Effect of Endogenous Clostridioides difficile Toxin Antibodies on Recurrence of C. difficile Infection.

BACKGROUND: Endogenous antibodies (eAbs) against Clostridioides (Clostridium) difficile toxins may protect against recurrence of C. difficile infection (rCDI). This hypothesis was tested using placebo group data from MODIFY (Monoclonal Antibodies for C. difficile Therapy) I and II (NCT01241552 and NCT01513239, respectively), global, randomized phase 3 trials that assessed the efficacy and safety of the antitoxin monoclonal antibodies bezlotoxumab and actoxumab in participants receiving antibiotic therapy for CDI. METHODS: A placebo infusion (normal saline) was administered on study day 1. Serum samples were collected on day 1, week 4, and week 12, and eAb-A and eAb-B titers were measured by 2 validated electrochemiluminescence immunoassays. Rates of initial clinical cure and rCDI were summarized by eAb titer category (low, medium, high) at each time point. RESULTS: Serum eAb titers were available from a total of 773 participants. The proportion of participants with high eAb-A and eAb-B titers increased over time. Rates of initial clinical cure were similar across eAb titer categories. There was no correlation between eAb-A titers and rCDI rate at any time point. However, there was a negative correlation between rCDI and eAb-B titer on day 1 and week 4. rCDI occurred in 22% of participants with high eAb-B titers at baseline compared with 35% with low or medium titers (P = .015). CONCLUSIONS: Higher eAb titers against toxin B, but not toxin A, were associated with protection against rCDI. These data are consistent with the observed efficacy of bezlotoxumab, and lack of efficacy of actoxumab, in the MODIFY trials. CLINICAL TRIALS REGISTRATION: NCT01241552 and NCT01513239.

Blood Aspergillus RNA is a promising alternative biomarker for invasive aspergillosis.

A critical challenge for the successful application of antifungal therapies for invasive aspergillosis (IA) is a lack of reliable biomarkers to assess early treatment response. Patients with proven or probable IA were prospectively enrolled, and serial blood samples were collected at 8 specified time points during 12-week antifungal therapy. Total nucleic acid was extracted from 2.5 ml blood and tested for Aspergillus-specific RNA by a pan-Aspergillus real-time nucleic acid sequence-based amplification (NASBA) assay. Serum 1, 3-ß-D-glucan (BG) and galactomannan (GM) were measured in parallel. Clinical outcome was evaluated at 6 and 12 weeks. Overall, 48/328 (14.6%) blood samples from 29/46 (63%) patients had positive NASBA detection at baseline and/or some point during the study. Positive NASBA results during the first 4 and 6 weeks of treatment are significantly associated with the 12-week outcome. Blood RNA load change during weeks 4-6 may be informative to predict outcome at 12 weeks. While independent of serum GM, the kinetic change of circulating Aspergillus RNA appears to be well correlated with that of BG on some patient individuals. Monitoring blood Aspergillus RNA during the first 4-6 weeks of antifungal treatment may help assess therapeutic response. Combination of circulating Aspergillus RNA and BG may be a useful adjunct to assess response.

Bayesian methods for the design and analysis of noninferiority trials.

The gold standard for evaluating treatment efficacy of a medical product is a placebo-controlled trial. However, when the use of placebo is considered to be unethical or impractical, a viable alternative for evaluating treatment efficacy is through a noninferiority (NI) study where a test treatment is compared to an active control treatment. The minimal objective of such a study is to determine whether the test treatment is superior to placebo. An assumption is made that if the active control treatment remains efficacious, as was observed when it was compared against placebo, then a test treatment that has comparable efficacy with the active control, within a certain range, must also be superior to placebo. Because of this assumption, the design, implementation, and analysis of NI trials present challenges for sponsors and regulators. In designing and analyzing NI trials, substantial historical data are often required on the active control treatment and placebo. Bayesian approaches provide a natural framework for synthesizing the historical data in the form of prior distributions that can effectively be used in design and analysis of a NI clinical trial. Despite a flurry of recent research activities in the area of Bayesian approaches in medical product development, there are still substantial gaps in recognition and acceptance of Bayesian approaches in NI trial design and analysis. The Bayesian Scientific Working Group of the Drug Information Association provides a coordinated effort to target the education and implementation issues on Bayesian approaches for NI trials. In this article, we provide a review of both frequentist and Bayesian approaches in NI trials, and elaborate on the implementation for two common Bayesian methods including hierarchical prior method and meta-analytic-predictive approach. Simulations are conducted to investigate the properties of the Bayesian methods, and some real clinical trial examples are presented for illustration.

Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population.

BACKGROUND: Insulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals. However, there are few reports on the time of onset of such effects independent of reversal of glucotoxicity. OBJECTIVE: The goal of our study was to test whether the thiazolidinedione pioglitazone has prominent early metabolic effects that can be detected in an obese, nondiabetic, insulin-resistant population. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group trial in men with nondiabetic insulin resistance using a hyperinsulinemic euglycemic clamp technique (at low and high doses of insulin at 10 and 40 mU/m(2)/min, respectively). The patients were given 30 mg daily oral pioglitazone or placebo for 28 days. Patients underwent a baseline clamp before initiation of treatment, and again at 14 and 28 days of treatment. RESULTS: Compared with placebo, under high-dose hyperinsulinemia, pioglitazone led to significant increases in glucose disposal rates (GDR) of 1.29 mg/kg/min (90% CI, 0.43-2.15; 39%; P=0.008) that were detectable at 2 weeks of treatment and persisted at 4 weeks of treatment. Under low-dose hyperinsulinemia, significant increases in GDR of 0.40 mg/kg/min (90% CI, 0.17-0.62; 95%; P=0.003) were observed at 4 weeks of treatment. These responses were accompanied by robust suppression of free fatty acids under hyperinsulinemic conditions, and by significant increases in circulating basal total adiponectin at 2 and 4 weeks of treatment. CONCLUSIONS: Significant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712.

High-dimensional analysis of the aging immune system: verification of age-associated differences in immune signaling responses in healthy donors.

BACKGROUND: Single-cell network profiling (SCNP) is a multiparametric flow cytometry-based approach that simultaneously measures evoked signaling in multiple cell subsets. Previously, using the SCNP approach, age-associated immune signaling responses were identified in a cohort of 60 healthy donors. METHODS: In the current study, a high-dimensional analysis of intracellular signaling was performed by measuring 24 signaling nodes in 7 distinct immune cell subsets within PBMCs in an independent cohort of 174 healthy donors [144 elderly (>65 yrs); 30 young (25-40 yrs)]. RESULTS: Associations between age and 9 immune signaling responses identified in the previously published 60 donor cohort were confirmed in the current study. Furthermore, within the current study cohort, 48 additional immune signaling responses differed significantly between young and elderly donors. These associations spanned all profiled modulators and immune cell subsets. CONCLUSIONS: These results demonstrate that SCNP, a systems-based approach, can capture the complexity of the cellular mechanisms underlying immunological aging. Further, the confirmation of age associations in an independent donor cohort supports the use of SCNP as a tool for identifying reproducible predictive biomarkers in areas such as vaccine response and response to cancer immunotherapies.

Reproducibility of hepatic fat fraction measurement by magnetic resonance imaging.

PURPOSE: To evaluate the reproducibility of magnetic resonance imaging (MRI)-determined hepatic fat fraction (%) across imaging sites with different magnet types and field strength. Reproducibility among MRI platforms is unclear, even though evaluating hepatic fat fractions (FFs) using MRI-based methods is accurate against MR spectroscopy. MATERIALS AND METHODS: Overweight subjects were recruited to undergo eight MRI examinations at five imaging centers with a range of magnet manufacturers and field strengths (1.5 and 3 T). FFs were estimated in liver and in fat-emulsion phantoms using three methods: 1) dual-echo images without correction (nominally out-of-phase [OP] and in-phase [IP]); 2) dual-dual-echo images (two sequences) with T2* correction (nominally OP/IP and IP/IP); and 3) six-echo images with spectral model and T2* correction, at sequential alternating OP and IP echo times (Methods 1, 2, and 3, respectively). RESULTS: Ten subjects were recruited. For Methods 1, 2, and 3, respectively, hepatic FF ranged from -2.5 to 27.0, 1.9 to 29.6, and 1.3 to 34.4%. Intraclass correlation coefficients were 0.85, 0.89, and 0.91 for each method, and within-subject coefficients of variation were 18.5, 9.9, and 10.3%, respectively. Mean phantom FFs derived by Methods 2 and 3 were comparable to the known FF for each phantom. Method 1 underestimated phantom FF. CONCLUSION: Methods 2 and 3 accurately assess FF. Strong reproducibility across magnet type and strength render them suitable for use in multicenter trials and longitudinal assessments.

Replicate Testing of Clinical Endpoints Can Prevent No-Go Decisions for Beneficial Vaccines.

In vaccine efficacy trials, inaccurate counting of infection cases leads to systematic under-estimation-or "dilution"-of vaccine efficacy. In particular, if a sufficient fraction of observed cases are false positives, apparent efficacy will be greatly reduced, leading to unwarranted no-go decisions in vaccine development. Here, we propose a range of replicate testing strategies to address this problem, considering the additional challenge of uncertainty in both infection incidence and diagnostic assay specificity/sensitivity. A strategy that counts an infection case only if a majority of replicate assays return a positive result can substantially reduce efficacy dilution for assays with non-systematic (i.e., "random") errors. We also find that a cost-effective variant of this strategy, using confirmatory assays only if an initial assay is positive, yields a comparable benefit. In clinical trials, where frequent longitudinal samples are needed to detect short-lived infections, this "confirmatory majority rule" strategy can prevent the accumulation of false positives from magnifying efficacy dilution. When widespread public health screening is used for viruses, such as SARS-CoV-2, that have non-differentiating features or may be asymptomatic, these strategies can also serve to reduce unneeded isolations caused by false positives.

Quantification of clesrovimab, an investigational, half-life extended, anti-respiratory syncytial virus protein F human monoclonal antibody in the nasal epithelial lining fluid of healthy adults.

BACKGROUND: Clesrovimab (MK-1654) is an investigational, half-life extended human monoclonal antibody (mAb) against RSV F glycoprotein in clinical trials as a prophylactic agent against RSV infection for infants. METHODS: This adult study measured clesrovimab concentrations in the serum and nasal epithelial lining fluid (ELF) to establish the partitioning of the antibody after dosing. Clesrovimab concentrations in the nasal ELF were normalized for sampling dilution using urea concentrations from ELF and serum. Furthermore, in vitro RSV neutralization of human nasal ELF following dosing was also measured to examine the activity of clesrovimab in the nasal compartment. FINDINGS: mAbs with YTE mutations are reported in literature to partition ∼1-2 % of serum antibodies into nasal mucosa. Nasal: serum ratios of 1:69-1:30 were observed for clesrovimab in two separate adult human trials after urea normalization, translating to 1.4-3.3 % of serum concentrations. The nasal PK and estimates of peripheral volume of distribution correlated with higher extravascular distribution of clesrovimab. These higher concentration of the antibody in the nasal ELF corroborated with the nasal sample's ability to neutralize RSV ex vivo. An overall trend of decreased viral plaque AUC was also noted with increasing availability of clesrovimab in the nasal ELF from a human RSV challenge study. INTERPRETATION: Along with its extended half-life, the higher penetration of clesrovimab into the nasal epithelial lining fluid and the associated local increase in RSV neutralization activity could offer infants better protection against RSV infection.

Evaluation of a stabilized RSV pre-fusion F mRNA vaccine: Preclinical studies and Phase 1 clinical testing in healthy adults.

Human respiratory syncytial virus (RSV) causes a substantial proportion of respiratory tract infections worldwide. Although RSV reinfections occur throughout life, older adults, particularly those with underlying comorbidities, are at risk for severe complications from RSV. There is no RSV vaccine available to date, and treatment of RSV in adults is largely supportive. A correlate of protection for RSV has not yet been established, but antibodies targeting the pre-fusion conformation of the RSV F glycoprotein play an important role in RSV neutralization. We previously reported a Phase 1 study of an mRNA-based vaccine (V171) expressing a pre-fusion-stabilized RSV F protein (mDS-Cav1) in healthy adults. Here, we evaluated an mRNA-based vaccine (V172) expressing a further stabilized RSV pre-fusion F protein (mVRC1). mVRC1 is a single chain version of RSV F with interprotomer disulfides in addition to the stabilizing mutations present in the mDS-Cav1 antigen. The immunogenicity of the two mRNA-based vaccines encoding mVRC1 (V172) or a sequence-optimized version of mDS-Cav1 to improve transcriptional fidelity (V171.2) were compared in RSV-naïve and RSV-experienced African green monkeys (AGMs). V172 induced higher neutralizing antibody titers than V171.2 and demonstrated protection in the AGM challenge model. We conducted a Phase 1, randomized, placebo-controlled, clinical trial of 25 µg, 100 µg, 200 µg, or 300 µg of V172 in healthy older adults (60-79 years old; N = 112) and 100 µg, 200 µg, or 300 µg of V172 in healthy younger adults (18-49 years old; N = 48). The primary clinical objectives were to evaluate the safety and tolerability of V172, and the secondary objective was to evaluate RSV serum neutralization titers. The most commonly reported solicited adverse events were injection-site pain, injection-site swelling, headache, and tiredness. V172 was generally well tolerated in older and younger adults and increased serum neutralizing antibody titers, pre-fusion F-specific competing antibody titers, and RSV F-specific T-cell responses.

Repeatability of edited lactate and other metabolites in astrocytoma at 3T.

PURPOSE: To assess the repeatability of measurement of lactate and other metabolites in tumors using magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: MRS with spectral editing for lactate was performed on 10 patients with astrocytoma (two Grade III, eight Grade IV) using an 8-channel receive coil at 3T. Lactate, lipid, choline, creatine, and N-acetyl aspartate (NAA) signals were measured in regions of tumor and contralateral white matter. Metabolites were quantified relative to unsuppressed water using LCModel fitting software. RESULTS: The within-patient coefficients of variation were ≈16% (tumor lactate), 6%-8% (tumor choline and contralateral choline, creatine, and NAA), and 22% (tumor lipid). As expected due to their low concentration in normal tissue, lactate and lipid were not reliably detected in white matter but were found at high levels in most tumors. NAA and creatine were lower in tumors than in normal white matter, and choline varied between above- and below-normal values. No consistent short-term variation in metabolite levels was observed, despite differences in the time elapsed since administration of contrast agent. CONCLUSION: MRS appears repeatable enough to provide longitudinal measures of metabolite content in tumors and contralateral tissue in the brain in vivo.

Evaluation of an experimental urodynamic platform to identify treatment effects: a randomized, placebo-controlled, crossover study in patients with overactive bladder.

AIMS: To evaluate a urodynamic platform designed to identify treatment effects in small numbers of patients after a short duration of treatment using a medication with known efficacy in overactive bladder (OAB). METHODS: Twenty women with OAB were randomized in a crossover study with 7-day treatment periods with either tolterodine 4 mg long-acting (LA) or placebo and 7-day washout. Patients underwent urodynamic study (UDS) at baseline, 4-hr post-dose on Day 1 (PD1) and 4 hr post-dose on Day 7 (PD7) in each treatment period. The primary endpoint was the change from baseline in volume at maximum cystometric capacity (MCC) at PD7. As a result of dosing errors, some patients allocated to tolterodine in Period 1 mistakenly received placebo on Day 7. The data from the time points at which patients were dosed incorrectly were excluded from the per protocol (PP) analysis. RESULTS: The PP and intent to treat (ITT) mean increase in volume at MCC on PD7 for tolterodine compared with placebo was 28.9% (P = 0.038, one-sided) and 23.2% (P = 0.008, one-sided), respectively. The PD7 mean increase in volume at first desire to void was 36.5% (P = 0.054, PP) and 40.3% (P = 0.008, ITT). No volume endpoint at PD1 was statistically significant. Of all the endpoints, MCC was the least variable. CONCLUSIONS: This crossover design was able to detect a clinically meaningful and statistically significant treatment effect consistent with the previous reports of tolterodine. Despite multiple urodynamics per patient, the study was able to recruit quickly. This model is valuable for evaluating therapeutic effects for existing and novel treatments for OAB.

Test-retest repeatability of MR elastography for noninvasive liver fibrosis assessment in hepatitis C.

PURPOSE: To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by MR elastography (MRE) in healthy and hepatitis-C-infected subjects. MATERIALS AND METHODS: A biopsy-correlated repeatability study using four-slice MRE was conducted in five healthy and four HCV-infected subjects. Subjects were scanned twice on day 1 and after 7-14 days. Each slice was acquired during a 14-s breath-hold with a commercially available acquisition technique (MR-Touch, GE Healthcare). Results were analyzed by two independent analysts. RESULTS: The intraclass correlation coefficient (ICC) was 0.85 (90% confidence interval [CI]: 0.71 to 0.98) for the between-scan average of maximum stiffness within each slice and 0.88 (90% CI: 0.78 to 0.99) for the average of mean stiffness within each slice for the primary analyst. For both analysts, the average of the mean liver stiffness within each slice was highly reproducible with ICC of 0.93 and 0.94. Within-subject coefficients of variation ranged from 6.07% to 10.78% for HCV+ and healthy subjects. CONCLUSION: MRE is a highly reproducible modality for assessing liver stiffness in HCV patients and healthy subjects and can discriminate between moderate fibrosis and healthy liver. MRE is a promising modality for noninvasive assessment of liver fibrosis (CLINICALTRIALS.GOV IDENTIFIER: NCT00896233).

Variability of urodynamic parameters in patients with overactive bladder.

AIMS: To report interpatient, intrapatient, and study site variability of urodynamic study (UDS) parameters in patients with overactive bladder (OAB). METHODS: Fifty-eight patients with OAB participated in a randomized, double-blind, placebo-controlled, urodynamic trial of an experimental OAB drug. Patients underwent 3 serial cystometries (CMGs) at three times: screening, pre-dose, and 4-hr postdose. This post hoc analysis describes intrapatient, interpatient, and site variability for the 6 CMGs prior to administration of study drug. Sites were given standard procedures for equipment calibration and UDS technique. Instilled volumes and pressures were recorded at first sensation of filling, first desire to void (FDV), strong desire to void (SDV), and maximum cystometric capacity (MCC). RESULTS: The UDS volume endpoint with the smallest observed within-patient variability based on coefficient of variation (%CV) was MCC (%CV 24). Pressure measurements of all bladder sensations had larger within-patient variability than volume (MCC %CV 105). The between-patient variability was greater than within-patient variability for all bladder sensation volumes. Between-patient MCC variability for the 6 pre-treatment CMGs ranged from %CV of 50 to 58, whereas the within-patient %CV for MCC was 21-23. Excellent reproducibility was observed for bladder volume for MCC (intraclass correlation coefficients, range: 0.80-0.84). The between-site variability was large, as demonstrated by the mean volumes by site for MCC (132-397 ml). CONCLUSIONS: MCC was the most reproducible sensation. Pressure measurements were substantially more variable than volume. Between-patient variability was substantially greater than within-patient variability. The observed intersite variability suggests that despite detailed instructions, sensations may not have been measured in a consistent manner across sites.

A phase 1, randomized, placebo-controlled study to evaluate the safety and immunogenicity of an mRNA-based RSV prefusion F protein vaccine in healthy younger and older adults.

Respiratory Syncytial Virus (RSV) causes lower respiratory tract infections that can be severe and sometimes fatal. The risk for severe RSV infection is highest in infants and older adults. A safe and effective RSV vaccine for older adults represents a serious unmet medical need due to higher morbidity and mortality in this age group. In this randomized, partially double-blind, placebo-controlled, phase 1 dose-escalation study, we evaluated the safety, tolerability and immunogenicity of an investigational messenger ribonucleic acid (mRNA) vaccine encoding the RSV fusion protein (F) stabilized in the prefusion conformation. The study was conducted in healthy younger adults (ages ≥18 and ≤49 years) and healthy older adults (ages ≥60 and ≤79 years). Participants received mRNA-1777 (V171) or placebo as a single intramuscular dose. For each dose level, three sentinel participants were administered open-label mRNA-1777 (V171). Seventy-two younger adults were randomized and administered 25, 100, or 200 µg mRNA-1777 (V171) or placebo, and 107 older adults were randomized and administered 25, 100, 200 or 300 µg mRNA-1777 (V171) or placebo. Primary objectives were safety and tolerability and secondary objectives included humoral and cell-mediated immunogenicity. All dose levels of mRNA-1777 (V171) were generally well tolerated and no serious adverse events related to the vaccine were reported. Immunization with mRNA-1777 (V171) elicited a humoral immune response as measured by increases in RSV neutralizing antibody titers, serum antibody titers to RSV prefusion F protein, D25 competing antibody titers to RSV prefusion F protein, and cell-mediated immune responses to RSV-F peptides.

A Phase 1 Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety, Tolerability, and Pharmacokinetics of a Respiratory Syncytial Virus Neutralizing Monoclonal Antibody MK-1654 in Healthy Adults.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection and related morbidity and mortality in infants. Passive immunization with an RSV-neutralizing antibody can provide rapid protection to this vulnerable population. Proof-of-concept for this approach has been demonstrated by palivizumab; however, the use of this antibody is generally restricted to the highest-risk infants due to monthly dosing requirements and its cost. To address the large unmet medical need for most infants, we are evaluating MK-1654, a fully human RSV-neutralizing antibody with half-life extending mutations targeting site IV of the fusion protein. In this 2-part, placebo-controlled, double-blind, first-in-human study, 152 healthy adults were randomized 3:1 to receive a single dose of MK-1654 or placebo in 5 cohorts (100 or 300 mg as an intramuscular dose or 300, 1000, or 3000 mg as an intravenous dose). Safety, pharmacokinetics, antidrug antibodies, and RSV serum-neutralizing antibody titers were evaluated through 1 year. MK-1654 serum concentrations increased proportionally with dose and resulted in corresponding elevations in RSV serum-neutralizing antibody titers. The antibody displayed a half-life of 73 to 88 days and an estimated bioavailability of 69% at the 300-mg dose. The overall safety profile of MK-1654 was similar to placebo, and treatment-emergent antidrug antibodies were low (2.6%) with no associated adverse events. These data support the continued development of MK-1654 for the prevention of RSV disease in infants.

Forward and reverse translational approaches to predict efficacy of neutralizing respiratory syncytial virus (RSV) antibody prophylaxis.

BACKGROUND: Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary. METHODS: Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population. FINDINGS: The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants. INTERPRETATION: An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.

Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases.

BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy of a prophylactic quadrivalent vaccine in preventing anogenital diseases associated with human papillomavirus (HPV) types 6, 11, 16, and 18. METHODS: In this randomized, placebo-controlled, double-blind trial involving 5455 women between the ages of 16 and 24 years, we assigned 2723 women to receive vaccine and 2732 to receive placebo at day 1, month 2, and month 6. The coprimary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer and the incidence of cervical intraepithelial neoplasia, adenocarcinoma in situ, or cancer associated with HPV type 6, 11, 16, or 18. Data for the primary analysis were collected for a per-protocol susceptible population of women who had no virologic evidence of HPV type 6, 11, 16, or 18 through 1 month after administration of the third dose. RESULTS: The women were followed for an average of 3 years after administration of the first dose. In the per-protocol population, those followed for vulvar, vaginal, or perianal disease included 2261 women (83%) in the vaccine group and 2279 (83%) in the placebo group. Those followed for cervical disease included 2241 women (82%) in the vaccine group and 2258 (83%) in the placebo group. Vaccine efficacy was 100% for each of the coprimary end points. In an intention-to-treat analysis, including those with prevalent infection or disease caused by vaccine-type and non-vaccine-type HPV, vaccination reduced the rate of any vulvar or vaginal perianal lesions regardless of the causal HPV type by 34% (95% confidence interval [CI], 15 to 49), and the rate of cervical lesions regardless of the causal HPV type by 20% (95% CI, 8 to 31). CONCLUSIONS: The quadrivalent vaccine significantly reduced the incidence of HPV-associated anogenital diseases in young women. (ClinicalTrials.gov number, NCT00092521 [ClinicalTrials.gov].).

"In-House" Data on the Outside-A Mobile Health Approach.

Mobile health (mHealth) technologies have the potential to capture dense patient data on the background of real-life behavior. Merck & Co., Inc. (Kenilworth, NJ), in collaboration with Koneksa Health, conducted a phase I clinical trial to validate cardiovascular mHealth technologies for concordance with traditional approaches and to establish sensitivity to detect effects of pharmacological intervention. This two-part study enrolled 18 healthy male subjects. Part I, a 5-day study, compared mHealth measures of heart rate (HR) and blood pressure (BP) to those from traditional methods. Hypotheses of similarity, in the clinic and at home, were tested individually for HR, systolic BP, and diastolic BP, at a 2-sided 0.05 alpha level, with a prespecified criterion for similarity being the percentage differences between the 2 measurements within 15%. Part II, a 7-day, 3-period randomized balanced crossover study, evaluated the mHealth technology's ability to detect effects of bisoprolol and salbutamol. Hypotheses that the changes from baseline in HR were greater in the bisoprolol (reduction in HR) and salbutamol (increase in HR) groups compared with no treatment were tested, at a 1-sided 0.05 alpha level. Linear mixed-effects models, Pearson's correlation coefficients, summary statistics, and exploratory plots were applied to analyze the data. The mHealth measures of HR and BP were demonstrated to be similar to those from traditional methods, and sensitive to changes in cardiovascular parameters induced by bisoprolol and salbutamol.

Fine-Needle Aspiration for the Evaluation of Hepatic Pharmacokinetics of Vaniprevir: A Randomized Trial in Patients With Hepatitis C Virus Infection.

Fine-needle aspiration (FNA) for serial hepatic sampling may be an efficient and less invasive alternative to core needle biopsy (CNB), the current standard for liver tissue sampling. In this randomized, open-label trial in 31 participants with hepatitis C virus genotype 1 infection (NCT01678131/Merck protocol PN048), we evaluated the feasibility of using FNA to obtain human liver tissue samples appropriate for measuring hepatic pharmacokinetics (PK), using vaniprevir as a tool compound. The primary end point was successful retrieval of liver tissue specimens with measurable vaniprevir concentrations at two of three specified FNA time points. Twenty-nine patients met the primary end point and, therefore, were included in the PK analyses. Hepatic vaniprevir concentrations obtained with FNA were consistent with known vaniprevir PK properties. The shape of liver FNA and CNB concentration-time profiles were comparable. In conclusion, FNA may be effective for serial tissue sampling to assess hepatic drug exposure in patients with liver disease.

Baseline characteristics and prevalence of HPV 6, 11, 16, 18 in young German women participating in phase III clinical trials of a quadrivalent HPV (6/11/16/18) vaccine.

INTRODUCTION: As limited data among German women exist about HPV, Chlamydia trachomatis (CT) and Neisseria gonorrhoeae, we report the prevalence of these genital infections and general baseline demographics of the young German women enrolled in the phase III trials of the quadrivalent HPV vaccine. MATERIALS AND METHODS: German females (n = 437; 9-23 years) were recruited among 3 international phase 3 studies of an HPV-6/11/16/18 vaccine. We present baseline characteristics, prevalence of HPV-6/11/16/18 and, for women aged 16-23, abnormal cervical cytology and sexually transmitted diseases. RESULTS: Chlamydia trachomatis and Neisseria gonorrhoeae prevalence was 5 and 0.3%, respectively. Approximately 17% of participants had HPV-6, 11, 16, or 18 DNA or antibodies. All subjects <17 years were naïve to the four vaccine types. DISCUSSION: The results of the vaccine trials have demonstrated that it is worth administering prophylactic HPV vaccines before sexual debut; however, none of these sexually active German women were positive to all four types and most were positive to only one type. Thus, all women had the potential to benefit from vaccination with a quadrivalent HPV vaccine.