HIV Clinical trials at MRC CTU
• MRC CTU focus is on long-term
large size clinical trials yielding
definitive results that may result in
changes in clinical practice
–Ongoing studies
–New study networks: INSIGHT and
European networks
–Planned new studies
•
•
•
•
•
BACKGROUND
ESPRIT is an international, phase III, openlabel, randomized trial
To compare the effects of subcutaneous rIL-2
and no rIL-2 on HIV disease progression and
death
HIV-1 patients with absolute CD4+ counts
300/ul at baseline who are taking combination
antiretroviral therapy (ART)
3 mandatory cycles of rIL-2 then cycling to
maintain CD4+ > double baseline or 1,000/ul
Primary end points: HIV progression of
disease, death.
ESPRIT: SUMMARY
• 247 sites in 25 countries
• 4,150 patients recruited; 356 (9%) in UK NTCC
• 2,090 patients randomised to rIL-2: 183 (9%) in UK
NTCC
• 320 end-points required
Median Change
Median Change in CD4 Cell Count from
Baseline with Inter-Quartile Range
500
400
300
200
100
0
BL
No. of
patients
4
2090
8
2023
12
1981
16
1975
20
1903
24
28
Month
1836 1628
1871
32
1469
36
1300
40
1091
44
878
48
675
Number of IL-2 Cycles Initiated after Induction Pha
100
% of patients
80
60
40
20
0
0
1
2
Number of Cycles
3-4
Percent at Goal by Follow-up
Visit 40
Percent
30
20
10
0
BL
4
8
12
16
20
24
28
32
36
40
44
48
1469
1300
1091
878
675
Month
No. of
patients
2090
2023
1981
1975
1903
1871
1836
1628
Patients Not at Goal at Time of Initiative*
Have cycled
Cycling plans
Total
N
%
Plan to cycle
513
296
57.7
Do not plan to cycle
744
76
10.2
Total
1257
* Patients with no medical contraindication to IL-2
Cycling Initiative Summary
• 10% of patients have medical contraindication
(no surprises)
– About 40% of patients not at goal plan to cycle
and 60% do not plan to
– Main reason for not planning to cycle
• Patient wish
– Leading cause of dose reduction or interruption
• Systemic adverse effects
– Few patients are using prophylactic medication
as specified in MOOP
Follow-up
• 4150 patients followed for a
median of 40.3 months
• 41,542 follow-up visits conducted
Missed Follow-up Visits by Region
Region
No. Visits
Attended
No.
Missed % Missed
Copenhagen
8,342
348
4.0
London
6,440
293
4.4
Minneapolis
13,764
881
6.0
Sydney
12,996
268
2.0
Total
41,542
1,790
4.1
Loss to Follow-up by Region
No.
Randomized
No.
Lost
Copenhagen
982
39
4.0
London
708
34
4.8
Minneapolis
1,227
102
8.3
Sydney
1,233
30
2.4
Total
4,150
205
4.9
Region
% Lost
SMART Rationale
• Need for better strategies to optimize
benefits and minimize risks of ART
• Continuous therapy may not be optimal
• Cessation of therapy at high CD4 counts
is probably safe if monitor and restart
before critical decline
• Strategy relevant for both resource rich
and (some) resource limited countries
SMART Study Design
Participants with CD4 > 350
n = 3000
n = 3000
Virologic Suppression
(VS) Strategy
[Use ART to maintain viral
load as low as possible
throughout follow-up]
Drug Conservation
(DC) Strategy
[Stop or defer ART until CD4
< 250; then episodic ART
based on CD4 cell count to
increase counts to > 350]
Follow-up for 6-9 years
SMART Study - International
SMART Study International
CPCRA
RCC
Sydney
RCC
Brazil
Canada
Peru
South Africa
United States
Argentina
Australia
Chile
Israel
Japan
New Zealand
Thailand
Uruguay
Copenhagen
RCC
Austria,
Belgium
Denmark,
Estonia
Finland,
Germany
Lithuania,
Luxembourg
Norway,
Poland
London
RCC
France
Greece
Ireland
Italy
Morocco
Switzerland
United
Kingdom
Enrollment- London
NCC
France
Greece
Ireland
Italy
Morocco
Switzerland
UK
Actual/Goal
193/185
69/75
1/10
58/135
38/25
37/100
170/200
SMART Enrollment
(As of 19 July 2005)
Goal
Enrolled
Pct.
Main SMART
6000
3909
65 %
QOL and Healthcare
Utilization
1200
1224
100 %
HIV Transmission Risk
Behavior
1010
786
78 %
Body Composition
300
219
73 %
Neurology
920
2
0%
Anal Dysplasia
560
2
0%
DC Group
Time to Re-initiation of ART
Median time to re-initiation: 18 months
Percent of DC Patients who have
(Re)initiated ART by Month
90
Not Consistent with DC Strategy
Consistent with DC Strategy
Percent by Month
80
70
60
50
40
30
20
10
33
th
30
by
M
on
th
27
by
M
on
th
24
by
M
on
th
21
by
M
on
th
18
by
M
on
th
15
M
on
th
by
by
M
on
th
12
9
by
M
on
th
6
by
M
on
th
3
M
on
th
by
M
on
by
by
M
on
th
1
0
Reasons for (re-)initiations not consistent with DC strategy:
62
50%
Patient wish only
32
25%
High HIV RNA
31
25%
Other
125
100%
Total
Summary
• Completion of study enrollment, overall and
for substudies, by April 06 – on track for
overall enrollment
• Need to improve co-enrollment in Neurology
and Anal Dysplasia substudies
• Maintain excellent follow-up and data quality
• Reduce departures from protocol guidelines
concerning adherence to VS and DC groups
STALWART
• Study of ALdesleukin With and
without AntiRetroviral Therapy
–OR
• ESPRIT 002
STALWART rationale
• BIG Q = can IL-2 be used to delay
initiation of ART
• INITIAL (Pilot) Qs =
• 1) Does IL-2 in early HIV maintain or
increase CD4 counts?
• 2) Is it better to give IL-2 with pericycle ART?
Comparison of IL-2 Vanguard Studies CD4+
Cell Responses
1300
Argentina
Thailand
Houston
United Kingdom
CD4+ (cells/cu mm)
1200
1100
1000
900
800
700
600
500
400
0
8
Weeks
16
24
STALWART
CD4 > 300
No prior IL-2
No ART within last 1y
No ART
No IL-2
IL-2 7.5MU for
5/7 every 8 weeks
X3
IL-2 7.5MU for 5/7
every 8 weeks X 3 +
peri-cycle HAART
Then prn to keep
CD4 above goal
Then prn to keep
CD4 above goal
STALWART
• Follow-up monthly to w32 then
every 4m until 12m after last patient
randomised
• Primary outcome measure =
Change in CD4 count from baseline
to w32
• Study powered to detect a 50 cell
difference b/w arms (especially
important for the 2 IL-2 arms)
STALWART Site Selection
• Criteria for sites:
– performance during first two years of ESPRIT
• ≥ 5 patients randomized
• ≥ 80% of patients had 3 cycles of IL-2
• ≤10% of visits missed
– commitment to randomize ≥ 5 patients
– other sites deemed appropriate by RCC and
ESPRIT EC
Site Selection and Recruitment Estimates
Sites
• Sydney RCC
– Argentina
– Australia
– Thailand
• Copenhagen RCC
–
–
–
–
Germany
Portugal
Poland
Spain
• London RCC
•
– Italy
– Morocco
– United Kingdom
Minneapolis/CPCRA RCC
– Brazil
– CPCRA
– DVA
– Houston
– NIH
TOTAL
Enrollment Estimates
18
217
8
6
4
90
47
80
18
132
3
3
2
10
21
21
20
70
15
100
5
1
9
30
10
60
10
92
2
3
2
2
1
20
31
11
15
15
61
541
Timeline
May 2005
– Protocol Version 1 available
– Invitation letter distributed
June - July 2005
– CRFs completed
– Protocol Information Manual completed
July 2005
– First STALWART training occurs
August 2005
– First patient enrolled
SMART or STALWART?
SMART
–the right choice for those who are willing to
take a 50/50 chance of starting ARVs now
STALWART
–the right choice for those who want to
postpone starting ARVs and see what IL-2
will do versus waiting
SPARTAC TRIAL
= Short Pulse Anti-Retroviral Treatment At
seroConversion
An International Randomised Controlled Trial of
Treatment at Primary HIV-1 infection
International trial recruiting from
Australia, Brazil, Ireland, Italy, South Africa, Uganda
and UK
British HIV Association guidelines state:
“There is still no answer to the question of
whether treatment at an early stage will
influence the longer-term natural history.
Given the present lack of clarity, it remains
reasonable to consider treating primary HIV
infection, ideally within a clinical trial”
Primary study question
Does treatment of Primary HIV infection delay
damage to the immune system and consequently
time to starting long-term anti-HIV therapy?
Scientific rationale for the study
•
Early treatment may preserve HIV-specific immunity
before irreversible damage occurs
•
May be no gain in treating early, so better to delay
treatment to reduce toxicity and possible resistance
•
No randomised trials on effect of HAART on primary
HIV infection
•
Pilot studies have shown immune system may benefit
from early treatment but unable to show whether this
delays damage to immune system in the long term.
The 3 study arms and design
Randomisation
A
48 week long
course ART
B
12 week short
course ART
Main outcome:
C
No antiretroviral
therapy
CD4 count <350 cells/μl on 2 occasions less than 4 weeks apart
Secondary study questions
Does treatment of Primary HIV infection have an
effect on:
HIV-specific immune response?
Progression to AIDS?
Virological failure of long-term therapy?
Drug resistance?
Inclusion criteria
•
Patient reached age of consent
•
Patient able and willing to give written informed
consent
•
Patient confirmed Primary HIV Infection by at
least one of the 5 criteria for PHI
Anti-HIV regimen at PHI
• Recommend Combivir and Kaletra but other regimens
allowed
• Following this intervention at PHI, all patient will cease
treatment.
•If disease progression necessitates treatment, anti-HIV
drugs will be introduced according to the local standards
of care.
Recruitment
• Sample size = 360
• Recruitment over 18 months
• Patients seen every 12 weeks
• Total duration of trial is 5 years
Current Status of SPARTAC Trial
70 patients recruited to date
Sites set up:
• 8 in UK (7 in London, 1 in Brighton)
• 1 in Ireland (Dublin)
• 1 in Johannesburg
• 10 in Australia (Sydney and Melbourne)
• 1 in Italy
Awaiting set up:
• Durban, Cape Town, Uganda, Brazil
INSIGHT
International Network for Strategic
Initiatives in Global HIV Trials
Response to NIH RFA for adult clinical trial
networks
Mission of INSIGHT
To develop strategies for the
optimization of treatment -- ART,
immunomodulatory therapies, and
interventions to prevent and treat the
complications of HIV and ART – in order
to prolong disease-free survival in an
demographically, socio-economically,
and geographically diverse group of
individuals with HIV.
Relationship of the Key Groups in the INSIGHT Organization
Data & Safety
Monitoring
Board
DAIDS
Managing
Partners
International Scientific
Steering Committee
(ISSC)
Network
Laboratory
Structure
CORE,
SDMC, &
ICCs
Communit
y Partners
INSIGHT
Executive
Committee
Quality
Oversight &
Performance
Evaluation
Committee
(QOPEC)
Community
Advisory Group
Endpoint
Review
Committee
(ERC)
Protocol
Teams
INSIGHT
International Steering Committee
• PIs from each country
• Annual meeting with protocol teams
–To review study progress
–To plan new studies (science retreats)
INSIGHT
Protocol Teams
•
•
•
•
•
Chair
Site clinician from each ICC region
DAIDS representative
Community representative
International Coordinating Center (ICC)
and Statistical and Data Management
Center (SDMC) representatives
Protocol teams report to Executive Committee
Sub-study teams will be similarly constructed and report to
protocol chair
General Plan for Communications
• ICC-sponsored regional and national
meetings
• Twice yearly investigator meetings in
conjunction with scientific conferences
• International steering committee meetings
once a year
• Protocol team meetings/teleconferences
• Executive committee
meetings/teleconferences
INSIGHT CTU APPLICATIONS
CTU
No. SCCs
No. Sites
London
6
79
Copenhagen
6
53
CPCRA
23
138
Sydney
4
63
Total
39
333
Research agenda
Ongoing Studies in INSIGHT
• ESPRIT – 4,150 patients; estimate 4
more years to accrue 320 events
• SMART – 3,927/6,000 patients
enrolled; estimate 7-8 more years
to accrue 910 events
• STALWART – 480 patients to be
enrolled over the next year
INSIGHT: new studies
Madrid Retreat
• 22-23 October 2004
• 75 investigators working in 3
groups for 1.5 days
• An agenda was crafted
MDR-VF Study Design
MDR-VF
Patients
MDR patients
who have some
options & CD4+ >
200 (SPARE)
3TC or
FTC
N = 300
Cycle
monthly:
NRTI then
NRTI +
RTVboosted PI
MDR patients who
have some
options & CD4+
50 - 200 (SPARE)
Continuous
RTV-boosted
PI + NRTIs
(control)
Cycle
monthly:
NRTI then
NRTI +
RTVboosted PI
N = 300
N = 300+
N = 300
Continuous
RTVboosted PI
+ NRTIs
(control)
MDR patients who
have no options
(MDC-MDR)
Cycle
monthly:
3 different
3-drug
regimens
Boosted
PI + NRTIs
(control)
N = 200
N = 200
OI-ART Study Design
Patients with CD4 < 200 and
presenting with an OI, e.g.,
invasive mycobacterial infection,
fungal infection, or
toxoplasmosis
With CMV
or PML
Without CMV
and PML
Imm. ART +
corticosteroids
Deferred ART
+
corticosteroids
Immediate
ART +
placebo
Deferred
ART +
placebo
Corticosteroids
Placebo
CVD: Polypill Design
Patients with 5 year risk of CVD > 7.5%
OR
with 5 year risk >5.0%
+
5+ years of ART
Polypill*
(N = 4,000)
*aspirin, ACE inhibitor, diuretic, statin
Placebo*
(N = 4,000)
Planned Studies
• SPARE Vanguard – 500 patients
• MDC-MDR Vanguard – 400
• MDR clinical outcome study – 3,300
• OI-ART – 3,200
• Polypill Vanguard – 400
• Polypill clinical outcome – 8,000
• HCV-DEP - 800
1,300 patients in vanguard studies
15,300 in clinical outcome trials
Next Steps
• Maintain excellence in ongoing studies.
• Prepare for reverse site visit on 26
October
• Update at next CROI meeting in February
• Funding…
Network Applications
• HVTN (HIV Vaccine Trials Network)
• MTN (Microbicide Trials Network)
• HPTN (HIV Prevention Trials Network)
• IMPAACT (International Maternal Pediatric
Adolescent AIDS Clinical Trials)
• ACTG (AIDS Clinical Trials Group)
and
• INSIGHT
see www.niaid.nih.gov/daids/rfa/network06/messageboard/
European HIV clinical trials
network
•Call for proposals June 2007
• Aim to create a network of excellence for
clinical resaerch in HIV/AIDS
• Designing and coordinating clinical trials and
“data gathering” on HIV/AIDS at European level
• Define optimal strategies for management of
HIV and guide the implementation of
interventions
• Participation of new member states and EE
encouraged
European HIV Clinical Trials
network
• Brain storming meeting
convened by EU, 6 June 05
• Follow-up meeting 11 July 05
• Aim to define objectives and
design of a network
Studies planned at MRC
TOSCA
• Trial Of Short Course
Antiretrovirals
Concept:
Brian Gazzard
TOSCA rationale
• Stopping HAART at high CD4 cell count is safe
• Biphasic CD4 loss, initial rapid followed by
slow decline
• BIG Q = Can early HAART “buy time” before
need to start continuous HAART
• Initial Q = After a 1y course of ART, is the rate
of subsequent CD4 decline equal, faster or
slower than the rate without treatment?
• Not done before (SMART: CD4 vs VL strategy;
few naïve patients; no untreated control)
CD4 count
800
700
600
500
400
300
200
100
0
0
12
24
36
48
60
72
84
months since randomisation
96
CD4 count
800
700
600
500
400
300
200
100
0
0
12
24
36
48
60
72
84
months since randomisation
96
CD4 count
800
700
600
500
400
300
200
100
0
0
12
24
36
48
60
72
84
months since randomisation
96
CD4 count
800
700
600
500
400
300
200
100
0
is this difference
substantially greater
than 12 months??
12 months
HAART
primary
endpoint
Standard
of care
0
12
24
36
48
60
72
84
months since randomisation
96
TOSCA design
• ART naive
• CD4 > 500 (? Feasible; consider > 400 /
350)
• Randomise to HAART 1y vs no Rx
• Primary endpoint = change in CD4 from
baseline at 3y (if advantage persists in
HAART arm then 1 year “buys” >2
additional years….?clinically worthwhile
/ attractive to patients) OR time to
threshold (CD4 = 250)
• N ~ 200- 300
TOSCA sub-studies
• Development of resistance after
stopping (staggered vs
replacement if NNRTI) using highly
sensitive resistance assays
• Immune responses to HepB / C
(motivated by increased risk of
death in hepatitis patients given
ART)
Potential subjects for TOSCA
• Prevalent patients with CD4 above entry
threshold and ART-naive
• New diagnoses with CD4 above entry
threshold
UK CHIC in
2002
CD4>400
CD4>500
Prevalent cases
1193
695
New diagnoses
513
353
Tenofovir as pre-exposure prophylaxis in MSM
Concept:
Mike Youle
TDF study rationale
• TDF has good safety profile and oncedaily dosing
• Potential for use as PrEP in high risk
individuals (taken continuously)
• Animal studies support efficacy in
preventing HIV
• Ongoing transmission of HIV in MSM in
spite of safe-sex education and condom
promotion
• Q = Is TDF effective in preventing HIV
transmission in MSM
TDF study design
• RDBPC trial
• Recruitment at GUM clinics
• MSM at high risk:
–
–
–
–
recent history of UAI
Recent STD
recreational drug use
Recent use of PEP
• Randomised to TDF or placebo for 12
months
• Primary endpoint = new HIV infections
at 12m
What incidence rate can we expect?
• De-tuned assay has been applied to residual
serum specimens from MSM attending STI
clinics. Estimate
– 3% incidence in London
– 1% incidence outside London
• Calculations are highly sensitive to assumed
interval between reactivity of detuned assay
and a standard sensitive screening assay (4-6
months??)
• More direct data from cohorts of gay men in
Australia – indicate ~2% incidence in those
with multiple risk factors
True efficacy
Efficacy aim to
exclude*
Required expected
no. events in
control arm
Total no. subjects:
2 arm trial, 2% annual
incidence, 12 months FU
0.6
0.2
57.2
5718
0.6
0.3
87.8
8772
0.6
0.4
167.1
16710
0.6
0.5
551.7
55170
0.7
0.2
35.4
3535
0.7
0.3
47.4
4738
0.7
0.4
70.8
7079
0.7
0.5
130.3
13034
0.8
0.2
24.5
2450
0.8
0.3
30.0
3001
0.8
0.4
39.0
3902
0.8
0.5
56.1
5609
0.9
0.2
20.0
1997
0.9
0.3
22.8
2280
0.9
0.4
26.9
2689
0.9
0.5
33.3
3333
Sample size calculated to ensure 80% probability that a 2-sided 95% CI will exclude this value
TDF study potential problems (1)
•
•
•
•
•
•
•
•
•
1) Politics / controversy / competition
Cambodia : stopped
Nigeria : stopped
Cameroon : suspended
Thailand : started but in jeopardy
Ghana : ongoing
Botswana : ongoing
Malawi (MSM) starting Sept
Peru (MSM) starting Sept
TDF study potential problems (2)
• Incidence may be low
• Standard of care will need to include
counselling, condom provision AND
ensuring easy access to post-exposure
prophylaxis (now recommended by
DHHS in MMWR 15 January 2005; and
European guidelines and BHIVA
guidelines)
• May result in ? 1% incidence
TDF study problems (3)
• Funding!! Will need many countries
involvement to get study numbers
? Who will fund this?
• Long term considerations of public
health implications / counteracting
effect of behaviour change