scholarly journals OC 8491 PREPVACC: A PHASE III, MAMS ADAPTIVE PROPHYLACTIC HIV VACCINE TRIAL WITH A SECOND RANDOMISATION TO COMPARE F/TAF WITH TDF/FTC PREP

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A10.1-A10
Author(s):  
Sarah Joseph ◽  
Pontiano Kaleebu ◽  
Eugene Ruzagira ◽  
Christian Holm Hansen ◽  
Janet Seeley ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Vaccine Trial ◽  
Final Analysis ◽  
Standard Of Care ◽  
Hiv Vaccine ◽  
Phase Iii ◽  
Hiv Incidence ◽  
Multi Stage ◽  
Adaptive Trial Design ◽  
Env Protein

BackgroundThere remains an urgent need for a prophylactic HIV vaccine to control generalised epidemics. PrEP has demonstrated effectiveness of 86% and is recommended by WHO; uptake is generally high, but retention is disappointing in some settings. The EDCTP2 project PrEPVacc will assess the efficacy of two combination prophylactic vaccine regimens (DNA, MVA and Env protein/adjuvant) each compared to placebo and the proportion of infections averted by F/TAF in comparison to TDF/FTC. A Registration Cohort, recruiting HIV negative volunteers at risk of HIV will precede the trial.MethodsThe PrEPVacc partnership agreed that 70% vaccine efficacy had public health relevance. The trial uses nstage software for multi-arm, multi-stage designs (MAMS) and the averted infections ratio (AIR) methodology with participants randomised (i) 1:1:1 to active product or placebo (ii) 1:1 to TDF/FTC : F/TAF until week 26 (presumed peak immunogenicity). Access to PrEP in the Registration Cohort and after week 26 will be standard of care. HIV seroconversions occurring between weeks 0–26 will inform the PrEP analysis, incorporating HIV incidence amongst those who do not take up PrEP locally in the Registration Cohort. Seroconversions after week 26 will inform vaccine analyses.ResultsUp to 556 participants per group affords 92% power to detect vaccine efficacy of 70% at the final analysis, assuming incidence of 4/100-person years and 10% loss with 81% and 97% power to conclude that F/TAF can avert half or more of the infections prevented by TDF/FTC if effectiveness of TDF/FTC is 70% and 80%, respectively.ConclusionPrEPVacc adopts a pragmatic approach to uncertainties around HIV incidence in settings where PrEP is increasingly available. This innovative adaptive trial design uses validated software to determine vaccine efficacy and a novel methodology to evaluate a new PrEP agent, overcoming the challenge of demonstrating non-inferiority when adherence to TDF/FTC is high and the number of outcome events very low.

Preparation for Phase III HIV vaccine efficacy trials: methods for the determination of HIV incidence

AIDS ◽  
1994 ◽  
Vol 8 (9) ◽  
pp. 1285-1291 ◽  
Author(s):  
William L. Heyward ◽  
Saladin Osmanov ◽  
Joseph Saba ◽  
Jose Esparza ◽  
Elizabeth Belsey ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Hiv Vaccine ◽  
Phase Iii ◽  
Hiv Incidence ◽  
Efficacy Trials

scholarly journals Phase III HIV vaccine trial in Thailand: a step toward a protective vaccine for HIV

2010 ◽  
Vol 9 (9) ◽  
pp. 997-1005 ◽  
Author(s):  
Monica Vaccari ◽  
Poonam Poonam ◽  
Genoveffa Franchini
Keyword(s):  
Vaccine Trial ◽  
Hiv Vaccine ◽  
Phase Iii

scholarly journals Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma

2013 ◽  
Vol 31 (5) ◽  
pp. 616-622 ◽  
Author(s):  
Antoni Ribas ◽  
Richard Kefford ◽  
Margaret A. Marshall ◽  
Cornelis J.A. Punt ◽  
John B. Haanen ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Objective Response ◽  
Response Duration ◽  
Final Analysis ◽  
Standard Of Care ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Test Statistic ◽  
Treatment Naïve ◽  
Intent To Treat

PurposeIn phase I/II trials, the cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy.Patients and MethodsPatients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine).ResultsIn all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96) for chemotherapy (hazard ratio, 0.88; P = .127). Objective response rates were similar in the two arms: 10.7% in the tremelimumab arm and 9.8% in the chemotherapy arm. However, response duration (measured from date of random assignment) was significantly longer after tremelimumab (35.8 v 13.7 months; P = .0011). Diarrhea, pruritus, and rash were the most common treatment-related adverse events in the tremelimumab arm; 7.4% had endocrine toxicities. Seven deaths in the tremelimumab arm and one in the chemotherapy arm were considered treatment related by either investigators or sponsor.ConclusionThis study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.

scholarly journals V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers

Animals ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 526 ◽  
Author(s):  
Duerr ◽  
Gorny
Keyword(s):  
Vaccine Efficacy ◽  
Natural Infection ◽  
Vaccine Trial ◽  
Clinical Findings ◽  
Hiv Vaccine ◽  
Model Systems ◽  
Potential Contribution ◽  
Vaccine Research ◽  
Specific Antibodies ◽  
Hiv 1

Most human immunodeficiency virus (HIV) vaccine trials have lacked efficacy and empirical vaccine lead targets are scarce. Thus far, the only independent correlate of reduced risk of HIV-1 acquisition in humans is elevated levels of V2-specific antibodies identified in the modestly protective RV144 vaccine trial. Ten years after RV144, human and non-human primate vaccine studies have reassessed the potential contribution of V2-specific antibodies to vaccine efficacy. In addition, studies of natural HIV-1 infection in humans have provided insight into the development of V1V2-directed antibody responses and their impact on clinical parameters and disease progression. Functionally diverse anti-V2 monoclonal antibodies were isolated and their structurally distinct V2 epitope regions characterized. After RV144, a plethora of research studies were performed using different model systems, immunogens, protocols, and challenge viruses. These diverse studies failed to provide a clear picture regarding the contribution of V2 antibodies to vaccine efficacy. Here, we summarize the biological functions and clinical findings associated with V2-specific antibodies and discuss their impact on HIV vaccine research.

Final analysis of phase III LATITUDE study in patients (pts) with newly diagnosed high-risk metastatic castration-naïve prostate cancer (NDx-HR mCNPC) treated with abiraterone acetate + prednisone (AA+P) added to androgen deprivation therapy (ADT).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 141-141 ◽  
Author(s):  
Karim Fizazi ◽  
Namphuong Tran ◽  
Luis Enrique Fein ◽  
Nobuaki Matsubara ◽  
Alfredo Rodríguez Antolín ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Standard Of Care ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Hazards Model ◽  
Total Death ◽  
Secondary Endpoints

141 Background: The first and second interim analyses (IA1 and IA2) of the LATITUDE study in NDx-HR mCNPC pts with addition of AA+P to ADT vs placebo (PBO)+ADT showed significant benefit in the coprimary endpoints of overall survival (OS) and radiographic progression free survival (rPFS), and secondary endpoints. Final OS analysis and updated safety results are presented. Methods: 1,199 pts were randomized (1:1) to AA (1 g QD) + P (5 mg QD) + ADT or PBO + ADT. Primary endpoint of OS and secondary endpoints were assessed (stratified proportional hazards model), and adverse events (AEs) were summarized from final analysis, which was planned for around 852 total death events. Results: Final analysis was conducted after a median follow-up of 51.8 mo (~22 mo from IA1) and 618 deaths were observed (275 [46%] in AA+P and 343 [57%] in PBO). Treatment was ongoing for 157 (26.3%) pts in AA+P; 72 (12.0%) crossed over from PBO to AA+P, of which 59 (81.9%) remained on treatment. AA+P treatment continued to show significant OS benefits vs PBO (HR: 0.7, 95% CI: 0.6-0.8; p<0.0001), along with significant improvements in secondary endpoints (table). Serious AEs were reported in 32.2% pts in AA+P and 25.1% in PBO. Grade 3/4 AEs of special interest (AA+P vs PBO; %) were hypertension (21.9 vs 10.5), hypokalemia (11.7 vs 1.7), hepatotoxicity (8.9 vs 3.5), cardiac disorders (3.9 vs 1) and fluid retention (0.8 vs 1). Conclusions: The final analysis continues to demonstrate a significant OS advantage of combining AA+P to ADT in NDx-HR mCNPC pts. These efficacy findings and AE profiles are consistent with IA1 and IA2 and reinforce AA+P as a standard of care in NDx-HR mCNPC pts. Clinical trial information: NCT01715285. [Table: see text]

scholarly journals Issues in Women's Participation in a Phase III Community HIV Vaccine Trial in Thailand

2013 ◽  
Vol 29 (11) ◽  
pp. 1524-1534 ◽  
Author(s):  
Jaranit Kaewkungwal ◽  
Punnee Pitisuttithum ◽  
Supachai Rerks-ngarm ◽  
Sorachai Nitayaphan ◽  
Chirasak Khamboonruang ◽  
...  
Keyword(s):  
Vaccine Trial ◽  
Hiv Vaccine ◽  
Phase Iii ◽  
Women's Participation

Some important issues in the planning of phase III HIV vaccine efficacy trials

Vaccine ◽  
1999 ◽  
Vol 17 (7-8) ◽  
pp. 989-1004 ◽  
Author(s):  
M.-C. Boily ◽  
B.R. Mâsse ◽  
K. Desai ◽  
M. Alary ◽  
R.M. Anderson
Keyword(s):  
Vaccine Efficacy ◽  
Hiv Vaccine ◽  
Phase Iii ◽  
Efficacy Trials

scholarly journals Expectation of Volunteers Towards the Vaccine Efficacy of the Prime-Boost HIV Vaccine Phase III Trial During Unblinding

2014 ◽  
Vol 30 (11) ◽  
pp. 1041-1045 ◽  
Author(s):  
Kessuda Khowsroy ◽  
Jittima Dhitavat ◽  
Yupa Sabmee ◽  
Pataramon Laowarakul ◽  
Jutarat Wattanakitwichai ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Hiv Vaccine ◽  
Phase Iii ◽  
Phase Iii Trial

scholarly journals Anti-V2 Antibody Deficiency in Individuals Infected With HIV-1

2018 ◽  
Author(s):  
Lily Liu ◽  
Liuzhe Li ◽  
Aubin Nanfack ◽  
Luzia M. Mayr ◽  
Sonal Soni ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Hiv Vaccine ◽  
Phase Iii ◽  
Dominant Factor ◽  
Plasma Samples ◽  
Electrostatic Charges ◽  
Glycosylation Sites ◽  
Significant Difference ◽  
Hiv 1 ◽  
Rv144 Vaccine

ABSTRACTThe positive correlation of high levels of plasma anti-V2 antibodies (Abs) with protective immunity in the Phase III anti-HIV RV144 vaccine trial generated interest in the induction of these Abs for HIV vaccine development. We analyzed plasma samples from 79 chronically infected Cameroonian individuals for Ab reactivity against three V1V2 fusion proteins and five cyclic V2 peptides and found that HIV-1 infection induces different levels of anti-V2 Abs. While the majority of plasma samples reacted strongly with one or more V2 antigens, 10% (8) of the samples were nonreactive. Deficiency of anti-V2 Abs was consistently found in longitudinal plasma samples tested over 8 to 54 months of HIV infection. There was a strong correlation between binding activities of plasma anti-V2 Abs and anti-gp120 and anti-gp41 Abs, suggesting that deficiency of V2 Abs could be related, in part, to a limited ability to elicit strong Ab responses. Analysis of gp120 sequences revealed that the V2 region of viruses from donors with V2-deficient versus V2-reactive Abs displayed a tendency toward longer length, more glycans, and lower isoelectric point and charge. No differences between these two patient groups were noted in the same parameters measured in the V1 region. These data suggest that immunogens containing a shorter V2 region with fewer glycosylation sites and higher electrostatic charges would be beneficial for induction of anti-V2 Abs, but the ability to mount a strong general Ab response to HIV-1 appears to be a dominant factor.IMPORTANCEThe results of the RV144 vaccine clinical trial showed a correlation between plasma Abs against a V1V2 fusion protein and a decreased risk of acquiring HIV-1 infection. This turned the focus of some HIV vaccine design to the induction of elevated levels of anti-V2 Abs to increase vaccine efficacy. In plasma samples from Cameroonian individuals infected with HIV-1, we observed broad variations in levels of anti-V2 Abs, and 8 of the 79 plasma samples tested displayed substantial deficiency of V2 Abs. Sequence analysis of the V2 region from plasma viruses and multivariate analyses of V2 characteristics showed a significant difference in several features between V2-deficient and V2-reactive plasma Abs. These results suggest that HIV vaccine immunogens containing a V2 region with shorter length, fewer glycosylation sites, and higher electrostatic charges may be beneficial for induction of a higher level of anti-V2 Abs and thus contribute to HIV vaccine efficacy.

scholarly journals A Simplified Bayesian Analysis Method for Vaccine Efficacy

2020 ◽  
Author(s):  
Carlo Graziani
Keyword(s):  
Bayesian Analysis ◽  
Vaccine Efficacy ◽  
Vaccine Trial ◽  
Nuisance Parameter ◽  
Phase Iii ◽  
Analysis Method ◽  
Final Phase ◽  
Posterior Density ◽  
One Dimensional ◽  
Probability Densities

AbstractWe describe a simplified Bayesian analysis of vaccine trial data, in which a reparametrization of the Poisson likelihood leads to a factorization in which the protective vaccine efficacy VES and the nuisance parameter appear in different factors. As a consequence the posterior density acquires a factorized form, and marginalization over the nuisance parameter is trivial. Estimates of VES accordingly become a matter of simple manipulations of one-dimensional posterior probability densities. We demonstrate the method using the publically-released data on the efficacy of three vaccines agains SARS-CoV-2: the final Phase III data from the Pfizer/BioNTech and Moderna mRNA vaccines and the interim data released for the Sputnik V adenovirus-based vaccine.

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