From SMART to Start - HIV Research Catalyst Forum

download report

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?