Download HIVTRI workshop: Treatment information for doctors and

Trial design: how do we know
what is real?
African Eye Trust Treatment Advocate
Training
20 September 2007
Simon Collins
www.i-Base.info
Trial design: i-Base training
London - September 2007
Two examples
i) something about HIV that
you know for sure (a fact)
ii) something about HIV that
you are not sure of (an
uncertainty)
Trial design: i-Base training
London - September 2007
Why?
i) List why you think the fact is
true
ii) List why you are uncertain
about the second point
Trial design: i-Base training
London - September 2007
Trust vs proof
As advocates we need to know how
reliable anything we say is.
•
What evidence is there?
•
What facts have been proven?
•
What are the conditions for that
evidence?
•
And what don’t we know?
Trial design: i-Base training
London - September 2007
Recent example
Discussion on the UK-CAB list about a
microbicide trial where everyone in the study
was given condoms, prevention advice, and
either a microbicide or placebo
•
How would you know if the microbicide
worked?
•
Was scientific explanation difficult to
follow?
Trial design: i-Base training
London - September 2007
Types of evidence
•
Observed evidence - from which we
can come up with ideas or hypotheses (eg
HIV prevalence)
•
Proven evidence - where a hypothesis
has been tested and specific results have
been seen
(eg - could HIV be a virus)
Trial design: i-Base training
London - September 2007
Recent example
Discussion on the CAB list about how
certain we are that HIV is a sexually
transmitted virus
Is HIV an infection? Does it exist?
History of HIV
• Case studies
• Epidemiological studies
• Cohort studies
Trial design: i-Base training
London - September 2007
NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org
ROLE OF VIRAL LOAD IN BOTH TRANSFUSION- AND HETEROSEXUAL-TRANSMISSION OF
HIV-1 INFECTION.
BACKGROUND: In the TSS, 90% of recipients of components from HIV-1 positive donors
became infected. In contrast, 32% of long-term heterosexual partners of the recipients became
infected. We examined the importance of plasma viral load in these two contexts representing
very different mechanisms and probabilities of transmission.
METHODS: Donors' sera stored at donation and recipients' sera collected throughout the period
of possible transmission to their partners were evaluated for quantitative HIV-1 RNA using the
Amplicor HIV Monitor Assay™ (Roche Molecular Systems, Inc.).
RESULTS: Mean RNA levels for transmitting and non-transmitting donors were 3.4 and 3.0 logl0
copies/m L (p= 0.0l). Levels for sexually transmitting and non-transmitting recipients were 4.3 and
3.6 logl0 copies/mL (P= 0.05).
CONCLUSION: Viral load appears to be the identifiably important determinant for both
transfusion- and heterosexual-transmission of HIV-1 infection. (Supported by NHLBI Contracts
NOl-HB-4-7002,4-7003, and 9-7074.)
3rd CROI - 1996 Abst 31
Trial design: i-Base training
London - September 2007
NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org
HETEROSEXUAL TRANSMISSION OF HIV-1 FROM TRANSFUSION RECIPIENTS.
INTRODUCTION: HIV-1 infected transfusion recipients (recips) are useful for studying
heterosexual HIV-1 transmission, as the duration of infection is known and confounding risk
behaviors are rare.
METHODS: The Roche HIV-1 Monitor Assay was used to quantitate HIV-1 RNA in frozen sera
from a cohort of 45 heterosexually active HIV-1 (+) transfusion recips (31 m, 14 f), of whom 6
males transmitted HIV-1 to female sexual partners (J AIDS 1994; 7:705-1 0).
RESULTS: HIV-1 RNA levels were similar in male and female recips (mean copies/mL: 25,642 vs
26,124, respectively). The table compares HIV-1 RNA load in male transmitters (TR) and nontransmitters (NGR): (table: see text).
N
HIV-1 RNA load
(copies/mL)
range
median
mean
S.D.
TR
6
7,700-143,000
43,400
64,645
57,064
NTR
25
200-181,000
5,760
16,289
35,847
CONCLUSIONS: The low rate of female to male HIV-1 transmission is probably due to
physiological rather than virological factors. There is a strong association between viral load and
heterosexual transmission from male to female. Therapies that reduce viral load may reduce the
rate of heterosexual spread of the epidemic.
3rd CROI, Abs 258
Trial design: i-Base training
London - September 2007
Different types of trial
•
experimental vs observational
•
cross-sectional vs longitudinal
•
prospective vs retrospective
Trial design: i-Base training
London - September 2007
Different types of studies
•
•
•
•
•
•
•
Randomised controlled trial (RCT) - gold
standard = prospective, randomised, doubleblinded, placebo-controled study’ - explain
Cohort study
Case-control study
Cross-sectional study
Case series/case note review
Literature review/systematic review
Meta-analysis
Trial design: i-Base training
London - September 2007
Key concepts
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•
•
•
•
•
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Randomisation
Blinding and double-blinding
Placebo, control
Study size and population (baseline)
Standard of care
Ethics
Informed consent
Trial design: i-Base training
London - September 2007
Randomisation
• Selecting people for any group or event by
chance - like throwing a dice or tossing a
coin - other examples - good and bad?
• Not haphazard allocation
• Not being able to predict the allocation of
each participant
Trial design: i-Base training
London - September 2007
Randomisation
• To ensure that there is a balance at the start
between the groups being studied and there are
no systematic differences (in known and
unknown variables)
• Provides a sound basis for statistical evaluation
of data.
• To ensure that any difference in outcome between
the different groups is due to differences in
treatment or other intervention
Trial design: i-Base training
London - September 2007
Blinding
• Not being able to predict the allocation of
each participant
• A participant not knowing the treatment
arm
• Double-blinding - neither the participant
nor the doctor know the treatment arm
Trial design: i-Base training
London - September 2007
Placebo
• Dummy pill that looks, tastes, smells and
feels like the drug being studied
(impossible to make a ritonavir liquid
placebo that wasn’t toxic)
• Placebo trials often involve patients taking
more pills
Trial design: i-Base training
London - September 2007
Control
• A treatment arm that acts as a comparison
to an intervention
• Usually this should be standard of care examples?
Examples : Prevention and treatment trials
Trial design: i-Base training
London - September 2007
Study size and population
• How does the size of a study affect the
results?
• How does it affect interpretation?
• Who is being studied?
• What else could be going on?
Trial design: i-Base training
London - September 2007
NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org
SAFETY PROFILE OF LAMIVUDINE (3TC) IN PATIENTS WITH ADVANCED HIV-INFECTION.
3TC is a new reverse transcriptase inhibitor which appears promising for the treatment of HIV
infection. One of its main advantages is the lack of side-effects compared to other nucleoside
analogues. However, there is little data on its tolerance in the advanced stages of HIV infection.
36 patients with advanced HIV infection were enrolled in a compassionate protocol at one centre.
There were 32 males and 4 females with a mean age of 39.6 + 9.2 years (range 18 - 55 years).
The mean CD4 count at onset of therapy was 80+/-68 cells/microliter. 15 patients received 3TC
as a single antiretroviral agent, and 21 patients received combination with AZT, ddI or ddC.
7 patients (19.4%) discontinued 3TC because of side-effects, and 17 patients (47.2%) reported
some side-effects. Side-effects attributed to 3TC was more common in patients receiving single
antiretroviral agent, 12 (80%) vs those receiving combination therapy, 5 (25%). Mean number of
medications received by patients with side effects (4.3) was similar to those with out adverse
events (4.5).
The most frequent side effects were hair loss 5 (13.9%), neuritis 5 (13.9%), anaemia 4 (11.1%),
leucopenia 4 (11.1%) with 2 severe neutropenia (less than 500 cell), nausea and vomiting 3
(8.3%). 3TC is less well tolerated in advanced HIV disease, compared to reports in earlier stages
of the disease, and can cause serious side effects.
3rd CROI, Abs 134
Trial design: i-Base training
London - September 2007
NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org
PLASMA HIV RNA LEVELS DURING STAVUDINE (D4T) THERAPY OF PATIENTS WITH
ADVANCED AIDS
OBJECTIVE: This is an interim report on the effect of d4T therapy on plasma viremia in patients
intolerant to other antiretroviral therapies or have experienced a significant clinical or immunologic
deterioration while receiving these therapies.
METHODS: Advanced AIDS patients enrolled in a d4T compassionate use study (Named Patient
Program) were evaluated at O (pretreatment), 1 and 3 months for changes in plasma viral load
(HIV RNA PCR, Roche Amplicor HIV Monitor Kit). All patients had a history of long-term
antiretroviral therapy (ZDV, DDI, or DDC). Subjects received one of three doses (40, 30 or 20 mg
d4T, b.i.d.) depending on weight and contraindications.
RESULTS: To date, 23 HIV-infected patients (CDC stage B2-C3) who had specimens available at
O and 1 month have been evaluated. Pretreatment viral loads ranged from 2,875,000 to 2,300
HIV RNA copies/ml with a median of 200,485. After one month of d4T therapy, the median viral
load decreased by 0.2 logs (P= 0.03, Wilcoxon signed rank test). There was no significant
difference in median plasma viral loads between the pretreatment and 3 month time points (N=13,
-0.16 log, P= 0.152).
CONCLUSION: One month of d4T therapy produced a small but significant reduction in the
plasma HIV-1 RNA load in our patients with advanced HIV disease..
3rd CROI, Abs 136
Trial design: i-Base training
London - September 2007
NOTE: STUDY FROM CROI 1996 - all online at AEGiS.org
VIROLOGICAL EFFICACY OF STAVUDINE VS PLACEBO IN EARLY HIV INFECTION.
OBJECTIVE: To compare the virological efficacy of two dose levels of stavudine with placebo in
asymptomatic HIV infected subjects (CD4 : 350-750 cells/mm©¯).
METHODS: Sixty six subjects were included on the basis of positive HIV PBMCs culture and
assigned randomly to either 80 mg (N=22) or 40 mg (N=22) of stavudine or to placebo (N=22).
Virological evaluation (virus isolation, quantitative cell viremia, plasma RNA quantitation
(NASBA), ICD p24) was performed at Day -35, Day 0 and monthly for the first three months (Ml,
M2, M3).
RESULTS: Baseline (mean of cell viremias : 8.3 NIU/106 cells and mean of plasma RNA viremia:
14732 copies/ml). A trend to the decrease of isolation rate was observed in the two stavudine
groups as compared to placebo group but this decrease was not significant. Cell viremia titers
exhibited significant decreases in the 80 mg group : 0.6 log at Ml, 1.0 log at M2 and M3 (p < 0.01
in the three cases). In the 40 mg group, viremia titer decreases were less marked (0.5 log at Ml
and M2, 0.7 log at M3) but still significant (p < 0.01 in the three cases). No significant change was
observed in placebo group. Partial results of plasma RNA viremia exhibited significant decreases
under therapy : 0,6 log at Ml and M3 in the 80 mg group, 0,4 log at Ml and M3 in the 40 mg group.
No significant change of plasma RNA viremia was observed in placebo group.
CONCLUSION: A dose-dependent efficacy of stavudine was observed as compared to placebo in
asymptomatic subjects with high CD4 cell count. The analysis of cell culture and plasma RNA
viremias provided concordant significant results. Implications for the design of future virological
evaluations will be discussed.
3rd CROI, Abs 142
Trial design: i-Base training
London - September 2007
Example
• How do you understand these examples of early
studies of 3TC and d4T
• Important to know history of drugs
• If the drug name was not included - could you
have guessed the study was talking about 3TC
• Risk of relying on results of small studies with
many confounding factors (ie advanced HIV)
Trial design: i-Base training
London - September 2007
Standard of care
• Should be common sense - the best
current treatment
• Standard of care should be given to every
person in a study as a minimum treatment
• It is unethical to pretend that current
knowledge doesn’t exist
Trial design: i-Base training
London - September 2007
Ethics
• Only randomise if there is
uncertainty
• Good ethics is good science
• Bad ethics is bad science
Trial design: i-Base training
London - September 2007
Ethics
Is it always ethical to have controls?
OR
Is it ever ethical not to have controls?
Trial design: i-Base training
London - September 2007
Informed consent
• Written and verbal information to ensure that
someone who joins a study understands the potential
risks and benefits
• That they understand what is required by joining the
study
• That they should be free to leave the study at any
time without it jeopardising their healthcare
• That they acknowledge and agree to these terms
Trial design: i-Base training
London - September 2007
Exercise
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Decide a hypothesis or idea
Design a study to test the hypothesis
Study size? - big event or small event?
What are the benefits of the study
What are the weaknesses of the study
Trial design: i-Base training
London - September 2007
Thank you…
www.i-Base.info
[email protected]
Some of these slides were adapted from a
presentation given by Tim Peto to the first UK-CAB
meeting in May 2002. Available online:
www.ukcab.net
Trial design: i-Base training
London - September 2007