HIV prevention trial design in an era of effective pre-exposure prophylaxis

Pre-exposure prophylaxis (PrEP) has demonstrated remarkable effectiveness protecting at-risk individuals from HIV-1 infection. Despite this record of effectiveness, concerns persist about the diminished protective effect observed in women compared with men and the influence of adherence and risk behaviors on effectiveness in targeted subpopulations. Furthermore, the high prophylactic efficacy of the first PrEP agent, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), presents challenges for demonstrating the efficacy of new candidates. Trials of new agents would typically require use of non-inferiority (NI) designs in which acceptable efficacy for an experimental agent is determined using pre-defined margins based on the efficacy of the proven active comparator (i.e. TDF/FTC) in placebo-controlled trials. Setting NI margins is a critical step in designing registrational studies. Under- or over-estimation of the margin can call into question the utility of the study in the registration package. The dependence on previous placebo-controlled trials introduces the same issues as external/historical controls. These issues will need to be addressed using trial design features such as re-estimated NI margins, enrichment strategies, run-in periods, crossover between study arms, and adaptive re-estimation of sample sizes. These measures and other innovations can help to ensure that new PrEP agents are made available to the public using stringent standards of evidence.     

Pharmacokinetics and Tolerability of Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate and Glycopyrronium/Formoterol Fumarate Dihydrate Metered Dose Inhalers in Healthy Chinese Adults: A Randomized,Double-blind,Parallel-group Study

PurposeThe objective of this study was to assess pharmacokinetic (PK) and safety profiles of 2 fixed-dose combinations in development for the treatment of chronic obstructive pulmonary disease (COPD): budesonide/glycopyrronium/formoterol fumarate dihydrate metered-dose inhaler (BGF MDI; triple combination) and glycopyrronium/formoterol fumarate dihydrate (GFF MDI; dual combination). The PK and safety profiles of BGF MDI and GFF MDI were assessed for the first time in healthy Chinese adults after single and repeated (7-day) dosing.MethodsThis Phase I, randomized, double-blind, parallel-group study was conducted at a single site in Shanghai, China. Male or female Chinese subjects, 18–45 years of age and in good general health, were randomized 1:1:1 to receive BGF MDI 320/14.4/10 μg, BGF MDI 160/14.4/10 μg, or GFF MDI 14.4/10 μg. PK parameters were assessed after a single dose (day 1) and at steady state (day 8), and included AUC_0–12, C_max, and T_max. Tolerability was assessed using physical examination findings, adverse events reporting, 12-lead ECG, vital signs, and clinical laboratory values.FindingsNinety-six subjects (mean age, 25.6 years; 83.3% male) were randomized and received treatment. All randomized subjects were included in the safety and PK populations. After single and repeated dosing, budesonide AUC_0–12 and C_max were increased dose proportionally from BGF MDI 160/14.4/10 μg to BGF MDI 320/14.4/10 μg, respectively (single dose: AUC_0–12, 811.8 vs 1748 h · pg/mL; C_max, 224.3 vs 459.3 pg/mL; repeated dosing: AUC_0–12, 1250 vs 2510 h · pg/mL; C_max, 315.4 vs 626.4 pg/mL). After single and repeated dosing, glycopyrronium AUC_0–12 and C_max were similar across all treatments (single dose: AUC_0–12, 27.20–29.40 h · pg/mL; C_max, 4.884–5.674 pg/mL; repeated dosing: AUC_0–12, 69.49–77.08 h · pg/mL; C_max, 11.30–13.12 pg/mL) and formoterol (single dose: AUC_0–12, 46.49–53.58 h · pg/mL; C_max 9.651–10.62 pg/mL; repeated dosing: AUC_0–12, 81.94–85.32 h · pg/mL; C_max, 16.13–17.71 pg/mL), suggesting that the addition of budesonide did not appreciably alter the PK properties of GFF MDI. All treatment-emergent adverse events were mild in severity and rates were similar across groups (range, 50.0%–56.3%). There were no new or unexpected findings on tolerability.ImplicationsOverall, all treatments were well tolerated and PK parameters were generally comparable to those previously reported in Western and Japanese healthy subjects, suggesting that the doses of BGF MDI and GFF MDI in development globally for COPD are also appropriate for Chinese patients with COPD. ClinicalTrials.gov identifier: NCT03075267.     

Macrophage polarization in response to ECM coated polypropylene mesh

The host response to implanted biomaterials is a highly regulated process that influences device functionality and clinical outcome. Non-degradable biomaterials, such as knitted polypropylene mesh, frequently elicit a chronic foreign body reaction with resultant fibrosis. Previous studies have shown that an extracellular matrix (ECM) hydrogel coating of polypropylene mesh reduces the intensity of the foreign body reaction, though the mode of action is unknown. Macrophage participation plays a key role in the development of the foreign body reaction to biomaterials, and therefore the present study investigated macrophage polarization following mesh implantation. Spatiotemporal analysis of macrophage polarization was conducted in response to uncoated polypropylene mesh and mesh coated with hydrated and dry forms of ECM hydrogels derived from either dermis or urinary bladder. Pro-inflammatory M1 macrophages (CD86+/CD68+), alternatively activated M2 macrophages (CD206+/CD68+), and foreign body giant cells were quantified between 3 and 35 days. Uncoated polypropylene mesh elicited a dominant M1 response at the mesh fiber surface, which was decreased by each ECM coating type beginning at 7 days. The diminished M1 response was accompanied by a reduction in the number of foreign body giant cells at 14 and 35 days, though there was a minimal effect upon the number of M2 macrophages at any time. These results show that ECM coatings attenuate the M1 macrophage response and increase the M2/M1 ratio to polypropylene mesh in vivo.     

GFF MDI for the improvement of lung function in COPD – A look at the PINNACLE-1 and PINNACLE-2 data and beyond

Introduction: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and incidence rates are continuing to rise. Long-acting bronchodilators are the foundation on which current pharmacological approaches to COPD management are built, with long-acting muscarinic antagonists (LAMAs) and long-acting β₂-agonists (LABAs) recommended across the spectrum of the disease continuum. Combining LAMAs and LABAs provides additional lung function improvements and relief of patient symptoms compared with either therapy alone. Several options for LAMA/LABA fixed-dose combinations (FDC) delivered via a single inhaler device are available; however, only recently has a LAMA/LABA FDC become available as a pressurized metered dose inhaler (MDI).

Areas covered: This article describes the rationale for the development of the LAMA/LABA FDC of glycopyrrolate and formoterol fumarate, formulated by Co-Suspension? Delivery Technology and delivered by MDI (GFF MDI). The clinical trial program of GFF MDI, including the pivotal Phase III studies (PINNACLE-1 and PINNACLE-2) that supported regulatory approval, are reviewed, providing insights into interpretation and future directions for research.

Expert commentary: LAMA/LABA FDCs are already a crucial part of the COPD treatment paradigm, but additional data are needed in order to maximize their role as maintenance therapies in patients with COPD.     

A prospective, randomized, controlled study comparing Gynemesh®, a synthetic mesh, and Pelvicol®, a biologic graft, in the surgical treatment of recurrent cystocele

We compared safety and efficacy of Gynemesh PS® and Pelvicol® for recurrent cystocele repair. One hundred ninety patients were randomly divided into Gynemesh PS® and Pelvicol® groups and underwent tension-free cystocele repair. The Chi-square test was used to compare categorical variables, the paired t test for continuous parametric variables, and the Mann–Whitney test for continuous nonparametric variables. Ninety-six Gynemesh PS® patients and 94 Pelvicol® patients were studied. Mesh erosions occurred in 6.3% of Gynemesh PS® patients. No erosions were observed in Pelvicol® patients (p?=?0.02). Objective cure was 71.9% for Gynemesh PS® and 56.4% for Pelvicol® (p?=?0.06). Subjective cure was the same in both groups except for better sexuality in the Pelvicol® group. At 24 months follow-up, only Gynemesh PS® patients had mesh erosions. Anatomical outcome was similar in the two groups. Pelvicol® gave a better impact on voiding and sexuality.     

Does the degree of experience for the tension-free vaginal tape procedure influence the results of the suprapubic arc sling procedure during the learning phase?

Aim The object was to evaluate whether the degree of experience for the tension-free vaginal tape (TVT) procedures influenced the early results of the suprapubic arc (SPARC) sling procedure. Materials and methods We performed the TVT from March 1999 to May 2003 and SPARC from June to April 2004 by experienced surgeon (A) and inexperienced surgeon (B), respectively. Patients were divided as four subgroups: first 50 patients who underwent the TVT by surgeon A (TVT A); first 15 patients who underwent the TVT by surgeon B (TVT B); first 50 patients who underwent the SPARC by surgeon A (SPARC A); first 15 patients who underwent the SPARC by surgeon B (SPARC B). Results Bladder perforations were noted in 4 (8.5%) in the TVT A group and 2 (13.3%) in the TVT B group, respectively (P = 0.626). There was no bladder perforation occurred in the SPARC A and B groups. The rates of transient postoperative urinary retention were 6.4% in the TVT A group and 0.0% in the TVT B group, respectively (P = 1.000). No retention occurred in the SPARC A and B groups. Stress urinary incontinence was cured by 89.4% in the TVT A group and 80.0% in the TVT B group, respectively (P = 0.388). Similar success rates were found in the SPARC A (85.4%) and SPARC B (92.3%) group (P = 1.000). Conclusion Our findings suggest that the degree of experience for the TVT procedure does not influence the results of the SPARC procedure during the learning phase.     

HIF and fumarate hydratase in renal cancer

Hereditary leiomyomatosis and renal cell cancer is a recently described hereditary cancer syndrome in which affected individuals are predisposed to the development of leiomyomas of the skin and uterus. In addition, this clinical entity also can result in the development of biologically aggressive kidney cancer. Affected individuals harbour a germline mutation of the fumarate hydratase (FH) gene, which encodes an enzyme that catalyses conversion of fumarate to malate in the Kreb's cycle. Thus far, proposed mechanisms for carcinogeneis associated with this syndrome include aberrant apoptosis, oxidative stress, and pseudohypoxic drive. At this time, the majority of accumulating data support a role for pseudohypoxic drive in tumour development. The link between FH mutation and pseudohypoxic drive may reside in the biochemical alterations resulting from diminished/absent FH activity. These biochemical derangements may interfere with oxygen homeostasis and result in a cellular environment conducive to tumour formation.