From SMART to StartFrom SMART to StartRandomized Controlled Clinical Trials Randomized Controlled Clinical Trials

(RCTs)(RCTs)

What they are? What they are?

Why are they important?Why are they important?

Paul Dalton Paul Dalton

IntroductionIntroduction

• Define TermsDefine Terms• Clinical TrialClinical Trial• RandomizationRandomization• ControlControl

• Later we will look at risk, harmLater we will look at risk, harm

Clinical TrialClinical Trial

• A clinical trial is the scientific study of a A clinical trial is the scientific study of a medicine, device or other kind of therapy in medicine, device or other kind of therapy in humans. humans.

• The first goal of any clinical trial to ensure the The first goal of any clinical trial to ensure the safety of its participantssafety of its participants

• A clinical trail can look at many kinds of A clinical trail can look at many kinds of questionsquestions• Specific drugsSpecific drugs• Treatment StrategiesTreatment Strategies• Natural HistoryNatural History

RandomizationRandomization

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

• Randomization protects the integrity of the Randomization protects the integrity of the research by ensuring that the people doing research by ensuring that the people doing the study (who have some interest in the the study (who have some interest in the outcome) do not consciously or unconsciously outcome) do not consciously or unconsciously skew the study by assigning people to skew the study by assigning people to different arms of a study in a hidden manner. different arms of a study in a hidden manner.

ControlControl

• 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 Need to have something concrete to judge an intervention byintervention by• Is A better than BIs A better than B• Is C better than nothingIs C better than nothing

Types of ControlTypes of Control

• ActiveActive• Direct drug to drug comparisonDirect drug to drug comparison

• Kaletra vs. Reyataz Kaletra 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 Comparing the study intervention to earlier

treatments. treatments.

Why RCTs?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 RCT>Non Randomized Controlled >Non Controlled>observationalControlled>observational

Hierarchy of EvidenceHierarchy of Evidence

The SMART StudyThe SMART Study

• SMART or SMART or SStrategies for trategies for MManagement of anagement of AAnti-nti-RRetroviral etroviral TTherapyherapy

• 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 Was to enroll around 6000 people, at over 300 sites in 33 countriessites in 33 countries

SMARTSMART

• Strategy TrailStrategy Trail

• Compared continuous HIV treatment (called Compared continuous HIV treatment (called Viral Suppression or VS) to CD4 guided Viral Suppression or VS) to CD4 guided intermittent therapy (called Drug Conservation intermittent therapy (called Drug Conservation or DC)or DC)

• VS group: start HIV treatment upon enrollment VS group: start HIV treatment upon enrollment and stay onand stay on

• DC group: start HIV treatment when CD4 count DC group: start HIV treatment when CD4 count falls to 250 (or below), stop when it rises to falls to 250 (or below), stop when it rises to 350 (or above) 350 (or above)

SMARTSMART

• The rationale for SMARTThe rationale for SMART• Widespread use of ART in economically developed countries Widespread use of ART in economically developed countries

has resulted in a significant decline in HIV-related illness and has resulted in a significant decline in HIV-related illness and death. However, ART effectiveness may wane over time as death. However, ART effectiveness may wane over time as the virus becomes resistant to drugs. There are also short- the virus becomes resistant to drugs. There are also short- and long-term toxicities, as well as cost and quality-of-life and long-term toxicities, as well as cost and quality-of-life issues, associated with lifelong ART. Therefore, a randomized issues, associated with lifelong ART. Therefore, a randomized clinical trial was implemented comparing the use of CD4+ clinical trial was implemented comparing the use of CD4+ cell-guided episodic ART (DC strategy) with continuous ART cell-guided episodic ART (DC strategy) with continuous ART (VS strategy).(VS strategy).

• The SMART trial was designed to compare the DC strategy The SMART trial was designed to compare the DC strategy with the VS strategy for progression to AIDS or death over a with the VS strategy for progression to AIDS or death over a minimum follow-up period of 6 years for each patient. It was minimum follow-up period of 6 years for each patient. It was hypothesized that the DC strategy would result in lower hypothesized that the DC strategy would result in lower rates of disease progression and serious toxicities as rates of disease progression and serious toxicities as compared to the VS strategy in the planned follow-up period compared to the VS strategy in the planned follow-up period ranging from 6 to 9 years.ranging from 6 to 9 years.

What Happened?What Happened?

• After about 90% of participants had been After about 90% of participants had been enrolled a group called the DSMB halted enrolled a group called the DSMB halted enrollment of the study and suggested all enrollment of the study and suggested all participants who met the criteria for starting participants who met the criteria for starting ARVs start taking them and stay on them. 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 An independent group of scientists (and

occasionally community members) review un-occasionally community members) review un-blinded results from an ongoing trial to ensure blinded results from an ongoing trial to ensure the safety of the participants. the safety of the participants.

Why did the Close Why did the Close SMART?SMART?

• Top Line Finding:Top Line Finding:• Participants in the DC arm were over 2 times as Participants in the DC arm were over 2 times as

likely to die or progress to AIDS compared to likely to die or progress to AIDS compared to those in the VS group. those in the VS group.

• Further results showed more heart, kidney, and Further results showed more heart, kidney, and liver disease along with more OIs and other liver disease along with more OIs and other AIDS defining events. AIDS defining events.

Smart ResultsSmart Results

SMART ResultsSMART 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/Death

0.1% 0.6% 6.6

Serious CV Disease

39 (1.4%) 68 (2.1%) 1.7

SMART in More DetailSMART in More Detail

• Relative vs. Absolute Risk Relative vs. Absolute Risk • Organ Disease findingsOrgan Disease findings

Continuous Treatment

Intermittent Treatment

Hazard Ratio

Major CV disease

31 48 1.6

Renal Disease

2 9 1.4

Liver Disease

7 10 1.4

SMART REsultsSMART REsults

SMART DISCUSSIONSMART DISCUSSION

• Created quite a stir among researchers, Created quite a stir among researchers, doctors and communitydoctors and community

• Compare to other trials (PART, DART, Compare to other trials (PART, DART, TRIVICAN) SMART was larger and had a more TRIVICAN) SMART was larger and had a more solid trial designsolid trial design

• Showed clearly a higher risk for treatment Showed clearly a higher risk for treatment interruptionsinterruptions

• Little STI research as a resultLittle STI research as a result

Now to STARTNow to START

• The “When to Start?” question is the single The “When to Start?” question is the single most important, unanswered question in HIVmost important, unanswered question in HIV

• There has been a long standing debate on the There has been a long standing debate on the wisdom of studying this question. 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

The START TrailThe START Trail

• Large Prospective Randomized Controlled Large Prospective Randomized Controlled When To Start TrialWhen To Start Trial

• Pilot Phase: n=900Pilot Phase: n=900

• Full Trail: n=4000Full Trail: n=4000

• Immediate vs. Delayed TreatmentImmediate vs. Delayed Treatment

The Importance of STartThe Importance of STart

• Current Guidelines Recommend Starting Current Guidelines Recommend Starting Treatment when CD4 counts fall to 500Treatment when CD4 counts fall to 500

• Also discuss the possibility of starting at Also discuss the possibility of starting at higher countshigher 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

Discussion and Discussion and QuestionsQuestions

RCTs?RCTs?

SMART?SMART?

START?START?