMENT 3/30/98: Subjects with plasma HIV RNA greater than 5,000 copies/ml may elect to continue or discontinue study medications in the treatment extension and seek the best available treatment.\] \[AS PER AMENDMENT 06/11/98: The dose of adefovir dipivoxil is reduced at or after Week 16. Alternatively, patients may discontinue adefovir dipivoxil/placebo and substitute appropriate antiretroviral agent(s) or add appropriate antiretroviral agent(s) to their reduced-dose regimen. Also, at the discretion of the protocol chairperson, patients who have been on study for more than 16 weeks may substitute appropriate FDA-approved antiretroviral agent(s) for any study medication that must be discontinued because of toxicity. Addition of nonnucleoside reverse transcriptase inhibitors, protease inhibitors, or investigational agents is specifically excluded.\]

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Required:

* Chemoprophylaxis for Pneumocystis carinii pneumonia for all patients who have a CD4 cell count of equal or less than 200 cells/mm3.

Allowed:

* Topical and oral antifungal agents except ketoconazole and itraconazole.
* Treatment, maintenance or chemoprophylaxis with approved agents for opportunistic infections.
* Antibiotics.
* Systemic corticosteroids for 21 days or less for acute problems.
* Recombinant erythropoietin (rEPO) and granulocyte-colony stimulating factor (G-CSF, filgrastim).
* Regularly prescribed medications such as antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives (not as a sole form of birth control), megestrol acetate, or testosterone.
* Alternative therapies, such as vitamins, acupuncture, and visualization techniques.
* \[AS PER AMENDMENT 3/30/98: Calcium channel blockers may be used only with caution.\]

Patients must have:

* HIV-1 infection documented by a licensed ELISA and confirmed by Western blot, HIV culture, HIV antigen, plasma HIV RNA, or a second antibody test other than ELISA.
* 2,000 to 200,000 HIV-1 RNA copies/ml as measured by any Roche-certified laboratory \[AS

PER AMENDMENT 3/30/98:

* using the Roche Amplicor HIV-1 Monitor\] within 30 days of study entry.
* Signed, informed consent from parent or legal guardian for patients less than 18 years of age.

Prior Medication: Required:

* More than 6 months cumulative indinavir therapy.
* Stable indinavir-containing antiretroviral regimen for at least 4 weeks \[2 weeks AS PER AMENDMENT 3/30/98\] prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

* Any active infection requiring acute treatment within 30 days \[21 days AS PER AMENDMENT 3/30/98\] prior to study entry.
* Unexplained temperature greater than 38.5 degrees for any 7 consecutive days within 30 days prior to study entry.
* Malignancy, including Kaposi's sarcoma, that requires systemic chemotherapy.

Concurrent Medication:

Excluded:

* Non-protocol-specified immunomodulatory and/or antiretroviral agents.
* Systemic cytotoxic chemotherapy.
* Ketoconazole, itraconazole, rifampin, rifabutin, alprazolam, amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, encainide, estazolam, flecainide, flurazepam, isotretinoin, meperidine, midazolam, piroxicam, propafenone, propoxyphene, quinidine, terfenadine, triazolam, zolpidem, phenytoin, phenobarbital, carbamazepine, and ergot alkaloids and \[ AS PER AMENDMENT 3/30/98: dexamethasone, ergot derivatives, and pimozide\].

Avoided:

* Herbal medications.

Prior Medication:

Excluded:

* At least 2 weeks or more total ritonavir and/or saquinavir (hard gelatin capsule).
* NNRTIs (nevirapine, delavirdine, DMP-266, etc.), saquinavir (soft gelatin capsule), nelfinavir, 141W94VX-478, and adefovir dipivoxil.
* Immunomodulator \[systemic immunomodulator AS PER AMENDMENT 3/30/98\] or investigational drug therapy within 30 days prior to entry.
* Active immunization within 30 days \[21 days AS PER AMENDMENT 3/30/98\] prior to entry.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Univ of Southern California / LA County USC Med Ctr
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Ctr
state: California
city: Menlo Park
country: United States
facility: Willow Clinic
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: Stanford at Kaiser / Kaiser Permanente Med Ctr
state: California
city: San Jose
country: United States
facility: Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium
state: California
city: Stanford
country: United States
facility: San Mateo AIDS Program / Stanford Univ
state: California
city: Stanford
country: United States
facility: Stanford Univ Med Ctr
state: California
city: Torrance
country: United States
facility: Harbor UCLA Med Ctr
state: California
city: Denver
country: United States
facility: Univ of Colorado Health Sciences Ctr
state: Colorado
city: Washington
country: United States
facility: Howard Univ
state: District of Columbia
city: Miami
country: United States
facility: Univ of Miami School of Medicine
state: Florida
city: Honolulu
country: United States
facility: Queens Med Ctr
state: Hawaii
city: Honolulu
country: United States
facility: Univ of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Univ Med School
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp
state: Illinois
city: Chicago
country: United States
facility: Rush Presbyterian - Saint Luke's Med Ctr
state: Illinois
city: Chicago
country: United States
facility: Louis A Weiss Memorial Hosp
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ Hosp
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp of Indiana / Life Care Clinic
state: Indiana
city: Baltimore
country: United States
facility: State of MD Div of Corrections / Johns Hopkins Univ Hosp
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hosp
state: Maryland
city: Boston
country: United States
facility: Boston Med Ctr
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess - West Campus
state: Massachusetts
city: Minneapolis
country: United States
facility: Univ of Minnesota
state: Minnesota
city: Buffalo
country: United States
facility: SUNY / Erie County Med Ctr at Buffalo
state: New York
city: New York
country: United States
facility: Beth Israel Med Ctr
state: New York
city: New York
country: United States
facility: Bellevue Hosp / New York Univ Med Ctr
state: New York
city: New York
country: United States
facility: Chelsea Ctr
state: New York
city: New York
country: United States
facility: Cornell Univ Med Ctr
state: New York
city: New York
country: United States
facility: St Vincent's Hosp / Mem Sloan-Kettering Cancer Ctr
state: New York
city: New York
country: United States
facility: Mount Sinai Med Ctr
state: New York
city: Rochester
country: United States
facility: Univ of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: Univ of North Carolina
state: North Carolina
city: Cincinnati
country: United States
facility: Univ of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Ohio State Univ Hosp Clinic
state: Ohio
city: Philadelphia
country: United States
facility: Univ of Pennsylvania at Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Univ of Pittsburgh Med Ctr
state: Pennsylvania
city: Providence
country: United States
facility: Brown Univ School of Medicine
state: Rhode Island
city: West Columbia
country: United States
facility: Julio Arroyo
state: South Carolina
city: Knoxville
country: United States
facility: Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr
state: Tennessee
city: Galveston
country: United States
facility: Univ of Texas Galveston
state: Texas
city: Seattle
country: United States
facility: Univ of Washington
state: Washington
Study officials:
name: R Gulick
role: STUDY_CHAIR
name: D Katzenstein
role: STUDY_CHAIR
References:
citation: Gulick RM, Hu XJ, Fiscus S, Fletcher CV, Haubrich R, Cheng H, Lagakos S, Acosta E, Swanstrom R, Mills C, Snyder S, Fischl M, Pettinelli C, Katzenstein D. Durability of salvage therapy with saquinavir SGC (SQV) in combination with ritonavir (RTV) or nelfinavir (NFV) plus delavirdine (DLV), adefovir dipivoxil (ADV), or both; ACTG 359: 48-week final results. 8th Conf Retro and Opportun Infect. 2001 Feb 4-8 (abstract no 338)
citation: Acosta EP, Gulick R, Katzenstein D, Haubrich R, Fischl M, Raasch R, Mills C, Pettinelli C, Remmel RP, Fletcher CV. Pharmacokinetic (PK) evaluation of saquinavir soft gel capsules (SQV)/ritonavir (RTV) or sqv/nelfinavir (NFV) in combination with delavirdine (DLV) and/or adefovir dipivoxil (ADV) - - ACTG 359. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:136 (abstract no 365)
citation: Gulick RM, et al. Salvage therapy with saquinavir sgc (SQV) in combination with ritonavir (RTV) or nelfinavir (NFV) and delavirdine (DLV), adefovir dipivoxil (ADV), or both-ACTG 359. Second International Workshop on Salvage Therapy for HIV Infection. 1999 May 19-21
citation: Fletcher CV, Testa MA, Haubrich R, Brundage R, Jiang H, Ickovics J, Martinez A, Snyder S, Gulick R. Relationships among Four Measures of Medication Adherence and Virologic Response in ACTG 359. 10th Conference on Retroviruses and Oppurtunistic Infections. Feb 2003. Abstract 577.
citation: Gulick RM, Hu XJ, Fiscus SA, Fletcher CV, Haubrich R, Cheng H, Acosta E, Lagakos SW, Swanstrom R, Freimuth W, Snyder S, Mills C, Fischl M, Pettinelli C, Katzenstein D. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. J Infect Dis. 2000 Nov;182(5):1375-84. doi: 10.1086/315867. Epub 2000 Oct 9.
citation: Gulick RM, Hu XJ, Fiscus SA, Fletcher CV, Haubrich R, Cheng H, Acosta E, Lagakos SW, Swanstrom R, Freimuth W, Snyder S, Mills C, Fischl M, Pettinelli C, Katzenstein D. Durability of response to treatment among antiretroviral-experienced subjects: 48-week results from AIDS Clinical Trials Group Protocol 359. J Infect Dis. 2002 Sep 1;186(5):626-33. doi: 10.1086/342681. Epub 2002 Aug 9.
citation: Fletcher CV, Jiang H, Brundage RC, Acosta EP, Haubrich R, Katzenstein D, Gulick RM. Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical Trials Group Study 359. J Infect Dis. 2004 Apr 1;189(7):1176-84. doi: 10.1086/382754. Epub 2004 Mar 16.
citation: Swanstrom R, Bosch RJ, Katzenstein D, Cheng H, Jiang H, Hellmann N, Haubrich R, Fiscus SA, Fletcher CV, Acosta EP, Gulick RM; AIDS Clinical Trials Group Protocol 359 Team. Weighted phenotypic susceptibility scores are predictive of the HIV-1 RNA response in protease inhibitor-experienced HIV-1-infected subjects. J Infect Dis. 2004 Sep 1;190(5):886-93. doi: 10.1086/422692. Epub 2004 Jul 23.
citation: Fletcher CV, Testa MA, Brundage RC, Chesney MA, Haubrich R, Acosta EP, Martinez A, Jiang H, Gulick RM. Four measures of antiretroviral medication adherence and virologic response in AIDS clinical trials group study 359. J Acquir Immune Defic Syndr. 2005 Nov 1;40(3):301-6. doi: 10.1097/01.qai.0000180078.53321.6a.
citation: Haubrich RH, Jiang H, Swanstrom R, Bates M, Katzenstein D, Petch L, Fletcher CV, Fiscus SA, Gulick RM; AIDS Clinical Trials Group Protocol 359 Team. Non-nucleoside phenotypic hypersusceptibility cut-point determination from ACTG 359. HIV Clin Trials. 2007 Mar-Apr;8(2):63-7. doi: 10.1310/hct0802-63.