Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy.

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

Systematic literature review of clinical trials evaluating pharmacotherapy for overactive bladder in elderly patients: An assessment of trial quality.

AIMS: Overactive bladder (OAB) disproportionately affects older-aged adults, yet most randomized controlled trials (RCTs) underrepresent patients ≥65. This systematic literature review (SLR) identified RCTs evaluating ß-3 adrenergic agonists or muscarinic antagonists in elderly patients with OAB, and compared study quality across trials. METHODS: MEDLINE® , Embase® , and Cochrane Collaboration Central Register of Clinical Trials databases were searched from inception through April 28, 2015 to identify published, peer-reviewed RCT reports evaluating ß-3 adrenergic agonists or muscarinic antagonists in elderly OAB patients (either ≥65 years or study-described as "elderly"). To assess study quality of RCT reports, we focused on internal/external validity, assessed via two scales: the validated Effective Public Health Practice Project [EPHPP]): Quality Assessment Tool for Quantitative Studies, and a tool commissioned by the Agency for Healthcare Research and Quality (AHRQ). RESULTS: Database searches yielded 1380 records that were then screened according to predefined inclusion/exclusion criteria. We included eight papers meeting study criteria. Despite scientific community efforts to improve RCT reporting standards, published reports still include incomplete and inconsistent reporting-of subject attrition, baseline patient characteristics, inclusion/exclusion criteria, and other important details. Only three of the eight OAB RCTs in this review received quality ratings of Strong (EPHPP) or Fair (AHRQ) and were multicenter with large samples. CONCLUSIONS: Despite the prevalence of OAB among older age individuals, relatively few RCTs evaluate OAB treatments explicitly among elderly subjects. The findings from this quality assessment suggest some areas for improvement in both conduct and reporting of future RCTs assessing OAB treatment in elderly.

Patterns of medical management of overactive bladder (OAB) and benign prostatic hyperplasia (BPH) in the United States.

AIMS: Overactive bladder (OAB) and benign prostatic hyperplasia (BPH) are highly prevalent conditions that place a large burden on the United States (US) health care system. We sought to analyze patterns of prescription medication usage for incident OAB in men and women, and for incident BPH in men using US health insurance claims data. MATERIALS AND METHODS: This study used Truven Health MarketScan® Commercial and Medicare Supplemental Research databases. The data were pooled from diverse points of care. BPH subjects included men age 18+ with the first and last two diagnoses of BPH ≥30 days apart and no BPH diagnosis for 1 year prior. OAB subjects included men and women age 18+, who were diagnosed similarly with incident OAB. The type of medication, medication continuation (persistence), and switching to a different medication were analyzed through September 30, 2013. RESULTS: Medication persistence was much higher overall for BPH than OAB (56% vs 34%, respectively, P < 0.0001), and was highest among men with BPH age 65+ (62%). Patients age 18-64 were less likely to continue medication than older adults (age 65+) for both BPH and OAB. A 9.4% of patients in the OAB cohort and 6.9% of men with BPH switched from one medication to another. CONCLUSIONS: Persistence was higher with BPH than OAB medications overall, whereas switching rates were higher in the OAB group. The lower persistence of OAB medication may be due to less efficacy or tolerability. The possibility of under treatment of OAB also warrants future investigations.

Patterns of Care for Newly Diagnosed Benign Prostatic Hyperplasia in the United States.

PURPOSE: We examined diagnostic tests and treatment patterns in men with new onset benign prostatic hyperplasia using consolidated national electronic health record data. MATERIALS AND METHODS: The Humedica® electronic health record database consists of de-identified patient records from approximately 25 million patients in the United States. Using this database, men with a new benign prostatic hyperplasia diagnosis (benign prostatic hyperplasia, bladder neck obstruction, urinary retention and incomplete bladder emptying) between July 1, 2009 and June 30, 2012 were included in study. Exclusion criteria included conditions such as genitourinary cancers, radiation cystitis, neurogenic bladder and urological pain diagnoses. Diagnostic tests and treatments were summarized and stratified by age (less than 65 vs 65 years or greater) and serum prostate specific antigen level. RESULTS: A total of 38,252 men met inclusion criteria. Mean followup was 1,020 days. Serum creatinine in 92% of patients, serum prostate specific antigen in 76% and urinalysis in 52% were the most common tests. Invasive testing was obtained in less than 20% of patients. Treatments included watchful waiting in 40% of patients, pharmacological therapy in 59.4% and surgery in 2.2%. α-Blockers were prescribed in 50.7% of men. Men older than 65 years and with higher prostate specific antigen levels were less likely to be treated with watchful waiting. Therapy with a 5-ARI (5-α reductase inhibitor) was prescribed in 23% to 29% of men across all prostate specific antigen categories. CONCLUSIONS: The majority of clinical care for new onset benign prostatic hyperplasia was in concordance with guideline recommendations. Based on prostate specific antigen values, 5-ARI therapy was underutilized in men with large prostates and was over utilized in men with small prostates.

Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients.

BACKGROUND: The Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) studies compared maraviroc versus placebo in treatment-experienced patients with CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1), screened using the original Trofile assay. A subset with non-R5 HIV infection entered the A4001029 trial. We retrospectively examined the performance of a genotypic tropism assay based on deep sequencing of the HIV env V3 loop in predicting virologic response to maraviroc in these trials. METHODS: V3 amplicons were prepared from 1827 screening plasma samples and sequenced on a Roche/454 GS-FLX to a depth of >3000 sequences/sample. Samples were considered non-R5 if ≥2% of their viral population scored greater than or equal to -4.75 or ≤3.5 using the PSSM(x4/R5) or geno2pheno algorithms, respectively. RESULTS: Deep sequencing identified more than twice as many maraviroc recipients as having non-R5 HIV, compared with the original Trofile. With use of genotyping, we determined that 49% of maraviroc recipients with R5 HIV at screening had a week 48 viral load <50 copies/mL versus 26% of recipients with non-R5. Corresponding percentages were 46% and 23% with screening by Trofile. In cases in which screening assays differed, median week 8 log10 copies/mL viral load decrease favored 454. Other parameters predicted by genotyping included likelihood of changing to non-R5 tropism. CONCLUSIONS: This large study establishes deep V3 sequencing as a promising tool for identifying treatment-experienced individuals who could benefit from CCR5-antagonist-containing regimens.

Deep V3 sequencing for HIV type 1 tropism in treatment-naive patients: a reanalysis of the MERIT trial of maraviroc.

BACKGROUND: Deep sequencing is a highly sensitive technique that can detect and quantify the proportion of non-R5 human immunodeficiency virus (HIV) variants, including small minorities, that may emerge and cause virologic failure in patients who receive maraviroc-containing regimens. We retrospectively tested the ability of deep sequencing to predict response to a maraviroc-containing regimen in the Maraviroc versus Efavirenz in Treatment-Naive Patients (MERIT) trial. Results were compared with those obtained using the Enhanced Sensitivity Trofile Assay (ESTA), which is widely used in clinical practice. METHODS: Screening plasma samples from treatment-naive patients who received maraviroc and efavirenz in the MERIT trial were assessed. Samples were extracted, and the V3 region of HIV type 1 glycoprotein 120 was amplified in triplicate and combined in equal quantities before sequencing on a Roche/454 Genome Sequencer-FLX (n = 859). Tropism was inferred from third variable (V3) sequences, with samples classified as non-R5 if ≥2% of the viral population scored ≤3.5 using geno2pheno. RESULTS: Deep sequencing distinguished between responders and nonresponders to maraviroc. Among patients identified as having R5-HIV by deep sequencing, 67% of maraviroc recipients and 69% of efavirenz recipients had a plasma viral load <50 copies/mL at week 48, similar to the ESTA results: 68% and 68%, respectively. CONCLUSIONS: Reanalysis of the MERIT trial using deep V3 loop sequencing indicates that, had patients originally been screened using this method, the maraviroc arm would have likely been found to be noninferior to the efavirenz arm.

Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin Amyloidosis: Insights From THAOS.

OBJECTIVES: Because patients with ATTRv cardiomyopathy are more likely to be male, this analysis aimed to increase information on associations between sex and genotype, phenotype, and degree of myocardial involvement in ATTRv amyloidosis. BACKGROUND: Transthyretin amyloid cardiomyopathy is a progressive, fatal disease that occurs due to accumulation of wild-type or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. METHODS: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing global longitudinal observational survey of patients with ATTR amyloidosis and asymptomatic carriers with TTR mutations. Data from THAOS (data cutoff: January 6, 2020) were analyzed to determine any sex-based differences in genotype, phenotype, and presence of cardiac and neurological symptoms in patients with ATTRv amyloidosis and in patients with ATTRv amyloidosis and cardiomyopathy. RESULTS: There were 2,790 patients with ATTRv amyloidosis enrolled in THAOS, with male patients more likely to have symptoms of cardiac involvement and a cardiac phenotype. Male prevalence was greater in patients with more severe cardiac manifestations of disease, as assessed with N-terminal pro-B-type natriuretic peptide, left-ventricular (LV) ejection fraction, mean LV wall thickness divided by height, and LV mass index divided by height. Sex, age at disease onset, and genotype category were identified by multivariate analyses as risk factors for the development of cardiomyopathy (defined as increased LV septum thickness divided by height). CONCLUSIONS: In this analysis, myocardial involvement was more frequent and pronounced in male patients with ATTRv amyloidosis, suggesting that there may be biological characteristics that inhibit myocardial amyloid infiltration in females or facilitate it in males.

Persistence of Tofacitinib in the Treatment of Rheumatoid Arthritis in Open-Label, Long-Term Extension Studies up to 9.5 Years.

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis evaluated tofacitinib persistence in patients with RA in long-term extension (LTE) studies up to 9.5 years. METHODS: Data were pooled from two LTE studies: ORAL Sequel (NCT00413699) and Study A3921041 (NCT00661661). Patients received tofacitinib 5 or 10 mg twice daily (BID), as monotherapy or with background conventional synthetic disease-modifying antirheumatic drugs. Kaplan-Meier estimates for tofacitinib drug survival and reasons for discontinuation were evaluated. Baseline factors were analyzed as predictors of persistence. RESULTS: In 4967 tofacitinib-treated patients entering LTE studies, mean (maximum) treatment duration was 3.5 (9.4) years. Median drug survival (95% confidence interval) was 4.9 (4.7, 5.1) years. Estimated 2- and 5-year drug survival rates were 75.5% and 49.4%, respectively. Median drug survival was similar between the tofacitinib 5 and 10 mg BID groups, and slightly higher for patients receiving tofacitinib monotherapy versus combination therapy. Overall, 50.7% of patients discontinued tofacitinib; of these, 47.2% were due to adverse events and 7.1% for lack/loss of efficacy. An increased risk of discontinuation was associated with baseline diabetes, hypertension, negative anticyclic citrullinated peptide (anti-CCP), negative rheumatoid factor (RF), and inadequate response to tumor necrosis factor inhibitors (TNFi-IR). CONCLUSION: Median drug survival of tofacitinib-treated patients participating in LTE studies was approximately 5 years and was similar for tofacitinib dosed at 5 and 10 mg BID. Reduced drug survival was associated with negative anti-CCP/RF status, TNFi-IR, and certain comorbidities. These data support tofacitinib use for long-term management of RA.

Tofacitinib in Rheumatoid Arthritis: Lack of Early Change in Disease Activity and the Probability of Achieving Low Disease Activity at Month 6.

OBJECTIVE: Optimal targeted treatment in rheumatoid arthritis requires early identification of failure to respond. This post hoc analysis explored the relationship between early disease activity changes and the achievement of low disease activity (LDA) and remission targets with tofacitinib. METHODS: Data were from 2 randomized, double-blind, phase III studies. In the ORAL Start trial, methotrexate (MTX)-naive patients received tofacitinib 5 or 10 mg twice daily, or MTX, for 24 months. In the placebo-controlled ORAL Standard trial, MTX inadequate responder patients received tofacitinib 5 or 10 mg twice daily or adalimumab 40 mg every 2 weeks, with MTX, for 12 months. Probabilities of achieving LDA (using a Clinical Disease Activity Index [CDAI] score ≤10 or the 4-component Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] ≤3.2) at months 6 and 12 were calculated, given failure to achieve threshold improvement from baseline (change in CDAI ≥6 or DAS28-ESR ≥1.2) at month 1 or 3. RESULTS: In ORAL Start, 7.2% and 5.4% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to show improvement in the CDAI ≥6 at month 3; of those who failed, 3.8% and 28.6%, respectively, achieved month 6 CDAI-defined LDA. In ORAL Standard, 18.8% and 17.5% of patients receiving tofacitinib 5 and 10 mg twice daily, respectively, failed to improve CDAI ≥6 at month 3; of those who failed, 0% and 2.9%, respectively, achieved month 6 CDAI-defined LDA. Findings were similar when considering improvements at month 1 or DAS28-ESR thresholds. CONCLUSION: In patients with an inadequate response to MTX, lack of response to tofacitinib after 1 or 3 months predicted a low probability of achieving LDA at month 6. Lack of an early response may be considered when deciding whether to continue treatment with tofacitinib.

Very early MRI responses to therapy as a predictor of later radiographic progression in early rheumatoid arthritis.

BACKGROUND: The objective of this study was to evaluate early changes in magnetic resonance imaging (MRI) and clinical disease activity measures as predictors of later structural progression in early rheumatoid arthritis (RA). METHODS: This was a post hoc analysis of data pooled across treatments from a three-arm (tofacitinib monotherapy, tofacitinib with methotrexate [MTX], or MTX monotherapy) trial of MTX-naïve patients with early, active RA. Synovitis, osteitis and erosions were assessed with the Outcome Measures in Rheumatology (OMERACT) RA MRI scoring system (RAMRIS) and RAMRIQ (automated quantitative RA MRI assessment system; automated RAMRIS) at months 0, 1, 3, 6 and 12. Radiographs were assessed at months 0, 6 and 12, and clinical endpoints were assessed at all timepoints. Univariate and multivariate analyses explored the predictive value of early changes in RAMRIS/RAMRIQ parameters and disease activity measures, with respect to subsequent radiographic progression. RESULTS: Data from 109 patients with a mean RA duration of 0.7 years were included. In univariate analyses, changes in RAMRIS erosions at months 1 and 3 significantly predicted radiographic progression at month 12 (both p <  0.01); changes in RAMRIQ synovitis and osteitis at months 1 and 3 were significant predictors of RAMRIS erosions and radiographic progression at month 12 (all p <  0.01). In subsequent multivariate analyses, RAMRIS erosion change at month 1 (p <  0.05) and RAMRIQ osteitis changes at months 1 and 3 (both p <  0.01) were significant independent predictors of radiographic progression at month 12. Univariate analyses demonstrated that changes in Clinical Disease Activity Index (CDAI) and Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR]) at months 1 and 3 were not predictive of month 12 radiographic progression. CONCLUSIONS: MRI changes seen as early as 1 month after RA treatment initiation have the potential to better predict long-term radiographic progression than changes in disease activity measures. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01164579 .

Characteristics of antimuscarinic responders versus suboptimal responders in a randomized clinical trial of patients with overactive bladder symptoms.

OBJECTIVE: To assess the characteristics of tolterodine extended-release (ER) 4 mg responders and suboptimal responders (≤50% decrease in UUI episodes/24 h) among patients with overactive bladder (OAB), including urgency urinary incontinence (UUI), and identify predictors of a >50% UUI response with fesoterodine 8 mg in tolterodine suboptimal responders. METHODS: Adult patients with OAB symptoms for ≥6 months and ≥8 micturitions, and ≥2 and <15 UUI episodes/24 h at week -2 received open-label tolterodine ER 4 mg during a 2 week run-in. Suboptimal responders after tolterodine treatment (week 0) were randomized to fesoterodine (4 mg for 1 week, 8 mg for weeks 2-12) or placebo once daily. Post-hoc analyses compared the percentage change from week -2 to week 0 in UUI episodes/24 h in tolterodine responders versus suboptimal responders and identified significant predictors of a UUI response at week 12 with fesoterodine 8 mg among tolterodine suboptimal responders. RESULTS: Of 897 patients, 610 (68%) were UUI suboptimal responders during the run-in period. UUI episodes/24 h at week -2 were similar in tolterodine responders and suboptimal responders (4.2 vs. 4.3), but responders showed a significantly greater median percentage decrease in UUI episodes/24 h after tolterodine treatment at week 0 (80.0% versus 15.3%; p < .0001). During double-blind treatment, the percentage of patients with a UUI response at week 12 was significantly greater with fesoterodine (69.9%) than placebo (57.0%; p = .0027). Fesoterodine (vs. placebo), no previous antimuscarinic use before tolterodine run-in, and less UUI severity at baseline were significant predictors of a UUI response. CONCLUSIONS: For patients with OAB, including UUI, who were treated initially with tolterodine and showed a suboptimal UUI response, nearly 70% demonstrated a UUI response with second-line fesoterodine 8 mg. No antimuscarinic use before tolterodine and fewer baseline UUI episodes were significant predictors of a UUI response with fesoterodine.

The health-related quality of life effects of once-daily cetirizine HCl syrup in children with seasonal allergic rhinitis.

Seasonal allergic rhinitis (SAR) can adversely impact children's physical, psychological, and social functioning and well-being, that is, their health-related quality of life (HRQL). This study assessed HRQL in children 6 to 11 years treated with cetirizine HCl syrup, while concurrently assessing symptomatic relief and safety. In an open-label, non-comparative study, 544 children from 124 centers in the United States were instructed to take cetirizine HCl syrup (10 cc of 1 mg/mL) each evening for 4 weeks. Children experienced statistically significant improvements in HRQL with significant reductions in mean symptom score (p < 0.001) during the treatment period. Results were consistent across age groups (6-7, 8-9, 10-11 years). These results suggest that the symptomatic relief and tolerability profile of cetirizine HC1 syrup daily translates into improvements in the HRQL of children with SAR. This 4-week open label study is among the first to evaluate the effect of antihistamine treatment on HRQL outcomes in children.

Isolated and spontaneous correction of proximal interphalangeal joint contractures in Dupuytren's disease: an exploratory analysis of the efficacy and safety of collagenase Clostridium histolyticum.

BACKGROUND AND OBJECTIVE: Dupuytren's contractures affecting proximal interphalangeal (PIP) joints are challenging to treat. We explored the effects of collagenase Clostridium histolyticum (CCH) on PIP joint contractures after injection of an affected metacarpophalangeal (MP) joint in the same finger and after injection of an isolated PIP joint contracture. METHODS: Two patient subsets were evaluated: those with MP/PIP joints contractures in the same finger, but only the MP joint contractures were treated (Group A); and those with isolated PIP joint contractures that were treated (Group B). Endpoints included correction and improvement in contracture. Fixed-flexion contracture (FFC) and range of motion (ROM) were also assessed; adverse events (AEs) were monitored. RESULTS: In Group A, 28 and 43 % of PIP contractures spontaneously corrected after the first and last injection of CCH, respectively, for MP contractures; 40 and 63 %, respectively, improved. In Group B, 31 and 39 % of PIP joint contractures corrected after the first and last injection of CCH, respectively, 56 and 66 %, respectively, improved. In Groups A and B, FFC improvements were largest after the last injection; ROM improvements were largest after the last injection in Group A and third injection in Group B. For 46 and 44 % of patients in Groups A and B, respectively, the first injection was the last injection. In Group B, the median (minimum, maximum) injections/joint was 1.0 (1.0, 4.0). Nearly all patients (98 %) experienced ≥1 AE; most were injection-site reactions. CONCLUSIONS: The efficacy of CCH for improving PIP joint contracture was similar whether treated in isolation or after treatment of an MP joint contracture.

Tofacitinib, an oral Janus kinase inhibitor, in patients from Colombia with rheumatoid arthritis: Pooled efficacy and safety analyses of data from phase III studies / Tofacitinib, un inhibidor oral de la janus kinasa, en pacientes colombianos con artritis reumatoide: análisis de eficacia y seguridad de los estudios de fase III

ABSTRACT Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objective: To conduct a post hoc analysis of tofacitinib efficacy and safety in Colombian patients enrolled in global phase III studies. Methods: Data were pooled from Colombian patients with RA across four phase III tofacitinib studies: ORAL Sync, ORAL Scan, ORAL Solo, and ORAL Start. Patients received tofacitinib 5 or 10 mg twice daily, methotrexate (ORAL Start only), or placebo as single therapy (ORAL Start and ORAL Solo), or in combination with csDMARDs (ORAL Sync and ORAL Scan). Data were pooled from three studies with similar patient populations (Sync, Scan, Solo) for efficacy analyses, and from all studies for safety analyses, up to Month 24. The efficacy analysis excluded ORAL Start due to the methotrexate-naive patient population, and placebo and methotrexate groups, due to low patient numbers. Results: Data pooled included 77 patients for efficacy, and 125 for safety analyses. Tofacitinib-treated patients showed improved American College of Rheumatology 20/50/70 response rates, a mean Disease Activity Score 28-4 (erythrocyte sedimentation rate), and a mean change from baseline in Health Assessment Questionnaire-Disability Index. Improvements were sustained in Months 12-24, although patient numbers were low post-Month 12. The most frequently reported adverse events were anemia, headache, influenza, and increased blood creatine phosphokinase. No tuberculosis cases, serious adverse events, or deaths were reported, and few cases of herpes zoster or malignancies occurred. Conclusions: Tofacitinib reduced RA signs and symptoms, and improved physical function. The efficacy and safety of tofacitinib in this Colombian sub-population were consistent with data from global phase III studies.

RESUMEN Introducción: Tofacitinib es un inhibidor oral de la janus kinasa para el tratamiento de la artritis reumatoide (AR). Objetivo: Análisis post hoc para evaluar la eficacia y seguridad de tofacitinib en los pacientes colombianos que participaron en los estudios globales de fase III. Métodos: La información se obtuvo de los pacientes colombianos con AR que participaron en 4 de los estudios de tofacitinib de fase III: ORAL Sync, ORAL Scan, ORAL Solo y ORAL Start. Los pacientes recibieron tofacitinib 5 o 10 mg 2 veces al día, ya sea en monoterapia (ORAL Start y ORAL Solo) o en combinación con csDMARDs (ORAL Scan y ORAL Sync), metotrexate (ORAL Start) o placebo. Para el análisis de eficacia se utilizaron 3 estudios que incluyeron poblaciones similares (Sync, Scan y Solo) y para el análisis de seguridad se utilizaron todos los estudios, hasta el mes 24. El análisis de eficacia excluyó tanto el estudio ORAL Start debido a población metotrexate naive como a los grupos placebo o metotrexate debido al bajo número de pacientes. Resultados: Se incluyeron 77 pacientes para el análisis de eficacia y 125 para seguridad. Los pacientes tratados con tofacitinib mostraron mejorías en las tasas de respuestas del American College of Rheumatology (ACR) 20/50/70, en el promedio del Disease Activity Score (DAS) 28-4 (velocidad de sedimentación globular) y en el cambio promedio desde la basal en el Health Assessment Questionnaire-Disability Index (HAQ-DI). Las mejorías fueron sostenidas desde el mes 12 al mes 24, aunque el número de pacientes luego del mes 12 fue bajo. Los eventos adversos más frecuentemente reportados fueron anemia, cefalea, influenza e incremento de la creatin-fosfoquinasa sérica. No se reportaron casos de tuberculosis, eventos adversos serios o muertes. Ocurrieron casos poco frecuentes de herpes zoster y malignidades. Conclusiones: Tofacitinib redujo los signos y síntomas de la AR y mejoró la función física. La eficacia y seguridad en esta subpoblación colombiana fue consistente con los resultados de los pacientes que participaron en los estudios globales de fase III.

A genotypic test for HIV-1 tropism combining Sanger sequencing with ultradeep sequencing predicts virologic response in treatment-experienced patients.

A tropism test is required prior to initiation of CCR5 antagonist therapy in HIV-1 infected individuals, as these agents are not effective in patients harboring CXCR4 (X4) coreceptor-using viral variants. We developed a clinical laboratory-based genotypic tropism test for detection of CCR5-using (R5) or X4 variants that utilizes triplicate population sequencing (TPS) followed by ultradeep sequencing (UDS) for samples classified as R5. Tropism was inferred using the bioinformatic algorithms geno2pheno([coreceptor]) and PSSM(x4r5). Virologic response as a function of tropism readout was retrospectively assessed using blinded samples from treatment-experienced subjects who received maraviroc (N = 327) in the MOTIVATE and A4001029 clinical trials. MOTIVATE patients were classified as R5 and A4001029 patients were classified as non-R5 by the original Trofile test. Virologic response was compared between the R5 and non-R5 groups determined by TPS, UDS alone, the reflex strategy and the Trofile Enhanced Sensitivity (TF-ES) test. UDS had greater sensitivity than TPS to detect minority non-R5 variants. The median log(10) viral load change at week 8 was -2.4 for R5 subjects, regardless of the method used for classification; for subjects with non-R5 virus, median changes were -1.2 for TF-ES or the Reflex Test and -1.0 for UDS. The differences between R5 and non-R5 groups were highly significant in all 3 cases (p<0.0001). At week 8, the positive predictive value was 66% for TF-ES and 65% for both the Reflex test and UDS. Negative predictive values were 59% for TF-ES, 58% for the Reflex Test and 61% for UDS. In conclusion, genotypic tropism testing using UDS alone or a reflex strategy separated maraviroc responders and non-responders as well as a sensitive phenotypic test, and both assays showed improved performance compared to TPS alone. Genotypic tropism tests may provide an alternative to phenotypic testing with similar discriminating ability.

Population-based sequencing of the V3-loop can predict the virological response to maraviroc in treatment-naive patients of the MERIT trial.

BACKGROUND: MERIT was a randomized trial comparing maraviroc (MVC) + Combivir versus efavirenz (EFV) + Combivir in drug-naive patients screened as having R5 HIV-1 by the original Trofile assay (OTA). We retrospectively evaluated treatment response after rescreening for viral tropism using population-based V3-loop sequencing. METHODS: HIV env V3-loop was amplified in triplicate using reverse transcriptase-polymerase chain reaction from stored screening plasma and sequenced. Automated base calling was performed using custom software (RECall) and tropism inferred by geno2pheno (5.75% false-positive rate). Tropism results by genotype were compared with those of OTA and Enhanced Sensitivity Trofile assay (ESTA), where all results were available (n = 876). RESULTS: Approximately 8% of patients screened as having R5 virus by OTA were classified as having non-R5 virus by V3-loop genotyping. These patients were less likely to have early or sustained week-48 treatment response to MVC, but not EFV. When restricted to patients with R5 virus by genotype, reanalysis of the primary study endpoint (plasma viral load <50 copies/mL at week 48) showed noninferiority of MVC twice daily to EFV (67% vs. 68%). Rescreening by genotype and ESTA had 84% concordance; patients receiving MVC twice daily rescreened as having R5 virus had greater than 1 log10 copies per milliliter decrease in viral load over those rescreened as having non-R5 virus. Where genotype and ESTA screening results were discordant outcomes were similar. CONCLUSIONS: The exclusion of ∼8% of patients with CXCR4-using virus by population-based sequencing would likely have resulted in noninferior responses in the MVC twice-daily and EFV arms. Rescreening by ESTA and population-based sequencing predicted similar virological response.

Baseline CD4(+) T-cell counts and weighted background susceptibility scores strongly predict response to maraviroc regimens in treatment-experienced patients.

BACKGROUND: Maraviroc-containing regimens are known to achieve virological suppression in many treatment-experienced patients. This study aimed to evaluate a more rigorous methodological approach to resistance-response analysis in large clinical studies and to better establish which subpopulations of patients were most likely to benefit from maraviroc by refining and extending previous subgroup analyses from the MOTIVATE studies. METHODS: Individual weighted optimized background therapy (OBT) susceptibility scores were calculated by combining genotypic or phenotypic resistance testing with prior drug use information. Virological response (HIV-1 RNA<50 copies/ml at week 48) using each of these methods was compared with a commonly used method of counting active drugs. Baseline predictors of virological response, including weighted or unweighted scoring, maraviroc use, baseline CD4(+) T-cell count, HIV-1 plasma viral load and tropism, were assessed by logistic regression modelling. RESULTS: Genotypic or phenotypic weighted methods were similarly predictive of virological response and better than counting active drugs. Weighted scoring and baseline CD4(+) T-cell count were the strongest predictors of virological response (P<0.0001): ≈70% of maraviroc patients with a weighted score ≥2 had a virological response, rising to ≈80% when the baseline CD4(+) T-cell count was ≥50 cells/mm(3). CONCLUSIONS: Approximately 80% of patients with a CD4(+) T-cell count ≥50 cells/mm(3) receiving maraviroc with the equivalent of at least two fully active agents achieved HIV-1 RNA<50 copies/ml at week 48 in the MOTIVATE studies. Genotypic and phenotypic weighted scores were similarly predictive of virological response.

Population-based V3 genotypic tropism assay: a retrospective analysis using screening samples from the A4001029 and MOTIVATE studies.

BACKGROUND: The MOTIVATE-1 and 2 studies compared maraviroc (MVC) along with optimized background therapy (OBT) vs. placebo along with OBT in treatment-experienced patients screened as having R5-HIV (original Monogram Trofile). A subset screened with non-R5 HIV were treated with MVC or placebo along with OBT in a sister safety trial, A4001029. This analysis retrospectively examined the performance of population-based sequence analysis of HIV-1 env V3-loop to predict coreceptor tropism. METHODS: Triplicate V3-loop sequences were generated using stored screening plasma samples and data was processed using custom software ('ReCall'), blinded to clinical response. Tropism was inferred using geno2pheno ('g2p'; 5% false positive rate). Primary outcomes were viral load changes after starting maraviroc; and concordance with prior screening Trofile results. RESULTS: Genotype and Trofile results were available for 1164 individuals with virological outcome data (N = 169 non-R5 by Trofile). Compared with Trofile, V3 genotyping had a specificity of 92.6% and a sensitivity of 67.4% for detecting non-R5 virus. However, when compared with clinical outcome, virological responses were consistently similar between Trofile and V3 genotype at weeks 8 and 24 following the initiation of therapy for patients categorized as R5. CONCLUSION: Despite differences in sensitivity for predicting non-R5 HIV, week 8 and 24 week virological responses were similar in this treatment-experienced population. These findings suggest the potential utility of V3 genotyping as an accessible assay to select patients who may benefit from maraviroc treatment. Optimization of the predictive tropism algorithm may lead to further improvement in the clinical utility of HIV genotypic tropism assays.

Comparison of cetirizine-pseudoephedrine and placebo in patients with seasonal allergic rhinitis and concomitant mild-to-moderate asthma: randomized, double-blind study.

BACKGROUND: Allergic rhinitis (AR) and asthma are common concurrent conditions. OBJECTIVES: To evaluate the effects of cetirizine hydrochloride (5 mg)-pseudoephedrine hydrochloride (120 mg) (cetirizine-D) twice daily on AR and asthma symptoms, pulmonary function, and asthma-related quality of life in 274 patients with confirmed seasonal AR and concomitant mild-to-moderate asthma. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study, after a 1-week screening period, patients took cetirizine-D or placebo for 4 weeks. The primary efficacy variable, AR total symptom severity complex score, was derived from patient daily diary ratings of sneezing, runny nose, itchy nose, postnasal drip, and nasal congestion. Asthma symptom severity total scores were derived from twice-daily diary ratings of wheezing, coughing, shortness of breath, and chest tightness. Pulmonary function was tested at clinic visits and by patients each morning and evening. Patients completed the Asthma Quality of Life Questionnaire at each visit. All tests were 2-sided, with statistical significance at the .05 level. RESULTS: Cetirizine-D reduced total symptom severity complex scores by 42.3% overall vs 23.6% with placebo (P < .001). Asthma symptom severity total scores were significantly improved with cetirizine-D at most times vs placebo. Cetirizine-D treatment was also associated with significantly improved Asthma Quality of Life Questionnaire overall scores. Pulmonary function test results were neutral. Cetirizine-D was well tolerated, with discontinuation and adverse event rates similar to placebo. Somnolence occurred in 8 patients (5.8%) taking cetirizine-D and in 1 (0.7%) taking placebo. CONCLUSIONS: Treatment with cetirizine-D twice daily significantly reduced rhinitis and asthma symptoms and improved overall asthma quality of life in patients with seasonal AR and concomitant mild-to-moderate asthma.

Comparative efficacy of cetirizine and fexofenadine for seasonal allergic rhinitis, 5-12 hours postdose, in the environmental exposure unit.

In a previous study, cetirizine and fexofenadine similarly relieved seasonal allergic rhinitis symptoms in the first 5 hours, but cetirizine was more effective at 21-24 hours postdose. This randomized, double-blind, placebo-controlled study compared the response to treatment between 5 and 12 hours. Eligible ragweed allergic subjects were exposed to pollen in the Environmental Exposure Unit and randomized (n = 599) to a single dose of cetirizine, 10 mg; fexofenadine, 180 mg; or placebo (2.5:2.5:1). The primary efficacy end point was the change from baseline in total symptom severity complex (TSSC) score at 12 hours postdose. TSSC score was the sum of self-rated scores (0 = absent to 3 = severe) for runny nose, sneezing, itchy nose/palate/throat, and itchy/watery eyes, recorded half-hourly. Mean baseline TSSC scores were similar: 9.2, cetirizine and fexofenadine; 8.9, placebo. Reductions in TSSC scores from baseline were 4.3 at 12 hours and 5.0 overall (i.e., average over 5-12 hours postdose) for cetirizine and 3.4 and 4.4, respectively, for fexofenadine. Cetirizine produced a 26% greater reduction in TSSC at 12 hours (p = 0.001) and 14% greater reduction in TSSC overall (p = 0.006) compared with fexofenadine. Cetirizine and fexofenadine reduced TSSC scores (p < 0.001) and individual symptoms (p < 0.05) more than placebo. However, cetirizine was more effective than fexofenadine (p < 0.05) for runny nose and sneezing (12 hours and overall), itchy/watery eyes (12 hours), and itchy nose/throat/palate (overall). Incidence of treatment-emergent adverse events and somnolence were similar among groups: cetirizine, 25.3 and 0.8%, respectively; fexofenadine, 29.6 and 0%, respectively; placebo, 35.0 and 0%, respectively. In conclusion, cetirizine produced greater relief of seasonal allergic rhinitis symptoms than fexofenadine at 12 hours postdose and over the 5- to 12-hour postdose period.