CSP #512 - Options in Management With Anti-Retrovirals (OPTIMA)

Tracking Information
First Submitted Date ICMJE	November 20, 2002
First Posted Date ICMJE	November 22, 2002
Results First Submitted Date	September 11, 2013
Results First Posted Date	February 13, 2014
Last Update Posted Date	April 23, 2015
Study Start Date ICMJE	January 2001
Actual Primary Completion Date	December 2007 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: April 3, 2015)	Number of Participants With New or Recurrent AIDS Event, or Death [ Time Frame: 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 ]New or recurrent AIDS event or Death were compared between Standard-ART (standard) and Mega-ART (intensification); Number of Participants With New or Recurrent AIDS Event, or Death [ Time Frame: 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 ]New or recurrent AIDS event or Death were compared between No ARDFP (continuation) and ARDFP (interruption); Number of Participants With New or Recurrent AIDS Event, or Death [ Time Frame: 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 ]New or recurrent AIDS event or Death were compared between No ARDFP (continuation)+Standard-ART (standard), No ARDFP (continuation)+Mega-ART (intensification), ARDFP (interruption)+Standard-ART (standard) and ARDFP (interruption)+Mega-ART (intensification)
Original Primary Outcome Measures ICMJE	Not Provided
Change History	Complete list of historical versions of study NCT00050089 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: April 3, 2015)	Number of Participants With a New, Non-HIV Related Serious Adverse Event [ Time Frame: 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 ]New, on-study non-HIV related Serious Adverse events were compared between Standard-ART (standard) and Mega-ART (intensification); Number of Participants With New, Non-HIV Related Serious Adverse Event [ Time Frame: 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 ]New, on-study non-HIV related Serious Adverse events were compared between ARDFP (interruption) and No ARDFP (continuation)
Original Secondary Outcome Measures ICMJE	Not Provided
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	CSP #512 - Options in Management With Anti-Retrovirals
Official Title ICMJE	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
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: No Antiretroviral Drug-Free Period (No ARDFP) and Standard-ART; No Antiretroviral Drug-Free Period (No ARDFP) and Mega-ART; Antiretroviral Drug-Free Period (ARDFP) and Standard-ART; 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.
Study Type ICMJE	Interventional
Study Phase	Not Applicable
Study Design ICMJE	Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	AIDS; HIV Infections
Intervention ICMJE	Other: No Antiretroviral Drug-Free Period (No ARDFP) vs ARDFP Continuation or interruption of ART treatment; Drug: Standard ART vs Mega ART Standard therapy vs Intensified therapy
Study Arms	Active Comparator: No ARDFP+Standard-ART No Antiretroviral Drug-Free Period (No ARDFP) and Standard-ART Interventions: Other: No Antiretroviral Drug-Free Period (No ARDFP) vs ARDFP Drug: Standard ART vs Mega ART; Active Comparator: No ARDFP+Mega-ART No Antiretroviral Drug-Free Period (No ARDFP) and Mega-ART Interventions: Other: No Antiretroviral Drug-Free Period (No ARDFP) vs ARDFP Drug: Standard ART vs Mega ART; Active Comparator: ARDFP+Standard-ART Antiretroviral Drug-Free Period (ARDFP) and Standard-ART Interventions: Other: No Antiretroviral Drug-Free Period (No ARDFP) vs ARDFP Drug: Standard ART vs Mega ART; Active Comparator: ARDFP+Mega-ART Antiretroviral Drug-Free Period (ARDFP) and Mega-ART Interventions: Other: No Antiretroviral Drug-Free Period (No ARDFP) vs ARDFP Drug: Standard ART vs Mega ART
Publications *	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.; 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.; 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.; 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.; 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.; 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.; 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.; 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.; 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.; 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.; 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.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: August 23, 2013)	368
Original Enrollment ICMJE; (submitted: June 23, 2005)	1700
Actual Study Completion Date	December 2007
Actual Primary Completion Date	December 2007 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Puerto Rico, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00050089
Other Study ID Numbers ICMJE	512
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	VA Office of Research and Development
Study Sponsor ICMJE	VA Office of Research and Development
Collaborators ICMJE	Medical Research Council; Canadian Institutes of Health Research (CIHR)
Investigators ICMJE	Study Chair: Sheldon Brown VA Medical Center, Bronx
PRS Account	VA Office of Research and Development
Verification Date	April 2015
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP