Alpha StatConsult LLC

Damascus, MD, United States

Alpha StatConsult LLC

Damascus, MD, United States

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Hendrix C.,Johns Hopkins University | Bumpus N.,Johns Hopkins University | Elliott J.,University of California at Los Angeles | Tanner K.,University of California at Los Angeles | And 5 more authors.
PLoS ONE | Year: 2014

This Phase 1, randomized, two-site (United States), double-blind, placebo-controlled study enrolled 18 sexually abstinent men and women. All received a single 300-mg dose of oral tenofovir disoproxil fumarate (TDF) and were then randomized 2:1 to receive single and then seven daily rectal exposures of vaginally-formulated tenofovir (TFV) 1% gel or a hydroxyethyl cellulose (HEC) placebo gel. Blood, colonic biopsies and rectal and vaginal mucosal fluids were collected after the single oral TDF, the single topical TFV gel dose, and after 7 days of topical TFV gel dosing for extracellular analysis of TFV and intracellular analysis of the active metabolite tenofovir diphosphate (TFVdp) in peripheral blood mononuclear cells (PBMCs) and isolated mucosal mononuclear cells (MMC), including CD4+ and CD4- cell subsets. With a single rectal dose, TFV plasma concentrations were 24-33 fold lower and half-life was 5 h shorter compared to a single oral dose (p = 0.02). TFVdp concentrations were also undetectable in PBMCs with rectal dosing. Rectal tissue exposure to both TFV and TFVdp was 2 to 4-log10 higher after a single rectal dose compared to a single oral dose, and after 7 daily doses, TFVdp accumulated 4.5 fold in tissue. TFVdp in rectal tissue homogenate was predictive (residual standard error, RSE = 0.47) of tissue MMC intracellular TFVdp concentration, with the CD4+ cells having a 2-fold higher TFVdp concentration than CD4- cells. TFV concentrations from rectal sponges was a modest surrogate indicator for both rectal tissue TFV and TFVdp (RSE = 0.67, 0.66, respectively) and plasma TFV (RSE = 0.38). TFV penetrates into the vaginal cavity after oral and rectal dosing, with rectal dosing leading to higher vaginal TFV concentrations (p<0.01). © 2014 Yang et al.


PubMed | Advanced Bioscience Laboratories, Guys And St Thomas Nhs Foundation Trust, Alpha StatConsult LLC, Imperial College London and 4 more.
Type: | Journal: AIDS research and human retroviruses | Year: 2016

The ex vivo challenge assay is being increasingly used as an efficacy endpoint during early human clinical trials of HIV prevention treatments. There is no standard methodology for the ex vivo challenge assay although the use of different data collection methods and analytical parameters may impact results and reduce the comparability of findings between trials. In this analysis we describe the impact of data imputation methods, kit type, testing schedule and tissue type on variability, statistical power and ex vivo HIV growth kinetics. Data were p24 antigen (pg/mL) measurements collected from clinical trials of candidate microbicides where rectal (n=502), cervical (n=88) and vaginal (n=110) tissues were challenged with HIV-1BaL ex vivo. Imputation of missing data using a non-linear mixed effect model was found to provide an improved fit compared to imputation using half the limit of detection. The rectal virus growth period was found to be earlier and of a relatively shorter duration than the growth period for cervical and vaginal tissue types. On average, only four rectal tissue challenge assays in each treatment and control group would be needed to find a one log difference in p24 to be significant (alpha = 0.05) but a larger sample size was predicted to be needed for either cervical (n=21) or vaginal (n=10) tissue comparisons. Overall, the results indicated that improvements could be made in the design and analysis of the ex vivo challenge assay to provide a more standardized and powerful assay to compare efficacy of microbicide products.


PubMed | Alpha StatConsult LLC, Johns Hopkins University, CONRAD, University of California at Los Angeles and University of Pittsburgh
Type: Clinical Trial, Phase I | Journal: PloS one | Year: 2014

This Phase 1, randomized, two-site (United States), double-blind, placebo-controlled study enrolled 18 sexually abstinent men and women. All received a single 300-mg dose of oral tenofovir disoproxil fumarate (TDF) and were then randomized 2:1 to receive single and then seven daily rectal exposures of vaginally-formulated tenofovir (TFV) 1% gel or a hydroxyethyl cellulose (HEC) placebo gel. Blood, colonic biopsies and rectal and vaginal mucosal fluids were collected after the single oral TDF, the single topical TFV gel dose, and after 7 days of topical TFV gel dosing for extracellular analysis of TFV and intracellular analysis of the active metabolite tenofovir diphosphate (TFVdp) in peripheral blood mononuclear cells (PBMCs) and isolated mucosal mononuclear cells (MMC), including CD4+ and CD4- cell subsets. With a single rectal dose, TFV plasma concentrations were 2433 fold lower and half-life was 5 h shorter compared to a single oral dose (p = 0.02). TFVdp concentrations were also undetectable in PBMCs with rectal dosing. Rectal tissue exposure to both TFV and TFVdp was 2 to 4-log10 higher after a single rectal dose compared to a single oral dose, and after 7 daily doses, TFVdp accumulated 4.5 fold in tissue. TFVdp in rectal tissue homogenate was predictive (residual standard error, RSE = 0.47) of tissue MMC intracellular TFVdp concentration, with the CD4+ cells having a 2-fold higher TFVdp concentration than CD4- cells. TFV concentrations from rectal sponges was a modest surrogate indicator for both rectal tissue TFV and TFVdp (RSE = 0.67, 0.66, respectively) and plasma TFV (RSE = 0.38). TFV penetrates into the vaginal cavity after oral and rectal dosing, with rectal dosing leading to higher vaginal TFV concentrations (p<0.01). Trial registration: ClinicalTrials.gov NCT00984971.


Buchman G.W.,Chesapeake Perl | Cohen M.E.,University of Pennsylvania | Xiao Y.,University of Pennsylvania | Richardson-Harman N.,Alpha StatConsult LLC | And 6 more authors.
Vaccine | Year: 2010

Concerns about infections caused by orthopoxviruses, such as variola and monkeypox viruses, drive ongoing efforts to develop novel smallpox vaccines that are both effective and safe to use in diverse populations. A subunit smallpox vaccine comprising vaccinia virus membrane proteins A33, B5, L1, A27 and aluminum hydroxide (alum) ± CpG was administered to non-human primates, which were subsequently challenged with a lethal intravenous dose of monkeypox virus. Alum adjuvanted vaccines provided only partial protection but the addition of CpG provided full protection that was associated with a more homogeneous antibody response and stronger IgG1 responses. These results indicate that it is feasible to develop a highly effective subunit vaccine against orthopoxvirus infections as a safer alternative to live vaccinia virus vaccination. © 2010 Elsevier Ltd.


Richardson-Harman N.,Alpha StatConsult LLC | Mauck C.,CONRAD | McGowan I.,University of Pittsburgh | Anton P.,University of California at Los Angeles
AIDS Research and Human Retroviruses | Year: 2012

A retrospective correlational analysis of UC781 (0.1, 0.25%) gel pharmacokinetics (PK) and pharmacodynamics (PD) was undertaken using data generated in the RMP-01/MTN-006 Phase 1 rectal safety study of the UC781 microbicide gel, where strong UC781-related inhibition of ex vivo biopsy infectibility (PD) was seen. Precision analysis, linear and logistical correlational methods were applied to model the dose-response relationship. Four analyses of explant virus growth were compared to determine tissue concentrations of UC781 needed to maintain ex vivo virus growth below a range of cut-points. SOFT, a cross-sectional index from a growth curve, and cumulative p24 endpoints were the most precise measurement of ex vivo HIV infection and significantly (p<0.01) correlated with rectal tissue UC781 concentrations. Cut-points reflecting infectibility, ranging from 200 to 1300 p24pg/ml, provided EC50,90,95 tissue levels of UC781. A cut-point of 200 p24pg/ml provided an EC50 of 2148 UC781ng/g tissue; a cut-point of 1100 p24 predicted a lower EC50 of 101 UC781ng/g. A 30- to 170-fold EC 90:EC50 ratio was found. Higher p24 cut-points provided more predictive models. Tissue UC781 levels and ex vivo infectibility data were correlated to model dose-response drug efficacy in this small Phase 1 trial. Logistic regression analyses showed EC50,90,95 values were inversely related to p24 cut-point levels, providing clinically relevant insights into tissue drug concentration necessary for ex vivo suppression of HIV tissue infectibility. This first PK-PD assessment of topical microbicides demonstrates feasibility in Phase 1 trials, enabling comparisons of microbicide efficacy (i.e., EC50,90,95) between formulations, compartments, and application methods. © Copyright 2012, Mary Ann Liebert, Inc.


PubMed | Alpha StatConsult LLC, Johns Hopkins University, University of California at Los Angeles, CONRAD and 2 more.
Type: Clinical Trial, Phase I | Journal: PloS one | Year: 2014

This study was designed to assess the dose-response relationship between tissue, blood, vaginal and rectal compartment concentrations of tenofovir (TFV) and tenofovir diphosphate (TFVdp) and ex vivo rectal HIV suppression following oral tenofovir disoproxil fumarate (TDF) and rectal administration of TFV 1% vaginally-formulated gel.Phase 1, randomized, two-site (US), double-blind, placebo-controlled study of sexually-abstinent males and females.Eighteen participants received a single 300 mg exposure of oral TDF and were then randomized 21 to receive a single then seven-daily rectal exposures of TFV 1% gel (40 mg TFV per 4 ml gel application) or hydroxyethyl-cellulose (HEC) placebo gel. Blood and rectal biopsies were collected for pharmacokinetic TDF and TFVdp analyses and ex vivo HIV-1 challenge.There was a significant fit for the TFVdp dose-response model for rectal tissue (p=0.0004), CD4+MMC (p<0.0001), CD4-MMC (p<0.0001), and TotalMMC (p<0.0001) compartments with r2 ranging 0.36-0.64. Higher concentrations of TFVdp corresponded with lower p24, consistent with drug-mediated virus suppression. The single oral treatment failed to provide adequate compartment drug exposure to reach the EC50 of rectal tissue TFVdp predicted to be necessary to suppress HIV in rectal tissue. The EC50 for CD4+MMC was within the single topical treatment range, providing evidence that a 1% topical, vaginally-formulated TFV gel provided in-vivo doses predicted to provide for 50% efficacy in the ex vivo assay. The 7-daily topical TFV gel treatment provided TFVdp concentrations that reached EC90 biopsy efficacy for CD4-MMC, CD4+MMC and TotalMMC compartments.The TFVdp MMC compartment (CD4+, CD4- and Total) provided the best surrogate for biopsy infectibility and the 7-daily topical TFV gel treatment provided the strongest PK profile for HIV suppression. ClinicalTrials.gov NCT00984971.


McGowan I.,University of Pittsburgh | Janocko L.,University of Pittsburgh | Burneisen S.,University of Pittsburgh | Bhat A.,Case Western Reserve University | Richardson-Harman N.,Alpha StatConsult LLC
Cytokine | Year: 2015

Objective: To determine the intra- and inter-subject variability of mucosal cytokine gene expression in rectal biopsies from healthy volunteers and to screen cytokine and chemokine mRNA as potential biomarkers of mucosal inflammation. Design and methods: Rectal biopsies were collected from 8 participants (3 biopsies per participant) and 1 additional participant (10 biopsies). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to quantify IL-1β, IL-6, IL-12p40, IL-8, IFN-γ, MIP-1α, MIP-1β, RANTES, and TNF-α gene expression in the rectal tissue. The intra-assay, inter-biopsy and inter-subject variance was measured in the eight participants. Bootstrap re-sampling of the biopsy measurements was performed to determine the accuracy of gene expression data obtained for 10 biopsies obtained from one participant. Cytokines were both non-normalized and normalized using four reference genes (GAPDH, β-actin, β2 microglobulin, and CD45). Results: Cytokine measurement accuracy was increased with the number of biopsy samples, per person; four biopsies were typically needed to produce a mean result within a 95% confidence interval of the subject's cytokine level approximately 80% of the time. Intra-assay precision (% geometric standard deviation) ranged between 8.2 and 96.9 with high variance between patients and even between different biopsies from the same patient. Variability was not greatly reduced with the use of reference genes to normalize data. Conclusions: The number of biopsy samples required to provide an accurate result varied by target although 4 biopsy samples per subject and timepoint, provided for >77% accuracy across all targets tested. Biopsies within the same subjects and between subjects had similar levels of variance while variance within a biopsy (intra-assay) was generally lower. Normalization of inflammatory cytokines against reference genes failed to consistently reduce variance. The accuracy and reliability of mRNA expression of inflammatory cytokines will set a ceiling on the ability of these measures to predict mucosal inflammation. Techniques to reduce variability should be developed within a larger cohort of individuals before normative reference values can be validated. © 2014 Elsevier Ltd.


PubMed | Alpha StatConsult LLC, Case Western Reserve University and University of Pittsburgh
Type: Journal Article | Journal: Cytokine | Year: 2014

To determine the intra- and inter-subject variability of mucosal cytokine gene expression in rectal biopsies from healthy volunteers and to screen cytokine and chemokine mRNA as potential biomarkers of mucosal inflammation.Rectal biopsies were collected from 8 participants (3 biopsies per participant) and 1 additional participant (10 biopsies). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to quantify IL-1, IL-6, IL-12p40, IL-8, IFN-, MIP-1, MIP-1, RANTES, and TNF- gene expression in the rectal tissue. The intra-assay, inter-biopsy and inter-subject variance was measured in the eight participants. Bootstrap re-sampling of the biopsy measurements was performed to determine the accuracy of gene expression data obtained for 10 biopsies obtained from one participant. Cytokines were both non-normalized and normalized using four reference genes (GAPDH, -actin, 2 microglobulin, and CD45).Cytokine measurement accuracy was increased with the number of biopsy samples, per person; four biopsies were typically needed to produce a mean result within a 95% confidence interval of the subjects cytokine level approximately 80% of the time. Intra-assay precision (% geometric standard deviation) ranged between 8.2 and 96.9 with high variance between patients and even between different biopsies from the same patient. Variability was not greatly reduced with the use of reference genes to normalize data.The number of biopsy samples required to provide an accurate result varied by target although 4 biopsy samples per subject and timepoint, provided for >77% accuracy across all targets tested. Biopsies within the same subjects and between subjects had similar levels of variance while variance within a biopsy (intra-assay) was generally lower. Normalization of inflammatory cytokines against reference genes failed to consistently reduce variance. The accuracy and reliability of mRNA expression of inflammatory cytokines will set a ceiling on the ability of these measures to predict mucosal inflammation. Techniques to reduce variability should be developed within a larger cohort of individuals before normative reference values can be validated.


Dezzutti C.S.,University of Pittsburgh | Uranker K.,University of Pittsburgh | Bunge K.E.,University of Pittsburgh | Richardson-Harman N.,Alpha StatConsult LLC | And 2 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2013

Objective: Ex vivo HIV-1 challenge has been proposed as a bioindicator of microbicide product effectiveness. The objective of this study was to establish optimal parameters for use of female genital tract tissue in this model. Design: Ex vivo challenge involves in vivo product use, followed by tissue biopsy, and exposure of the tissue to HIV-1 in the laboratory. Methods: Paired ectocervical and vaginal biopsies were collected from 42 women, and 28 women had additional biopsies from each site collected after 5% lidocaine (n = 14) or chlorhexidine (n = 14) treatment. Tissues were transported immediately to the laboratory and exposed to HIV-1. HIV-1 infection was followed by p24 enzyme-linked immunosorbent assay on culture supernatants and at study end after weighing and fixing the tissue for immunohistochemistry to detect p24 expressing cells. Results: Although both tissue types were equally infected with HIV-1 based on the immunohistochemistry results, ectocervical tissues had significantly higher HIV-1 replication than vaginal tissues (P < 0.005). Lidocaine and chlorhexidine had minimal impact on HIV-1 infection and replication. Point estimates for p24 levels were defined for 95% probability of p24-positive tissues and were 3.43 log10 for ectocervical tissue and 2.50 log10 for vaginal tissue based on the weight-adjusted cumulative p24 end points. Conclusions: Although similar proportions of ectocervical and vaginal tissues support HIV-1 infection, higher levels of HIV-1 replication were observed in ectocervical tissues. Defining point estimates for HIV-1 infection in fresh ectocervical and vaginal tissues provides valuable information for the evaluation of HIV-1 preventative treatments during early clinical studies. Copyright © 2013 by Lippincott Williams & Wilkins.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 148.82K | Year: 2016

DESCRIPTION Preclinical animal research is critical for driving and setting the conceptual framework for subsequent clinical trials and the establishment of new and novel therapeutic approaches However preclinical studies are frequently plagued by weak experimental design poor randomization procedures insufficient sample size arbitrary deletion of apparent outliers and overly simplistic statistical analysis that do not account for potential confounds These factors have contributed to the less than optimal predictive value of preclinical research In part these shortcomings are due to insufficient training in experimental design and statistical analysis and the lack of easy accessibility to trained statisticians for guidance Although statistical packages are commercially available many are not user friendly and their use without appropriate knowledge of experimental design and subsequent statistical analysis can be problematic The goals and objectives of this Phase proposal are to design AniStatTM a cloud based service to improve the rigor and reporting of animal studies that will be created to meet the needs of the animal research community This project involves a new collaboration between individuals with expertise in experimental design statistical analysis software development and establishment and use of animal models in biomedical research Alpha StatConsult biostatisticians software developers and an animal research collaborator will provide a plan for how AniStatTM could address each item including cost time effort software interface video tutorials and a user friendly prototype of the software as a mock up of the web based interface for each item These designs will be developed through a Delphi process where stakeholders will provide expert insights on priority capabilities and interactive visualizations fr AniStatTM A successful outcome of this proposal will be a final prioritized list of software capabilities schematic prototype of the software to be developed as a Software as a Service SaaS model and pilot validation of the software The SaaS product will be developed in a Phase II SBIR proposal to allow animal researchers with little formal instruction in experimental design and statistics to use AniStatTM over the internet with pricing based on a monthly fee The goal is for AniStatTM to help guide and assist scientists to design and report on effective and reproducible animal studies PUBLIC HEALTH RELEVANCE The financial and scientific costs of irreproducible animal research are of concern to health care stakeholders as the resulting lack of progress in health care innovations and cures will have a long term negative impact on public health The purpose of this Phase effort is to use a collaborative and scientific survey process to design AniStatTM a user friendly and readily accessible web interface that will allow researchers to use best practices in animal research design analysis and reporting The AniStatTM technology will be designed as a Software as a Service model to provide a user friendly platform for data analysis and reporting in order increase reproducibility in preclinical animal research

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