HIV Transplant Investigators Meeting: Introduction and Welcome 8:00 – 8:10 Nancy Bridges, NIH Peter Stock, UCSF Michelle Roland, UCSFSlide 2
Meeting Objectives 8:10 – 8:20 Michelle Roland Administrative Issues Protocol Review Policy OtherSlide 3
Objectives: Administrative Issues U01 and "Terms and Conditions of Award" Subcontracts: IRB and administrative issues Site visits pre-start up Steering and Operations Committee; Publications and Presentations Subcommittee Data Management Adverse Events ReportingSlide 4
Objectives: Protocol Issues Study Aims Inclusion and Exclusion Criteria Schedule of Events and "Sub-Study Clusters" Medication Regimens and Drug Interactions Immunosuppressants, ARVs, and Prophylaxis Clinical Issues HCV, HBV, and Rejection Stopping RulesSlide 5
Meeting Objectives: Policy and Other Issues Publications and Media Policy Reimbursement Donor Consent Complete Good Clinical Practices (GCP) Training Resources on the EMMES Study Website Community Advisory Board Coordinator Meeting Tomorrow More GPC preparing Data passage Specimen transporting and following Anal HPV swabs and follow-up ( UCSF, U Maryland, Mt. Sinai liver, Columbia, Cedars-Sinai )Slide 6
Budget and Regulatory Issues 8:20 – 8:30 Michelle Roland IRB Approvals Regulatory Documents to NIH Site Visits Pre-Start Up Subcontract Conditions ("Milestones")Slide 7
Subcontract Requirements Milestone #1, initial 15 Centers will get introductory financing IRB Approvals to Natasha Tomilin Regulatory Documents to Natasha Tomilin Milestone #2, to reestablish subcontract, must exhibit efficiency (screening, enlistment and transplantation), information quality and administrative adherence. These components will be investigated around like clockwork from the season of starting subsidizing. Concerns will be conveyed when recognizedSlide 8
Good Clinical Practices Training 8:30 – 10:00 Barbara PenningtonSlide 9
Study Aims 10:15 – 10:25 Peter Stock Primary Aims Secondary AimsSlide 10
Specific Aims 2 theory driven points Patient survival Graft survival 4 exploratory pointsSlide 11
Primary Aim 1: Evaluate the effect of immunosuppression on patient survival Hypothesis: Liver and kidney transplant beneficiaries will have survival rates practically identical to other patient gatherings without HIV contamination that are as of now thought to be satisfactory transplant hopefuls.Slide 12
Control Groups We suspect, as with more established subjects, that transplantation of HIV+ patients is a worthy yet high hazard strategy. We expect survival might be not as much as that of age coordinated controls yet that outcomes ought to be like those seen in other poor visualization bunches (e.g. diabetics, hospitalized patients, and so on). The >65 year old standardizing gathering was chosen since it is generally normal (7% of livers) and speaks to numerous organ disappointment causes.Slide 13
Also: age-race-benefactor source-coordinated controls from the national registry. The impact of transplantation on mortality will be inspected by looking at the death rate of subjects anticipating transplant to those accepting an allograft.Slide 14
Primary Aim 2: Evaluate the effect of HIV disease and HAART on join survival Hypothesis 1: HIV+ liver and kidney transplant beneficiaries will have unite survival rates similar to other patient gatherings without HIV contamination that are presently viewed as adequate hopefuls.Slide 15
Graft survival in HBV/HCV co-infection Hypothesis 2: HIV+ liver transplant beneficiaries co-contaminated with hepatitis B or C will have unite survival equivalent to other patient gatherings with the same viral hepatitis diseases however without HIV contamination that are right now viewed as adequate applicants.Slide 16
Graft survival in HIVAN Hypothesis 3: HIV+ kidney transplant beneficiaries with HIV nephropathy (HIVAN) will have repeat of HIVAN bringing about impeded renal capacity and join survival in spite of the utilization of HAART.Slide 17
Secondary Aim 1: Explore the effect of post-transplant immunosuppression on changes in CD4+ T cell tallies and HIV-1 RNA levels.Slide 18
Rationale Immunosuppression may quicken HIV ailment movement, bringing about decreases in CD4+ T-cell numbers, expanded rates of irresistible and neoplastic shrewd difficulties, and HIV-1 RNA leap forward on HAART. Such speeding up might be interceded through viral and additionally have immunologic pathways. On the other hand, immunosuppression may bring about consumption of HIV-1 repositories or decreases in viral bounce back and enhanced HIV-related results.Slide 19
Secondary Aim 2: Explore the effect of post-transplant immunosuppression on the host-reaction to viral co-pathogens, including hepatitis B and C, the human herpesviruses (CMV, EBV, HHV-6, HHV-8) and HPV.Slide 20
Rationale The blend of immunosuppression and HIV could adjust viral initiation as well as host insusceptible control of infections that are related with the improvement of clinically noteworthy sickness post-transplant.Slide 21
Secondary Aim 3: Explore the effect of HIV contamination on the alloimmune reaction and dismissal rates.Slide 22
Rationale HIV+ transplant beneficiaries may have bothers of the invulnerable framework that impact the resistant reaction to strong organ allografts that may have suggestions for immunosuppression prerequisites.Slide 23
Secondary Aim 4: Explore the pharmacokinetic connections between immunosuppressive specialists and the hepatically used antiretroviral operators.Slide 24
Committees 10:25 – 10:40 Michelle Roland Steering Committee Operations CommitteeSlide 26
Steering Committee Key Responsibilities Approve convention and any consequent changes Approve the outline and usage of all aide contemplates Facilitate the lead and checking of the fundamental trial and assistant reviews Interpret ponder information: security and endpoint Oversee detailing of study results Recommend the expansion or expulsion of locales partaking in the review endless supply of "points of reference"Slide 27
Implementation and Performance The primary trial and aide studies will be executed with endorsement of the Steering Committee and the NIAID Program Officer Sites will be required to acknowledge and actualize the convention and methods affirmed by the Steering Committee Q6 month agent meeting to consider convention corrections SC will supervise instruments for evaluating the execution of every foundation, with specific thoughtfulness regarding: gathering of sufficient quantities of qualified subjects opportune accommodation and nature of required information scrupulous recognition of convention necessitiesSlide 28
Protocol Exemptions/Violations No exceptions to incorporation/rejection criteria for enlistment. Convention infringement ought to be driven by patient care needs. Limit however much as could be expected Report to IRB and NIH Will be checked on by Steering Committee for conceivable convention change Use of investigational specialists must be endorsed by guiding board (MOP)Slide 29
Current Members Peter Stock and Michelle Roland Don Stablein: Senior Biostatistician 2 Independent examiners: To Be Named Robert Zackin and Debi Surlas: Community Representatives 2 Daniella Livnat: NIAID Program Officer Nancy Bridges: DAIT Medical Officer Larry Fox: DAIDS Medical Officer 1 John Fung and 1, 2 Margaret Ragni University of Pittsburgh 1, 2 Timothy Pruett, University of Virginia 1 Rotate yearly 2 Non-voting individualsSlide 30
Operations Committee Monthly video chat Review wellbeing reports (AE/SAE) Monitor site execution (gathering, development, and withdrawal) Review insurance of Human Subjects in research Address unexpected issues Make proposals concerning the convention and study execution to the Steering Committee for endorsementSlide 31
Current Members Peter Stock and Michelle Roland Daniella Livnat: NIAID Program Officer Nancy Bridges: DAIT Medical Officer Larry Fox: DAIDS Medical Officer Natasha Tomilin: NIAID Project Manager Laurie Carlson: UCSF Study Coordinator Rodney Rogers: UCSF Project Manager Don Stablein: Senior BiostatisticianSlide 32
Stopping Rules 10:40 - 10:55 Don Stablein Study Design and Control Groups Sample Size MonitoringSlide 33
Design Summary Protocol contains isolate single arm assessments of kidney transplant liver transplant Dual Primary Endpoints understanding survival join survival (passing is an occasion)Slide 34
Sample Size 150 Kidney 125 Liver 3 Year accumulation period Developed utilizing a Sequential Probability Ratio Test with 95% power for the predefined speculations of 1 year quiet survivalSlide 35
Developing the Hypotheses Anticipate patients may not work out quite as well as normal, but rather trust results will be like other high hazard patients Choose invalid utilizing national information for a high hazard aggregate more established (>64 year old) patients more established patients have co-morbidities transplants are basic result information are accessible Choose elective utilizing basic delta (distinction) for both endpoints inside organSlide 36
Null and Alternative Hypotheses One Year Event RatesSlide 37
DSMB Monitoring Construct upper certainty restrict with 1-followed importance level of .0001 at regular intervals. Prescribe ceasing if the focused on national esteem is not inside the interimSlide 38
Operating Characteristics for Stopping Guidelines Using Semi-Annual Confidence Limits with .0001 1-Sided Significance Level. % of Trials Recommended for Stopping Prior to Completing 3 Year Accrual Period, 2000 reproduces per cellSlide 39
Other Safety Monitoring Serious Adverse Events: every day to co-PIs and NIH Medical Officers HIV Progression Alert Levels: day by day answer to Operations Committee Viral Load: new onset noticeable or >/= 1 log increment CD4 Count: 25% decrease w/o dismissal treatment Other Adverse Events: month to month Long term unite and quiet survivalSlide 40
Inclusion and Exclusion Criteria 10:
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