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, open-label, 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 in CD4 Cell Count from Baseline with Inter-Quartile Range

0

100

200

300

400

500

BL 4 8 12 16 20 24 28 32 36 40 44 48

Med

ian

Ch

ang

e

MonthNo. ofpatients 2090 2023 1981 1975 1903 1871 1836 1628 1469 1300 1091 878 675

Number of IL-2 Cycles Initiated after Induction Phase

0

20

40

60

80

100

0 1 2 3 - 4

Number of Cycles

% o

f p

atie

nts

Percent at Goal by Follow-up Visit

0

10

20

30

40

BL 4 8 12 16 20 24 28 32 36 40 44 48

Per

cent

Month

No. ofpatients 2090 2023 1981 1975 1903 1871 1836 1628 1469 1300 1091 878 675

Patients Not at Goal at Time of Initiative*

Plan to cycle 513 296 57.7

Do not plan to cycle 744 76 10.2

Total 1257

Total N %

*Patients with no medical contraindication to IL-2

Cycling plans

Have cycled

• 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

Cycling Initiative Summary

Follow-up

• 4150 patients followed for a median of 40.3 months

• 41,542 follow-up visits conducted

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

Missed Follow-up Visits by Region

RegionNo.

Missed % MissedNo. Visits Attended

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

Loss to Follow-up by Region

RegionNo.Lost % Lost

No. Randomized

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

Drug Conservation (DC) Strategy

[Stop or defer ART until CD4 < 250; then episodic ART

based on CD4 cell count to increase counts to > 350]

Virologic Suppression (VS) Strategy

[Use ART to maintain viral load as low as possible throughout follow-up]

Participants with CD4 > 350

Follow-up for 6-9 years

n = 3000 n = 3000

SMART Study - InternationalSMART Study - International

SMART Study International

CPCRARCC

BrazilCanadaPeruSouth AfricaUnited States

SydneyRCC

ArgentinaAustraliaChileIsraelJapanNew ZealandThailandUruguay

CopenhagenRCC

Austria, BelgiumDenmark, EstoniaFinland, GermanyLithuania, LuxembourgNorway, PolandPortugal, Russia, Spain

LondonRCC

FranceGreeceIrelandItalyMoroccoSwitzerlandUnited 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

Main SMART 6000 3909 65 %

QOL and Healthcare 1200 1224 100 % Utilization

HIV Transmission Risk 1010 786 78 % Behavior

Body Composition 300 219 73 %

Neurology 920 2 0 %

Anal Dysplasia 560 2 0 %

Goal Enrolled Pct.

(As of 19 July 2005)

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

0

10

20

30

40

50

60

70

80

90

by Month 1by Month 3by Month 6by Month 9by Month 12by Month 15by Month 18by Month 21by Month 24by Month 27by Month 30by Month 33

Not Consistent with DC StrategyConsistent with DC Strategy

Pe

rce

nt

by

Mo

nth

Reasons for (re-)initiations not consistent with DC strategy:62 50% Patient wish only32 25% High HIV RNA31 25% Other125 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 peri-cycle ART?

Comparison of IL-2 Vanguard Studies CD4+ Cell Responses

400

500

600

700

800

900

1000

1100

1200

1300

0 8 16 24Weeks

CD4+ (cells/cu mm)

Argentina

Thailand

Houston

United Kingdom

STALWART

No ART

No IL-2

IL-2 7.5MU for 5/7 every 8 weeks X 3

Then prn to keep

CD4 above goal

CD4 > 300No prior IL-2No ART within last 1y

IL-2 7.5MU for 5/7 every 8 weeks X 3 + peri-cycle HAART

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 Enrollment Estimates• Sydney RCC 18 217

– Argentina 8 90– Australia 6 47– Thailand 4 80

• Copenhagen RCC 18 132– Germany 3 21– Portugal 3 21– Poland 2 20– Spain 10 70

• London RCC 15 100– Italy 5 30 – Morocco 1 10– United Kingdom 9 60

• Minneapolis/CPCRA RCC 10 92– Brazil 2 20– CPCRA 3 31– DVA 2 11– Houston 2 15– NIH 1 15

TOTAL 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

A48 week long course ART

B12 week short

course ART

CNo

antiretroviral therapy

Main outcome: 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

International Network for Strategic

Initiatives in Global HIV Trials

INSIGHT

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

DAIDS

International Scientific Steering Committee

(ISSC)

INSIGHT Executive Committee

Community Advisory Group

Managing Partners

Community Partners

NetworkLaboratory Structure

CORE, SDMC, &

ICCs

Quality Oversight & Performance Evaluation Committee (QOPEC)

Endpoint Review

Committee (ERC)

Protocol Teams

Data & Safety Monitoring

Board

• PIs from each country

• Annual meeting with protocol teams–To review study progress–To plan new studies (science retreats)

INSIGHTInternational Steering Committee

INSIGHTProtocol 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 studiesMadrid 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)

MDR patients who have some

options & CD4+ 50 - 200 (SPARE)

MDR patients who have no options

(MDC-MDR)

3TC or FTC

Cycle monthly: NRTI then

NRTI + RTV-

boosted PI

Continuous RTV-boosted

PI + NRTIs (control)

Cycle monthly: NRTI then

NRTI + RTV-

boosted PI

Continuous RTV-

boosted PI + NRTIs (control)

Cycle monthly: 3 different

3-drug regimens

Boosted PI + NRTIs (control)

N = 300+

N = 300

N = 300 N = 200 N = 200N = 300

OI-ART Study Design Patients with CD4 < 200 and

presenting with an OI, e.g., invasive mycobacterial infection,

fungal infection, or toxoplasmosis

Without CMV and PML

With CMVor PML

Imm. ART +corticosteroids

Deferred ART +

corticosteroids

ImmediateART +

placebo

DeferredART +

placeboCorticosteroids Placebo

CVD: Polypill DesignPatients with 5 year risk of CVD > 7.5%

OR

with 5 year risk >5.0%

+

5+ years of ART

Polypill*(N = 4,000)

Placebo*(N = 4,000)

*aspirin, ACE inhibitor, diuretic, statin

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 studies15,300 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

• INSIGHTsee www.niaid.nih.gov/daids/rfa/network06/messageboard/

•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

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)

0100200300400500600700800

0 12 24 36 48 60 72 84 96

months since randomisation

CD4 count

0100200300400500600700800

0 12 24 36 48 60 72 84 96

months since randomisation

CD4 count

0100200300400500600700800

0 12 24 36 48 60 72 84 96

months since randomisation

CD4 count

0100200300400

500600700800

0 12 24 36 48 60 72 84 96

months since randomisation

CD4 countStandard of care

12 months HAART

is this difference substantially greater than 12 months??

primary endpoint

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 once-daily 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