Clinical trial NCT00050089: CSP #512 - Options in Management With Anti-Retrovirals
Official title: CSP #512 - Options in Management With Anti-Retrovirals (OPTIMA), Management of Patients With HIV Infection for Whom First and Second-line Highly Active Anti-Retroviral Therapy Has Failed
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: AIDS
HIV Infections
Keywords: AIDS
antiretrovirals
ART
drug-free period
HAART
HIV
human immunodeficiency virus
randomized
structured treatment interruptions
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Medical Research Council
name: Canadian Institutes of Health Research (CIHR)
First posted: 2002-11-22
Enrollment: 368
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: This 'pragmatic' trial is a 2X2 open randomized study of patients in advanced HIV disease who have failed on conventional Highly Active Antiretroviral Therapy (HAART) regimens including all three classes of anti-HIV drugs. The first randomization will allocate patients to an intended 3-month antiretroviral drug-free period (ARDFP) or No ARDFP. The second randomization will allocate patients to Mega-ART (5+ drugs) or to Standard-ART (up to 4 drugs). The total study duration is 6.5 years with 5 years of intake and 1.5 year (minimum) of follow-up; median duration of patient follow-up is about 4 years. The target sample size is 390 patients and will provide 75% power to detect a 30% reduction in the hazard rate for the primary endpoint with mega-ART. Sixty-four sites will be participating in the trial--24 VA, 19 UK and 21 Canada.

Detailed description: Primary Hypothesis:

Compared to patients in Standard Antiretroviral Therapy (ART), patients in Mega-ART assuming full compliance, will experience a 30% reduction in the hazard of reaching a clinical endpoint (AIDS event or death).

Secondary Hypotheses:

Time to development of a new, non-HIV related serious adverse event, health related quality of life, the incidence of grade 3 or 4 clinical or laboratory adverse events and changes in virological and immunological markers (CD4 cell count, viral load, resistance profiles) will vary between the different treatment strategies.

Interventions:

Eligible patients will be randomized to one of four treatment strategy arms:

1. No Antiretroviral Drug-Free Period (No ARDFP) and Standard-ART
2. No Antiretroviral Drug-Free Period (No ARDFP) and Mega-ART
3. Antiretroviral Drug-Free Period (ARDFP) and Standard-ART
4. Antiretroviral Drug-Free Period (ARDFP) and Mega-ART

Note: The 'first' randomization will be ARDFP vs No ARDFP. Patients randomized to No ARDFP will receive their 'second' randomization at the same time. However, patients randomized to an Antiretroviral Drug Free Period (ARDFP) will receive their 'second' randomized assignment (Standard or Mega-ART) at the end of the ARDFP.

Note: All Serious Adverse Events were coded using the MedDRA coding dictionary; other (not serious) Adverse Events were collected as part of the study but were not coded using MedDRA or any other standardized coding dictionary.

This is the first trial of a Tri-National collaboration effort between the UK MRC, the Canadian CIHR and the VA CSP. The OPTIMA Trial was reviewed and approved by CSEC on October 12, 2000. The pre-kickoff meeting was held on March 21, 2001 in Washington, DC. The VA study kickoff meeting was held in Dallas, TX on May 16-18, 2001 and the Canadian kickoff was held in Toronto on May 29, 2001. The UK will have individual site initiation. As of October 17, 2005 there have been 357 patients enrolled in OPTIMA, at 64 sites in the three countries (279 in the VA, 41 in Canada and 37 in the UK). To date there are 64 sites actively participating in the study (24 in the VA, 19 in UK and 21 in Canada). Last date of patient follow-up was December 31, 2007.

Eligibility criteria: Inclusion Criteria:

* Ability to provide informed consent
* Age of 18 years or more
* Serologic or virologic diagnosis of HIV infection
* Failure of at least two different multi-drug regimens that include drugs of all 3 classes that the patient can tolerate or laboratory evidence of resistance to drugs in each of the 3 classes
* Had at least 3 months of current ART and are still on treatment
* Two most recent results (which can include screening) on current ART of CD4 count less than or equal to 300 cells/mm3 or less than or equal to 15%, and a plasma viral load greater than or equal to 5,000 copies/ml (Roche Amplicor, v1.0), or greater than or equal to 2,500 copies/ml (by bDNA: Bayer v3.0/Chiron v3.0 or PCR:Roche Amplicor Monitor/COBAS v1.5)

Exclusion Criteria:

* Pregnancy, breast-feeding or planned pregnancy
* Likelihood of poor protocol follow-up or if Mega-Art is not feasible (due to significant intolerance of many ARV drugs)
* Serious, uncontrolled major opportunistic infection (OI) within 14 days of screening
* Likelihood of early death due to non-HIV disease

Primary outcomes:
measure: Number of Participants With New or Recurrent AIDS Event, or Death
timeFrame: From date of randomization until onset of primary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years
measure: Number of Participants With New or Recurrent AIDS Event, or Death
timeFrame: From date of randomization until onset of primary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years
measure: Number of Participants With New or Recurrent AIDS Event, or Death
timeFrame: From date of randomization until onset of primary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years
Secondary outcomes:
measure: Number of Participants With a New, Non-HIV Related Serious Adverse Event
timeFrame: From date of randomization until onset of secondary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years
measure: Number of Participants With New, Non-HIV Related Serious Adverse Event
timeFrame: From date of randomization until onset of secondary outcome or end of study follow-up (12/31/2007) whichever occured first, up to 6.5 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Carl T. Hayden VA Medical Center
state: Arizona
city: Long Beach
country: United States
facility: VA Medical Center, Long Beach
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System, San Diego
state: California
city: West Los Angeles
country: United States
facility: VA Greater Los Angeles Healthcare System, West LA
state: California
city: West Haven
country: United States
facility: VA Connecticut Health Care System (West Haven)
state: Connecticut
city: Washington
country: United States
facility: VA Medical Center, DC
state: District of Columbia
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System
state: Florida
city: Miami
country: United States
facility: VA Medical Center, Miami
state: Florida
city: St. Petersburg
country: United States
facility: Bay Pines VAMC (111J)
state: Florida
city: West Palm Beach
country: United States
facility: West Palm Beach VA Medical Center
state: Florida
city: Decatur
country: United States
facility: Atlanta VA Medical and Rehab Center, Decatur
state: Georgia
city: Chicago
country: United States
facility: Jesse Brown VAMC (WestSide Division)
state: Illinois
city: Hines
country: United States
facility: Edward Hines, Jr. VA Hospital
state: Illinois
city: Baltimore
country: United States
facility: VA Maryland Health Care System, Baltimore
state: Maryland
city: Boston
country: United States
facility: VA Medical Center, Jamaica Plain Campus
state: Massachusetts
city: Ann Arbor
country: United States
facility: VA Ann Arbor Healthcare System
state: Michigan
city: East Orange
country: United States
facility: VA New Jersey Health Care System, East Orange
state: New Jersey
city: Bronx
country: United States
facility: VA Medical Center, Bronx
state: New York
city: New York
country: United States
facility: New York Harbor HCS
state: New York
city: Durham
country: United States
facility: VA Medical Center, Durham
state: North Carolina
city: Cincinnati
country: United States
facility: VA Medical Center, Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: VA Medical Center, Cleveland
state: Ohio
city: Portland
country: United States
facility: VA Medical Center, Portland
state: Oregon
city: Philadelphia
country: United States
facility: VA Medical Center, Philadelphia
state: Pennsylvania
city: Columbia
country: United States
facility: WJB Dorn Veterans Hospital, Columbia
state: South Carolina
city: Dallas
country: United States
facility: VA North Texas Health Care System, Dallas
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center (152)
state: Texas
city: San Antonio
country: United States
facility: VA South Texas Health Care System, San Antonio
state: Texas
city: San Juan
country: Puerto Rico
facility: VA Medical Center, San Juan
Study officials:
affiliation: VA Medical Center, Bronx
name: Sheldon Brown
role: STUDY_CHAIR
References:
citation: Kyriakides TC, Babiker A, Singer J, Cameron W, Schechter MT, Holodniy M, Brown ST, Youle M, Gazzard B; OPTIMA Study Team. An open-label randomized clinical trial of novel therapeutic strategies for HIV-infected patients in whom antiretroviral therapy has failed: rationale and design of the OPTIMA Trial. Control Clin Trials. 2003 Aug;24(4):481-500. doi: 10.1016/s0197-2456(03)00029-1.
citation: Bedimo R, Kyriakides T, Brown S, Weidler J, Lie Y, Coakley E, Holodniy M. Predictive value of HIV-1 replication capacity and phenotypic susceptibility scores in antiretroviral treatment-experienced patients. HIV Med. 2012 Jul;13(6):345-51. doi: 10.1111/j.1468-1293.2011.00981.x. Epub 2012 Jan 26.
citation: Kyriakides TC, Babiker A, Singer J, Piaseczny M, Russo J. Study conduct, monitoring and data management in a trinational trial: the OPTIMA model. Clin Trials. 2004;1(3):277-81. doi: 10.1191/1740774504cn022oa.
citation: Dau B, Ayers D, Singer J, Harrigan PR, Brown S, Kyriakides T, Cameron DW, Angus B, Holodniy M. Connection domain mutations in treatment-experienced patients in the OPTIMA trial. J Acquir Immune Defic Syndr. 2010 Jun;54(2):160-6. doi: 10.1097/QAI.0b013e3181cbd235.
citation: Bansback N, Sun H, Guh DP, Li X, Nosyk B, Griffin S, Barnett PG, Anis AH; OPTIMA TEAM. Impact of the recall period on measuring health utilities for acute events. Health Econ. 2008 Dec;17(12):1413-9. doi: 10.1002/hec.1351.
citation: Desai S, Kyriakides T, Holodniy M, Al-Salman J, Griffith B, Kozal M. Evolution of genotypic resistance algorithms and their impact on the interpretation of clinical trials: an OPTIMA trial substudy. HIV Clin Trials. 2007 Sep-Oct;8(5):293-302. doi: 10.1310/hct0805-293.
citation: Barnett PG, Chow A, Joyce VR, Bayoumi AM, Griffin SC, Nosyk B, Holodniy M, Brown ST, Sculpher M, Anis AH, Owens DK. Determinants of the cost of health services used by veterans with HIV. Med Care. 2011 Sep;49(9):848-56. doi: 10.1097/MLR.0b013e31821b34c0.
citation: Nosyk B, Sun H, Bansback N, Guh DP, Li X, Barnett P, Bayoumi A, Griffin S, Joyce V, Holodniy M, Owens DK, Anis AH. The concurrent validity and responsiveness of the health utilities index (HUI 3) among patients with advanced HIV/AIDS. Qual Life Res. 2009 Sep;18(7):815-24. doi: 10.1007/s11136-009-9504-0. Epub 2009 Jun 27.
citation: Anis AH, Nosyk B, Sun H, Guh DP, Bansback N, Li X, Barnett PG, Joyce V, Swanson KM, Kyriakides TC, Holodniy M, Cameron DW, Brown ST; OPTIMA Team1. Quality of life of patients with advanced HIV/AIDS: measuring the impact of both AIDS-defining events and non-AIDS serious adverse events. J Acquir Immune Defic Syndr. 2009 Aug 15;51(5):631-9. doi: 10.1097/QAI.0b013e3181a4f00d.
citation: Joyce VR, Barnett PG, Bayoumi AM, Griffin SC, Kyriakides TC, Yu W, Sundaram V, Holodniy M, Brown ST, Cameron W, Youle M, Sculpher M, Anis AH, Owens DK. Health-related quality of life in a randomized trial of antiretroviral therapy for advanced HIV disease. J Acquir Immune Defic Syndr. 2009 Jan 1;50(1):27-36. doi: 10.1097/QAI.0b013e31818ce6f3.
citation: Joyce VR, Barnett PG, Chow A, Bayoumi AM, Griffin SC, Sun H, Holodniy M, Brown ST, Kyriakides TC, Cameron DW, Youle M, Sculpher M, Anis AH, Owens DK. Effect of treatment interruption and intensification of antiretroviral therapy on health-related quality of life in patients with advanced HIV: a randomized, controlled trial. Med Decis Making. 2012 Jan-Feb;32(1):70-82. doi: 10.1177/0272989X10397615. Epub 2011 Mar 7.
citation: Holodniy M, Brown ST, Cameron DW, Kyriakides TC, Angus B, Babiker A, Singer J, Owens DK, Anis A, Goodall R, Hudson F, Piaseczny M, Russo J, Schechter M, Deyton L, Darbyshire J; OPTIMA Team. Results of antiretroviral treatment interruption and intensification in advanced multi-drug resistant HIV infection from the OPTIMA trial. PLoS One. 2011 Mar 31;6(3):e14764. doi: 10.1371/journal.pone.0014764.