Transcript From SMART to Start - HIV Research Catalyst Forum
From SMART to Start Randomized Controlled Clinical Trials (RCTs) What they are? Why are they important? Paul Dalton Introduction • Define Terms • Clinical Trial • Randomization • Control • Later we will look at risk, harm Clinical Trial • A clinical trial is the scientific study of a medicine, device or other kind of therapy in humans. • The first goal of any clinical trial to ensure the safety of its participants • A clinical trail can look at many kinds of questions • Specific drugs • Treatment Strategies • Natural History Randomization • Randomization: to select or assign study participants in a blind manner (like flipping a coin), especially to reduce the potential for bias. • Randomization protects the integrity of the research by ensuring that the people doing the study (who have some interest in the outcome) do not consciously or unconsciously skew the study by assigning people to different arms of a study in a hidden manner. Control • Control here means something to compare to. • Need to account for the ‘placebo effect’ • Need to have something concrete to judge an intervention by • Is A better than B • Is C better than nothing Types of Control • Active • Direct drug to drug comparison • Kaletra vs. Reyataz • Placebo • One group gets drug, the other a dummy drug • Placebo effect • Historic • Comparing the study intervention to earlier treatments. Why RCTs? • All research has value • There is a hierarchy of data • RCT>Non Randomized Controlled >Non Controlled>observational Hierarchy of Evidence RCTs Non Randomized Trials Cohorts Expert Opinion Observation/Anecdote The SMART Study • SMART or Strategies for Management of AntiRetroviral Therapy • Largest study of its kind ever done in HIV • Was to enroll around 6000 people, at over 300 sites in 33 countries SMART • Strategy Trail • Compared continuous HIV treatment (called Viral Suppression or VS) to CD4 guided intermittent therapy (called Drug Conservation or DC) • VS group: start HIV treatment upon enrollment and stay on • DC group: start HIV treatment when CD4 count falls to 250 (or below), stop when it rises to 350 (or above) SMART • The rationale for SMART • Widespread use of ART in economically developed countries has resulted in a significant decline in HIV-related illness and death. However, ART effectiveness may wane over time as the virus becomes resistant to drugs. There are also short- and long-term toxicities, as well as cost and quality-of-life issues, associated with lifelong ART. Therefore, a randomized clinical trial was implemented comparing the use of CD4+ cell-guided episodic ART (DC strategy) with continuous ART (VS strategy). • The SMART trial was designed to compare the DC strategy with the VS strategy for progression to AIDS or death over a minimum follow-up period of 6 years for each patient. It was hypothesized that the DC strategy would result in lower rates of disease progression and serious toxicities as compared to the VS strategy in the planned follow-up period ranging from 6 to 9 years. What Happened? • After about 90% of participants had been enrolled a group called the DSMB halted enrollment of the study and suggested all participants who met the criteria for starting ARVs start taking them and stay on them. • The Data Safety and Monitoring Board • An independent group of scientists (and occasionally community members) review un-blinded results from an ongoing trial to ensure the safety of the participants. Why did the Close SMART? • Top Line Finding: • Participants in the DC arm were over 2 times as likely to die or progress to AIDS compared to those in the VS group. • Further results showed more heart, kidney, and liver disease along with more OIs and other AIDS defining events. Smart Results SMART Results Continuous Treatment Intermittent Treatment Hazard Ratio Number Enrolled 2752 2720 Time on ARVs 93% 33% Disease Progression 17 (3.7%) 47 (1.5%) 2.7 Death 30 (0.9%) 55 (1.7%) 1.8 Serious Disease Progression/Dea th 0.1% 0.6% 6.6 Serious CV Disease 39 (1.4%) 68 (2.1%) 1.7 SMART in More Detail • Relative vs. Absolute Risk • Organ Disease findings Continuous Treatment Intermittent Treatment Hazard Ratio Major CV disease 31 48 1.6 Renal Disease 2 9 1.4 10 1.4 Liver Disease 7 SMART REsults SMART DISCUSSION • Created quite a stir among researchers, doctors and community • Compare to other trials (PART, DART, TRIVICAN) SMART was larger and had a more solid trial design • Showed clearly a higher risk for treatment interruptions • Little STI research as a result Now to START • The “When to Start?” question is the single most important, unanswered question in HIV • There has been a long standing debate on the wisdom of studying this question. • Some think that such a trial is • Unnecessary • Impractical • Too expensive • Won’t enroll The START Trail • Large Prospective Randomized Controlled When To Start Trial • Pilot Phase: n=900 • Full Trail: n=4000 • Immediate vs. Delayed Treatment The Importance of STart • Current Guidelines Recommend Starting Treatment when CD4 counts fall to 500 • Also discuss the possibility of starting at higher counts • Decision has created controversy • 1. Were there enough data • 2. Would this harm the START trial Discussion and Questions RCTs? SMART? START?