1. From SMART to Start Randomized Controlled Clinical Trials (RCTs) What they are? Why are they important? Paul Dalton

2. Introduction Define TermsDefine Terms Clinical TrialClinical Trial RandomizationRandomization ControlControl Later we will look at risk, harmLater we will look at risk, harm

3. Clinical Trial A clinical trial is the scientific study of a medicine, device or other kind of therapy in humans.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 participantsThe first goal of any clinical trial to ensure the safety of its participants A clinical trail can look at many kinds of questionsA clinical trail can look at many kinds of questions Specific drugsSpecific drugs Treatment StrategiesTreatment Strategies Natural HistoryNatural History

4. Randomization Randomization: to select or assign study participants in a blind manner (like flipping a coin), especially to reduce the potential for bias.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.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.

5. Control Control here means something to compare to.Control here means something to compare to. Need to account for the ‘placebo effect’Need to account for the ‘placebo effect’ Need to have something concrete to judge an intervention byNeed to have something concrete to judge an intervention by Is A better than BIs A better than B Is C better than nothingIs C better than nothing

6. Types of Control ActiveActive Direct drug to drug comparisonDirect drug to drug comparison Kaletra vs. ReyatazKaletra vs. Reyataz PlaceboPlacebo One group gets drug, the other a dummy drugOne group gets drug, the other a dummy drug Placebo effectPlacebo effect HistoricHistoric Comparing the study intervention to earlier treatments.Comparing the study intervention to earlier treatments.

7. Why RCTs? All research has valueAll research has value There is a hierarchy of dataThere is a hierarchy of data RCT>Non Randomized Controlled >Non Controlled>observationalRCT>Non Randomized Controlled >Non Controlled>observational

8. Hierarchy of Evidence RCTs Non Randomized Trials Cohorts Expert Opinion Observation/Anecdote

9. The SMART Study SMART or S trategies for M anagement of A nti- R etroviral T herapySMART or S trategies for M anagement of A nti- R etroviral T herapy Largest study of its kind ever done in HIVLargest study of its kind ever done in HIV Was to enroll around 6000 people, at over 300 sites in 33 countriesWas to enroll around 6000 people, at over 300 sites in 33 countries

10. SMART Strategy TrailStrategy Trail Compared continuous HIV treatment (called Viral Suppression or VS) to CD4 guided intermittent therapy (called Drug Conservation or DC)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 onVS 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)DC group: start HIV treatment when CD4 count falls to 250 (or below), stop when it rises to 350 (or above)

11. SMART The rationale for SMARTThe 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).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.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.

12. 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.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 BoardThe 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.An independent group of scientists (and occasionally community members) review un-blinded results from an ongoing trial to ensure the safety of the participants.

13. Why did the Close SMART? Top Line Finding: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.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.Further results showed more heart, kidney, and liver disease along with more OIs and other AIDS defining events.

14. Smart Results

15. SMART Results Continuous Treatment Intermittent Treatment Hazard Ratio Number Enrolled27522720 Time on ARVs93%33% Disease Progression 17 (3.7%)47 (1.5%)2.7 Death30 (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

16. SMART in More Detail Relative vs. Absolute RiskRelative vs. Absolute Risk Organ Disease findingsOrgan Disease findings Continuous Treatment Intermittent Treatment Hazard Ratio Major CV disease 3148 1.6 Renal Disease 291.4 Liver Disease7101.4

17. SMART REsults

18. SMART DISCUSSION Created quite a stir among researchers, doctors and communityCreated quite a stir among researchers, doctors and community Compare to other trials (PART, DART, TRIVICAN) SMART was larger and had a more solid trial designCompare to other trials (PART, DART, TRIVICAN) SMART was larger and had a more solid trial design Showed clearly a higher risk for treatment interruptionsShowed clearly a higher risk for treatment interruptions Little STI research as a resultLittle STI research as a result

19. Now to START The “When to Start?” question is the single most important, unanswered question in HIVThe “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.There has been a long standing debate on the wisdom of studying this question. Some think that such a trial isSome think that such a trial is UnnecessaryUnnecessary ImpracticalImpractical Too expensiveToo expensive Won’t enrollWon’t enroll

20. The START Trail Large Prospective Randomized Controlled When To Start TrialLarge Prospective Randomized Controlled When To Start Trial Pilot Phase: n=900Pilot Phase: n=900 Full Trail: n=4000Full Trail: n=4000 Immediate vs. Delayed TreatmentImmediate vs. Delayed Treatment

21. The Importance of STart Current Guidelines Recommend Starting Treatment when CD4 counts fall to 500Current Guidelines Recommend Starting Treatment when CD4 counts fall to 500 Also discuss the possibility of starting at higher countsAlso discuss the possibility of starting at higher counts Decision has created controversyDecision has created controversy 1. Were there enough data1. Were there enough data 2. Would this harm the START trial2. Would this harm the START trial

22. Discussion and Questions RCTs?SMART?START?