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 Median Change Month No. ofpatients 2090 2023 1981 1975 1903 1871 1836 1628 1469 1300 1091 878 675
Number of IL-2 Cycles Initiated after Induction Phase % of patients Number of Cycles
Percent at Goal by Follow-up Visit Percent Month No. ofpatients 2090 2023 1981 1975 1903 1871 1836 1628 1469 1300 1091 878 675
Patients Not at Goal at Time of Initiative* Have cycled Plan to cycle 513 296 57.7 Do not plan to cycle 744 76 10.2 Total 1257 Cycling plans Total N % * 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 No. Visits Attended No.Missed Region % 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 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] Follow-up for 6-9 years
CPCRA RCC Sydney RCC Copenhagen RCC London RCC Brazil Canada Peru South Africa United States Argentina Australia Chile Israel Japan New Zealand Thailand Uruguay • Austria, Belgium • Denmark, Estonia • Finland, Germany • Lithuania, Luxembourg • Norway, Poland • Portugal, Russia,Spain • France • Greece • Ireland • Italy • Morocco • Switzerland • United Kingdom SMART Study International
(As of 19 July 2005) SMART Enrollment GoalEnrolledPct. 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 %
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 Percent by Month 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 peri-cycle ART?
STALWART CD4 > 300 No prior IL-2 No ART within last 1y IL-2 7.5MU for 5/7 every 8 weeks X 3 Then prn to keep CD4 above goal IL-2 7.5MU for 5/7 every 8 weeks X 3 + peri-cycle HAART Then prn to keep CD4 above goal No ART No IL-2
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 letterdistributed 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 C No 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
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-freesurvival in an demographically, socio-economically, and geographically diverse group of individuals with HIV.
Data & Safety Monitoring Board DAIDS Managing Partners Community Partners International Scientific Steering Committee (ISSC) Community Advisory Group INSIGHT Executive Committee Network Laboratory Structure Quality Oversight & Performance Evaluation Committee (QOPEC) CORE, SDMC, & ICCs Protocol Teams Endpoint Review Committee (ERC) Relationship of the Key Groups in the INSIGHT Organization
INSIGHTInternational Steering Committee • PIs from each country • Annual meeting with protocol teams • To review study progress • To plan new studies (science retreats)
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