Strategic Timing of Antiretroviral Treatment - Full Text View

Sponsor:	University of Minnesota - Clinical and Translational Science Institute
Collaborators:	National Institute of Allergy and Infectious Diseases (NIAID) Copenhagen HIV Programme (CHIP) -- Copenhagen, Denmark Medical Research Council (MRC) Clinical Trials Unit -- London, United Kingdom The National Centre in HIV Epidemiology and Clinical Research The Institute for Clinical Research at the Veterans Affairs Medical Center -- Washington, D.C., USA Agence Nationale de Recherche sur le SIDA (ANRS), France German Federal Ministry of Education and Research NEAT - European AIDS Treatment Network National Health and Medical Research Council, Australia National Institutes of Health Clinical Center (CC) Division of Clinical Research, NIAID, NIH National Cancer Institute (NCI) National Heart, Lung, and Blood Institute (NHLBI) National Institute of Mental Health (NIMH) National Institute of Neurological Disorders and Stroke (NINDS) Abbott Bristol-Myers Squibb Gilead Sciences GlaxoSmithKline Merck Tibotec Pharmaceutical Limited
Information provided by:	University of Minnesota - Clinical and Translational Science Institute
ClinicalTrials.gov Identifier:	NCT00867048

Purpose

Background:

Most guidelines agree that if a person's number of CD4+ cells (white blood cells that help fight infection) drops below 350 cells/mm3, or that person has symptoms of AIDS, he or she should start taking HIV medicines. There are randomized trials that support this recommendation. (Randomized trials provide the best evidence for new treatments or to guide when treatment should be started -- the randomization makes sure the treatment groups are alike and assigns the treatment without the doctor's or participant's choice being involved. One group also gets the current standard of care treatment to be a good comparison to any new treatment.) Some experts believe that treatment should be started even when the number of CD4+ cells is above 350 cells/mm3. For example, guidelines issued in the US in December 2009 include a new recommendation for starting HIV medicines if your CD4+ cell count is between 350 and 500 cells/mm3. However, this recommendation is not based on any information from randomized trials. We are doing this study to find out if the chances of getting one of these serious illnesses or of getting AIDS are less if you start taking HIV medicines at a time when your CD4+ cell count is still fairly high, instead of waiting to take HIV medicines at a CD4+ count where there is strong evidence that starting medicines is the right thing to do.

Objectives:

To find out if the chance of developing a serious illness or of getting AIDS is less if patients start taking HIV medicines at a time when their CD4+ cell count is still fairly high, instead of waiting until the CD4+ count is at the level recommended by the guidelines.
To learn more about how a strategy of starting HIV medicines early might affect other aspects of care, such as the chances of developing other illnesses or resistance to HIV medicines, the frequency of doctor visits, the cost of medical care, and general health and satisfaction.

Eligibility:

Patients 18 years of age and older who are infected with HIV, have CD4+ cell counts of greater than 500 cells/mm3, and who have never had antiretroviral therapy to treat HIV.

Design:

Initial screening visits (2) to draw blood for CD4+ cell counts and provide a full medical history
Patients will be randomly split into two groups:

Early: Patients will begin receiving HIV medications from the start of the study.

Deferred: Patients will begin to take HIV medications at the time recommended by current guidelines.

HIV medications for each patient will be determined by the study doctors.
Evaluations during the treatment period:
Physical examination, including vital signs and body weight checks, and pregnancy test for women who can become pregnant.
Questions about daily life, including sexual behaviors.
Blood and urine tests.
Heart tests with electrocardiogram.
Patients will return for evaluations every 4 months for the duration of the study.

Substudies will take advantage of the START randomization to compare outcomes in people starting ART early vs. later.

Condition	Intervention	Phase
HIV Infection	Drug: All licensed antiretroviral medications	Phase IV

Study Type:	Interventional
Study Design:	Treatment, Randomized, Open Label, Dose Comparison, Parallel Assignment, Safety/Efficacy Study
Official Title:	Strategic Timing of AntiRetroviral Treatment

Resource links provided by NLM:

MedlinePlus related topics: AIDS

U.S. FDA Resources

Further study details as provided by University of Minnesota - Clinical and Translational Science Institute:

Primary Outcome Measures:

Composite endpoint of AIDS, serious non-AIDS diagnoses, and all-cause mortality [ Time Frame: 4.5 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Components of the composite primary outcome measure [ Time Frame: 4.5 years ] [ Designated as safety issue: Yes ]
Specific non-AIDS diagnoses [ Time Frame: 4.5 years ] [ Designated as safety issue: Yes ]
Adverse events [ Time Frame: 4.5 years ] [ Designated as safety issue: Yes ]
Hospitalization, health-care utilization, quality of life [ Time Frame: 4.5 years ] [ Designated as safety issue: No ]
HIV drug resistance and transmission risk behavior [ Time Frame: 4.5 years ] [ Designated as safety issue: Yes ]
Change in neurocognitive function (in a subset of participants) [ Time Frame: 4.5 years ] [ Designated as safety issue: No ]
Obtain a whole blood sample from which DNA will be extracted to study validated genetic variants that determine the risk of the various primary and secondary outcomes assessed in START (in a subset of participants) [ Time Frame: Blood taken at study entry and stored in a central repository indefinitely ] [ Designated as safety issue: No ]
Evaluate understanding of study information and satisfaction with the consent process among START participants, after receiving information from either a standard or a concise consent form (at a subset of sites) [ Time Frame: Before randomization into START ] [ Designated as safety issue: No ]
Large and small artery elasticity (in a subset of participants) [ Time Frame: 4.5 years ] [ Designated as safety issue: No ]
Rate of lung function decline (in a subset of participants) [ Time Frame: 4.5 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	4000
Study Start Date:	March 2009
Estimated Study Completion Date:	March 2015
Estimated Primary Completion Date:	March 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Early ART: Experimental Initiate ART immediately following randomization	Drug: All licensed antiretroviral medications In both arms, participants may be prescribed any licensed antiretroviral medication, in accordance with national treatment guidelines. The nature of the intervention is the timing of when to begin treatment with these medications, as described in the two treatment arms.
Deferred ART: Active Comparator Defer ART until the CD4+ count declines to <350 cells/cu mm or AIDS develops	Drug: All licensed antiretroviral medications In both arms, participants may be prescribed any licensed antiretroviral medication, in accordance with national treatment guidelines. The nature of the intervention is the timing of when to begin treatment with these medications, as described in the two treatment arms.

Detailed Description:

The purpose of this randomized study is to determine whether immediate initiation of antiretroviral treatment (ART) is superior to deferral of ART until the CD4+ declines below 350 cells/mm(3) in terms of morbidity and mortality in HIV-1 (subsequently referred to as HIV) infected persons who are antiretroviral naive with a CD4+ count above 500 cells/mm(3).

The study will proceed in two phases: (1) a pilot phase, involving at least 900 participants; and (2) a definitive phase, expanding enrollment to an estimated 4,000 participants. Upon completion of the pilot phase, a recommendation will be made to the primary funder (DAIDS, NIAID, NIH) concerning whether the study should be expanded and prolonged into a definitive study. Successful completion of the pilot phase requires enrollment of at least 900 participants in 1 year by 70 designated sites supported by DAIDS. Additional sites, funded by organizations other than DAIDS, will also participate in the pilot and definitive phase.

Substudies will take advantage of the START randomization to compare outcomes in people starting ART early vs. later. These will measure outcomes that do not require the entire sample size of START to determine whether early ART is related to a difference in these outcomes over the course of the study.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

INCLUSION CRITERIA:

Signed informed consent
HIV infection documented by a plasma HIV RNA viral load, rapid HIV test or any licensed* ELISA test; and confirmed by another test using a different method such as a rapid HIV test, Western Blot, HIV culture, HIV antigen, or HIV pro-viral DNA at any time prior to study entry.
Age greater than or equal to 18 years
Karnofsky performance score greater than or equal to 80 (an indication that the participant can perform normal activities)
Perceived life expectancy of at least 6 months
For women of child-bearing potential, willingness to use contraceptives as described in the product information of the ART drugs they are prescribed
Two consecutive CD4+ cell counts greater than 500 cells/mm(3) at least 2 weeks apart within 60 days before randomization
- The term licensed refers to an FDA-approved kit or, for sites located in countries other than the United States, a kit that has been certified or licensed by an oversight body within that country. Confirmation of the initial test result must use a test method that is different than the one used for the initial assessment.

EXCLUSION CRITERIA:

Any previous use of ART or IL-2
Diagnosis of any clinical AIDS event before randomization (including esophageal candidiasis and chronic Herpes simplex infection)
Presence of HIV progression such as oral thrush, unexplained weight loss, or unexplained fever
Cardiovascular event (myocardial infarction, angioplasty, coronary-artery bypass grafting, stroke) within 6 months before randomization
Non-AIDS-defining cancer, excluding basal and squamous cell skin cancer, within 6 months before randomization
Dialysis within 6 months before randomization
History of decompensated liver disease
Current imprisonment, or compulsory detention (involuntary incarceration) for treatment of a psychiatric or physical illness
Current pregnancy or breastfeeding (a negative serum or urine pregnancy test is required within 14 days before randomization for women of child-bearing potential)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00867048

Show 87 Study Locations

Sponsors and Collaborators

University of Minnesota - Clinical and Translational Science Institute

National Institute of Allergy and Infectious Diseases (NIAID)

Copenhagen HIV Programme (CHIP) -- Copenhagen, Denmark

Medical Research Council (MRC) Clinical Trials Unit -- London, United Kingdom

The National Centre in HIV Epidemiology and Clinical Research

The Institute for Clinical Research at the Veterans Affairs Medical Center -- Washington, D.C., USA

Agence Nationale de Recherche sur le SIDA (ANRS), France

German Federal Ministry of Education and Research

NEAT - European AIDS Treatment Network

National Health and Medical Research Council, Australia

National Institutes of Health Clinical Center (CC)

Division of Clinical Research, NIAID, NIH

National Cancer Institute (NCI)

National Heart, Lung, and Blood Institute (NHLBI)

National Institute of Mental Health (NIMH)

National Institute of Neurological Disorders and Stroke (NINDS)

Abbott

Bristol-Myers Squibb

Gilead Sciences

GlaxoSmithKline

Merck

Tibotec Pharmaceutical Limited

Investigators

Principal Investigator:	James D Neaton, PhD	University of Minnesota - Clinical and Translational Science Institute
Study Chair:	Abdel Babiker, PhD	Medical Research Council Clinical Trials Unit, London
Study Chair:	Sean Emery, PhD	National Centre in HIV Epidemiology & Clinical Research, UNSW, Sydney
Study Chair:	Fred Gordin, MD	Veterans Affairs Medical Center -- Washington, DC
Study Chair:	Jens Lundgren, MD, DMSc	Copenhagen HIV Programme

More Information

Additional Information:

INSIGHT network website, including information on the START trial This link exits the ClinicalTrials.gov site

Publications:

Egger M, May M, Chêne G, Phillips AN, Ledergerber B, Dabis F, Costagliola D, D'Arminio Monforte A, de Wolf F, Reiss P, Lundgren JD, Justice AC, Staszewski S, Leport C, Hogg RS, Sabin CA, Gill MJ, Salzberger B, Sterne JA; ART Cohort Collaboration. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002 Jul 13;360(9327):119-29. Erratum in: Lancet 2002 Oct 12;360(9340):1178.

May M, Sterne JA, Sabin C, Costagliola D, Justice AC, Thiébaut R, Gill J, Phillips A, Reiss P, Hogg R, Ledergerber B, D'Arminio Monforte A, Schmeisser N, Staszewski S, Egger M; Antiretroviral Therapy (ART) Cohort Collaboration. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. 2007 May 31;21(9):1185-97.

Silverberg MJ, Neuhaus J, Bower M, Gey D, Hatzakis A, Henry K, Hidalgo J, Lourtau L, Neaton JD, Tambussi G, Abrams DI. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS. 2007 Sep 12;21(14):1957-63.

Responsible Party:	University of Minnesota ( James D. Neaton, Ph.D/Principal Investigator )
Study ID Numbers:	0603M83587, U01AI068641, 2008-006439-12
Study First Received:	March 20, 2009
Last Updated:	February 3, 2010
ClinicalTrials.gov Identifier:	NCT00867048 History of Changes
Health Authority:	Argentina: Ministry of Health; Australia: National Health and Medical Research Council; Belgium: Institutional Review Board; Brazil: Ethics Committee; Chile: Instituto de Salud Publica de Chile; Denmark: Ethics Committee; European Union: European Medicines Agency; Finland: Ethics Committee; France: National Consultative Ethics Committee for Health and Life Sciences; Germany: Ethics Commission; Greece: Ethics Committee; Israel: Ethics Commission; Italy: National Bioethics Committee; Mali: Ministry of Health; Morocco: Ministry of Public Health; Peru: Ethics Committee; Poland: Ethics Committee; Singapore: Domain Specific Review Boards; South Africa: National Health Research Ethics Council; Spain: Ethics Committee; Switzerland: Ethikkommission; Thailand: Ethical Committee; United Kingdom: Research Ethics Committee; United States: Federal Government; United States: Institutional Review Board

Keywords provided by University of Minnesota - Clinical and Translational Science Institute:

HAART
CD4 Count
Early Intervention
HIV

HIV Infection
HIV Infections
treatment naive

Additional relevant MeSH terms:

Communicable Diseases
RNA Virus Infections
Sexually Transmitted Diseases, Viral
Slow Virus Diseases
Immune System Diseases
Acquired Immunodeficiency Syndrome
Infection

Immunologic Deficiency Syndromes
Virus Diseases
HIV Infections
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections

ClinicalTrials.gov processed this record on February 08, 2010