CSP #512 - Options in Management With Anti-Retrovirals

HIV Infections Clinical Trial

— OPTIMA  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00050089
• Other study ID #: 512
• Status: Completed
• Phase: N/A
• First received: November 20, 2002
• Last updated: April 3, 2015
• Start date: January 2001
• Est. completion date: December 2007

Study information

• Verified date: April 2015
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 368
• Est. completion date: December 2007
• Est. primary completion date: December 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• AIDS
• HIV Infections

Intervention

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

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

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

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

Locations

Country	Name	City	State
Puerto Rico	VA Medical Center, San Juan	San Juan
United States	VA Ann Arbor Healthcare System	Ann Arbor	Michigan
United States	VA Maryland Health Care System, Baltimore	Baltimore	Maryland
United States	VA Medical Center, Jamaica Plain Campus	Boston	Massachusetts
United States	VA Medical Center, Bronx	Bronx	New York
United States	Jesse Brown VAMC (WestSide Division)	Chicago	Illinois
United States	VA Medical Center, Cincinnati	Cincinnati	Ohio
United States	VA Medical Center, Cleveland	Cleveland	Ohio
United States	WJB Dorn Veterans Hospital, Columbia	Columbia	South Carolina
United States	VA North Texas Health Care System, Dallas	Dallas	Texas
United States	Atlanta VA Medical and Rehab Center, Decatur	Decatur	Georgia
United States	VA Medical Center, Durham	Durham	North Carolina
United States	VA New Jersey Health Care System, East Orange	East Orange	New Jersey
United States	North Florida/South Georgia Veterans Health System	Gainesville	Florida
United States	Edward Hines, Jr. VA Hospital	Hines	Illinois
United States	Michael E. DeBakey VA Medical Center (152)	Houston	Texas
United States	VA Medical Center, Long Beach	Long Beach	California
United States	VA Medical Center, Miami	Miami	Florida
United States	New York Harbor HCS	New York	New York
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	VA Medical Center, Philadelphia	Philadelphia	Pennsylvania
United States	Carl T. Hayden VA Medical Center	Phoenix	Arizona
United States	VA Medical Center, Portland	Portland	Oregon
United States	VA South Texas Health Care System, San Antonio	San Antonio	Texas
United States	VA San Diego Healthcare System, San Diego	San Diego	California
United States	Bay Pines VAMC (111J)	St. Petersburg	Florida
United States	VA Medical Center, DC	Washington	District of Columbia
United States	VA Connecticut Health Care System (West Haven)	West Haven	Connecticut
United States	VA Greater Los Angeles Healthcare System, West LA	West Los Angeles	California
United States	West Palm Beach VA Medical Center	West Palm Beach	Florida

Sponsors (3)

Lead Sponsor	Collaborator
VA Office of Research and Development	Canadian Institutes of Health Research (CIHR), Medical Research Council

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (11)

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 no — View 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. — View 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. — View 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. — View 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. — View 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. — View 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 — View 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 — View 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. — View 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. — View 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 — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With New or Recurrent AIDS Event, or Death	New or recurrent AIDS event or Death were compared between Standard-ART (standard) and Mega-ART (intensification)	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	No
Primary	Number of Participants With New or Recurrent AIDS Event, or Death	New or recurrent AIDS event or Death were compared between No ARDFP (continuation) and ARDFP (interruption)	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	No
Primary	Number of Participants With New or Recurrent AIDS Event, or Death	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)	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	No
Secondary	Number of Participants With a New, Non-HIV Related Serious Adverse Event	New, on-study non-HIV related Serious Adverse events were compared between Standard-ART (standard) and Mega-ART (intensification)	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	Yes
Secondary	Number of Participants With New, Non-HIV Related Serious Adverse Event	New, on-study non-HIV related Serious Adverse events were compared between ARDFP (interruption) and No ARDFP (continuation)	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	Yes