Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial.

BACKGROUND: Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). MATERIALS AND METHODS: NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. RESULTS: Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. CONCLUSION: These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC. IMPLICATIONS FOR PRACTICE: In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.

Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens.

PURPOSE: To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study. METHODS: In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks. Descriptive statistics summarized scores over time, mixed models evaluated differences between treatment arms, and Kaplan-Meier methods were used to assess time to deterioration in HRQoL scores of ≥ 10 points. RESULTS: Of the 621 patients randomized in NALA, patients were included in the HRQoL analysis if they completed baseline and at least one follow-up questionnaire. The summary, global health status, physical functioning, fatigue, constipation, and systemic therapy side effects scores were stable over time with no persistent differences between treatment groups. There were no differences in time to deterioration (TTD) for the QLQ-C30 summary score between treatment arms; the hazard ratio (HR) for N + C vs. L + C was 0.94 (95% CI 0.63-1.40). Only the diarrhea score worsened significantly more in the N + C arm as compared to the L + C arm, and this remained over time (HR for TTD for N + C vs. L + C was 1.71 [95% CI 1.32-2.23]). CONCLUSION: In NALA, patients treated with N + C maintained their global HRQoL over time, despite a worsening of the diarrhea-related scores. These results may help guide optimal treatment selection for HER2-positive MBC.

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens.

PURPOSE: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein. METHODS: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety. RESULTS: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity. CONCLUSION: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. CLINICAL TRIAL REGISTRATION: NCT01808573.

Preoperative vaginal estrogen and midurethral sling exposure: a retrospective cohort study.

INTRODUCTION AND HYPOTHESIS: We evaluated whether the use of estrogen vaginally prior to synthetic midurethral sling insertion mediates the risk of mesh exposure. A secondary aim was to evaluate other factors that may be associated with mesh exposure. METHODS: We performed a retrospective cohort study of patients undergoing midurethral sling insertion from January to December 2010 within the Southern California Permanente Medical Group. Women who used estrogen vaginally prior to surgery were classified as those who filled a prescription between 1 and 45 days before surgery or whose medical records indicated its use at the time of preoperative evaluation. Logistic regression analysis was used to calculate odds ratios (OR) and 95 % confidence intervals (CI) for factors associated with mesh exposure while controlling for confounding variables. RESULTS: A total of 1544 patients met inclusion criteria, of whom 248 (16.1 %) used estrogen vaginally prior to surgery. Mean age was 53.7 years (range 27-89). Thirty-seven (2.4 %) women were diagnosed with mesh exposure, of whom 19 underwent surgical reoperation. In multivariate logistic regression analysis, preoperative use of estrogen vaginally was not associated with the risk of mesh exposure (OR 0.79, CI 0.26-2.38, p = 0.67). Age, body mass index, menopausal status, use of hormone replacement therapy, smoking status, and diabetes were not associated with risk of mesh exposure. CONCLUSIONS: Preoperative use of estrogen vaginally did not appear to mediate the risk of mesh exposure following midurethral sling placement in this cohort.

Laparoscopic Hysterectomy and Urinary Tract Injury: Experience in a Health Maintenance Organization.

STUDY OBJECTIVES: To evaluate the incidence, detection, characteristics, and management of urinary tract injury in a cohort undergoing laparoscopic hysterectomy, and to identify potential risk factors for urinary tract injury with laparoscopic hysterectomy. DESIGN: Retrospective analysis (Canadian Task Force classification II-2). SETTING: Kaiser Permanente San Diego Medical Center, 2001 to 2012. PATIENTS: Women who underwent attempted laparoscopic hysterectomy for benign indications. INTERVENTIONS: Total laparoscopic hysterectomy, laparoscopic-assisted vaginal hysterectomy, and laparoscopic supracervical hysterectomy. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical characteristics, surgical techniques, and perioperative complications were abstracted from the medical record. Multivariable logistic regression analysis assessed independent risk factors for ureteral or bladder injury. RESULTS: A total of 3523 patients (mean age, 45.9 ± 8.0 years; median parity, 2; range, 0-10), with a median body mass index (BMI) of 29 kg/m(2) (range, 16-72 kg/m(2)), underwent laparoscopic hysterectomy; 20% had intraoperative cystoscopy. The incidence of urinary tract injury was 1.3% (46 of 3523); of the 46 patients with injuries, 19 (0.54%) had ureteral injuries, 25 (0.71%) had bladder injuries, and 2 (0.06%) had both types. Of the 21 ureteral injuries, 6 (29%) were diagnosed intraoperatively and 15 (71%) were diagnosed postoperatively, including 4 with normal intraoperative cystoscopy. Of the 27 bladder injuries, 23 (85%) were identified intraoperatively. In multivariable logistic analysis, a BMI of 26 to 30 kg/m(2) (compared with >30 kg/m(2)) was associated with an increased risk of ureteral injury, and a BMI ≤25 kg/m(2) (compared with >30 kg/m(2)) and the presence of endometriosis were associated with an increased risk of bladder injury. CONCLUSION: Urinary tract injury occurred in 1.3% of laparoscopic hysterectomies, with ureteral injuries almost as common as bladder injuries. Normal intraoperative cystoscopy findings did not exclude the presence of ureteral injury.

No association between TNF inhibitor and methotrexate therapy versus methotrexate in changes in hemoglobin A1C and fasting glucose among psoriasis, psoriatic arthritis, and rheumatoid arthritis patients.

BACKGROUND: The use of tumor necrosis factor inhibitors (TNFi) has been associated with a reduced incidence of type 2 diabetes mellitus. OBJECTIVE: To compare changes in hemoglobin A1C and fasting glucose for patients exposed to TNFi. METHODS: In this retrospective cohort study, patients with at least 3 recorded diagnosis codes for psoriasis, psoriatic arthritis, or rheumatoid arthritis between January 1, 2004 and July 31, 2011. Patients were Kaiser Permanente Southern California members for at least 1 year prior to the index date. RESULTS: For hemoglobin A1C, there were 344 patients in the MTX cohort, and 118 patients in the TNFi+MTX cohort. In the covariate adjusted main effects ANCOVA model, the TNFi+MTX cohort had a lower mean change in hemoglobin A1C of -0.18 mg/dL (95% CI: -0.35, -0.01) compared to the MTX cohort, although the difference is small and this model was not complete as there were significant interactions. For fasting glucose, there were 524 patients in the MTX cohort, and 121 patients in the TNFi+MTX cohort. In the covariate adjusted main effects ANCOVA model, change in fasting glucose was not significantly different between groups: -0.58 mg/dL (95% CI: -5.05, 3.88) for the TNFi+MTX cohort compared to the MTX cohort, although this model was not complete as there was a significant interaction. CONCLUSIONS: The use of TNF inhibitors with MTX was not associated with a significant difference in the change of hemoglobin A1C or fasting glucose compared to MTX alone.

Epimacular brachytherapy for neovascular age-related macular degeneration: a randomized, controlled trial (CABERNET).

PURPOSE: To evaluate the safety and efficacy of epimacular brachytherapy (EMBT) for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Multicenter, randomized, active-controlled, phase III clinical trial. PARTICIPANTS: Four hundred ninety-four participants with treatment-naïve neovascular AMD. METHODS: Participants with classic, minimally classic, and occult lesions were randomized in a 2:1 ratio to EMBT or a ranibizumab monotherapy control arm. The EMBT arm received 2 mandated, monthly loading injections of 0.5 mg ranibizumab. The control arm received 3 mandated, monthly loading injections of ranibizumab then quarterly injections. Both arms also received monthly as needed (pro re nata) retreatment. MAIN OUTCOME MEASURES: The proportion of participants losing fewer than 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline visual acuity (VA) and the proportion gaining more than 15 ETDRS letters from baseline VA. RESULTS: At 24 months, 77% of the EMBT group and 90% of the control group lost fewer than 15 letters. This difference did not meet the prespecified 10% noninferiority margin. This end point was noninferior using a 20% margin and a 95% confidence interval for the group as a whole and for classic and minimally classic lesions, but not for occult lesions. The EMBT did not meet the superiority end point for the proportion of participants gaining more than 15 letters (16% for the EMBT group vs. 26% for the control group): this difference was statistically significant (favoring controls) for occult lesions, but not for predominantly classic and minimally classic lesions. Mean VA change was -2.5 letters in the EMBT arm and +4.4 letters in the control arm. Participants in the EMBT arm received a mean of 6.2 ranibizumab injections versus 10.4 in the control arm. At least 1 serious adverse event occurred in 54% of the EMBT arm, most commonly postvitrectomy cataract, versus 18% in the control arm. Mild, nonproliferative radiation retinopathy occurred in 3% of the EMBT participants, but no case was vision threatening. CONCLUSIONS: The 2-year efficacy data do not support the routine use of EMBT for treatment-naïve wet AMD, despite an acceptable safety profile. Further safety review is required.

Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography.

PURPOSE: To report the fluorescein angiography (FA) and optical coherence tomography (OCT) results of a clinical trial of epimacular brachytherapy (EMBT) used for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Pivotal multicenter, active-controlled, randomized clinical trial. PARTICIPANTS: A total of 494 participants with treatment-naïve, neovascular AMD. METHODS: Participants with classic, minimally classic, and occult lesions were randomized to receive (a) EMBT and 2 mandated monthly ranibizumab injections followed by pro re nata (PRN) ranibizumab or (b) 3 mandated monthly ranibizumab injections followed by mandated quarterly plus PRN ranibizumab. Participants underwent FA at screening and at months 1, 6, 12, 18, and 24. Optical coherence tomography scans were undertaken monthly for 24 months. The FA and OCT images were analyzed at respective independent reading centers. MAIN OUTCOME MEASURES: Change at 24 months in mean FA total lesion size and choroidal neovascularization (CNV) size and change in mean OCT centerpoint thickness. RESULTS: The mean (standard deviation) changes in FA total lesion size in the EMBT and control arms were +1.9 (8.7) and -3.0 (7.2) mm(2), respectively, with a mean change in total CNV size of +0.4 (8.4) and -4.7 (6.5) mm(2), respectively. Mean (standard deviation) changes in OCT centerpoint thickness were -144 (246) and -221 (185) µm, respectively. Retrospective subgroup analyses showed no significant difference between treatment arms in mean centerpoint thickness in some subgroups, including eyes with classic lesions. The control arm showed a significantly larger reduction in mean total lesion size and mean CNV size than the EMBT arm in all subgroups analyzed. Nine eyes in the EMBT arm showed features consistent with mild, nonproliferative radiation retinopathy, but with a mean gain of 5.0 Early Treatment Diabetic Retinopathy Study letters. CONCLUSIONS: Both FA and OCT suggest that EMBT with PRN ranibizumab results in an inferior structural outcome than quarterly plus PRN ranibizumab. Some subgroup analyses suggest that classic lesions may be more responsive than occult lesions, although generally both subgroups are inferior to ranibizumab. A non-vision-threatening radiation retinopathy occurs in 2.9% of eyes over 24 months, but longer follow-up is needed. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Association between the type and length of tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis.

OBJECTIVE: We sought to assess whether the type of TNF inhibitor therapy (soluble receptor versus monoclonal antibody) has an effect on MI risk; and determine whether length of TNF inhibitor therapy has an effect on MI risk. DESIGN: Retrospective cohort study. SETTING: Between January 1, 2004 and November 30, 2010. PARTICIPANTS: At least 3 ICD9 codes for psoriasis (696.1) or psoriatic arthritis (696.0) (without antecedent MI). INTERVENTION: None. MAIN OUTCOME MEASURE: Incident MI. RESULTS: In the 3 subgroups of TNF inhibitors, 976 received etanercept; 217 received monoclonal antibody; and 480 received etanercept or monoclonal antibody, in addition, 5075 received topical therapy and 2097 received oral therapy. In the Cox proportional hazards analysis, etanercept (HR, 0.53; 95% CI, 0.31-0.92) was associated with a significant reduction of MI risk, compared to topical agents and, monoclonal antibody only (HR, 0.25; 95% CI, 0.06-1.03), and etanercept or monoclonal antibody (HR, 0.53; 95% CI, 0.27-1.06) were associated with a non-significant reduction of MI risk compared to topical agents. Using year 1 as reference, those who received TNF inhibitor therapy at year 2 (HR, 1.15; 95% CI, 0.30-4.44), at year 3 (HR, 1.89; 95% CI, 0.64-5.58), and at year 4 and above (HR, 1.16; 95% CI, 0.46-2.94) had a non-significant increase of MI risk. CONCLUSIONS: Treatment with etanercept, compared to treatment with topical agents, was associated with a significant decreased risk of MI in psoriasis patients. Treatment with monoclonal antibody and etanercept or monoclonal antibody, compared to treatment with topical agents, was associated with a non-significant decreased risk of MI risk in psoriasis patients. There were no statistically significant changes in risk of MI associated with length of TNF inhibitor treatment.

Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer.

PURPOSE: Neratinib plus capecitabine (N+C) demonstrated significant progression-free survival (PFS) benefit in NALA (NCT01808573), a randomized phase III trial comparing N+C with lapatinib + capecitabine (L+C) in 621 patients with HER2-positive (HER2+) metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens in the metastatic setting. We evaluated correlations between exploratory biomarkers and PFS. PATIENTS AND METHODS: Somatic mutations were evaluated by next-generation sequencing on primary or metastatic samples. HER2 protein expression was evaluated by central IHC, H-score, and VeraTag/HERmark. p95 expression (truncated HER2) was measured by VeraTag. HRs were estimated using unstratified Cox proportional hazards models. RESULTS: Four hundred and twenty samples had successful sequencing: 34.0% had PIK3CA mutations and 5.5% had HER2 (ERBB2) mutations. In the combined patient populations, PIK3CA mutations trended toward shorter PFS [wild-type vs. mutant, HR = 0.81; 95% confidence interval (CI), 0.64-1.03], whereas HER2 mutations trended toward longer PFS [HR = 1.69 (95% CI, 0.97-3.29)]. Higher HER2 protein expression was associated with longer PFS [IHC 3+ vs. 2+, HR = 0.67 (0.54-0.82); H-score ≥240 versus <240, HR = 0.77 (0.63-0.93); HERmark positive vs. negative, HR = 0.76 (0.59-0.98)]. Patients whose tumors had higher HER2 protein expression (any method) derived an increased benefit from N+C compared with L+C [IHC 3+, HR = 0.64 (0.51-0.81); H-score ≥ 240, HR = 0.54 (0.41-0.72); HERmark positive, HR = 0.65 (0.50-0.84)], as did patients with high p95 [p95 ≥2.8 relative fluorescence (RF)/mm2, HR = 0.66 (0.50-0.86) vs. p95 < 2.8 RF/mm2, HR = 0.91 (0.61-1.36)]. CONCLUSIONS: PIK3CA mutations were associated with shorter PFS whereas higher HER2 expression was associated with longer PFS. Higher HER2 protein expression was also associated with a greater benefit for N+C compared with L+C.

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.

PURPOSE: NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS: Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS: A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION: N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the ability of sapropterin dihydrochloride (pharmaceutical preparation of tetrahydrobiopterin) to increase phenylalanine (Phe) tolerance while maintaining adequate blood Phe control in 4- to 12-year-old children with phenylketonuria (PKU). STUDY DESIGN: This international, double-blind, randomized, placebo-controlled study screened for sapropterin response among 90 enrolled subjects in Part 1. In Part 2, 46 responsive subjects with PKU were randomized (3:1) to sapropterin, 20 mg/kg/d, or placebo for 10 weeks while continuing on a Phe-restricted diet. After 3 weeks, a dietary Phe supplement was added every 2 weeks if Phe control was adequate. RESULTS: The mean (+/-SD) Phe supplement tolerated by the sapropterin group had increased significantly from the pretreatment amount (0 mg/kg/d) to 20.9 (+/-15.4) mg/kg/d (P < .001) at the last visit at which subjects had adequate blood Phe control (<360 micromol/L), up to week 10. Over the 10-week period, the placebo group tolerated only an additional 2.9 (+/-4.0) mg/kg/d Phe supplement; the mean difference from the sapropterin group (+/-SE) was 17.7 +/- 4.5 mg/kg/d (P < .001). No severe or serious related adverse events were observed. CONCLUSIONS: Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU.

Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study.

BACKGROUND: Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration. METHODS: We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT00104247. FINDINGS: 88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9.7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) micromol/L in patients assigned to receive sapropterin, and 888 (323) micromol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) micromol/L, compared with a 3 (240) micromol/L increase in the placebo group (p<0.0001). After 6 weeks, 18/41 (44%) patients (95% CI 28-60) in the sapropterin group and 4/47 (9%) controls (95% CI 2-20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 micromol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0.0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p=0.80). Upper respiratory tract infections were the most common disorder. INTERPRETATION: In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances.

Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria.

Phenylketonuria (PKU) is an inherited metabolic disease characterized by phenylalanine (Phe) accumulation, which can lead to neurocognitive and neuromotor impairment. Sapropterin dihydrochloride, an FDA-approved synthetic formulation of tetrahydrobiopterin (6R-BH4, herein referred to as sapropterin) is effective in reducing plasma Phe concentrations in patients with hyperphenylalaninemia due to tetrahydrobiopterin (BH4)-responsive PKU, offering potential for improved metabolic control. Eighty patients, > or =8 years old, who had participated in a 6-week, randomized, placebo-controlled study of sapropterin, were enrolled in this 22-week, multicenter, open-label extension study comprising a 6-week forced dose-titration phase (5, 20, and 10 mg/kg/day of study drug consecutively for 2 weeks each), a 4-week dose-analysis phase (10 mg/kg/day), and a 12-week fixed-dose phase (patients received doses of 5, 10, or 20 mg/kg/day based on their plasma Phe concentrations during the dose titration). Dose-dependent reductions in plasma Phe concentrations were observed in the forced dose-titration phase. Mean (SD) plasma Phe concentration decreased from 844.0 (398.0) micromol/L (week 0) to 645.2 (393.4) micromol/L (week 10); the mean was maintained at this level during the study's final 12 weeks (652.2 [382.5] micromol/L at week 22). Sixty-eight (85%) patients had at least one adverse event (AE). All AEs, except one, were mild or moderate in severity. Neither the severe AE nor any of the three serious AEs was considered related to sapropterin. No AE led to treatment discontinuation. Sapropterin is effective in reducing plasma Phe concentrations in a dose-dependent manner and is well tolerated at doses of 5-20 mg/kg/day over 22 weeks in BH4-responsive patients with PKU.

Post-trial access to tested interventions: the views of IRB/REC chair, investigators, and research participants in a multinational HIV/AIDS study.

Controversy exists regarding an ethical requirement to make products proven effective in research available after the trial. Little is known about the views of several stakeholders. Phone or self-administered questionnaires were completed by 65 IRB/REC chairs, 117 investigators, and 500 research participants in a multinational HIV trial to assess their views about posttrial access to interventions proven effective in the study. A total of 83% of research participants, 29% of IRB/REC chairs, and 42% of researchers (p = 0.046) thought IL-2 should be guaranteed for every HIV-infected person in the world if proven effective. Most European and Latin American research participants thought IL-2 should be provided free, while North American, Australian, and Thai participants commonly said at a price the average person could afford (p < 0.001). Most IRB/REC chairs and researchers thought the CIOMS "reasonable availability" requirement applied to people in the country where the study was conducted and meant a drug should be available at a price the average person could afford and that host country governments had primary responsibility for making it available. Most research participants believe an HIV drug proven effective in research should be made available to everyone in the world who needs it. IRB/REC chairs and researchers were less expansive both in who and how they thought a drug should be guaranteed.

Risk of myocardial infarction in psoriasis patients: a retrospective cohort study.

BACKGROUND: Psoriasis may or may not be associated with a higher risk for myocardial infarction (MI). We sought to assess differences in MI incidence between control, mild psoriasis and severe psoriasis patients. METHODS: We performed a retrospective cohort study of Kaiser Permanente Southern California members with psoriasis between 1 January 2004 and 30 June 2012, assessing the risk and incidence rates of MI. RESULTS: There were 50,865 control patients matched to 10,173 patients with mild psoriasis and 19,205 control patients matched to 3841 patients with severe psoriasis. The MI incidence per 1000 person-years for mild psoriasis controls, mild psoriasis, severe psoriasis controls and severe psoriasis were 4.9, 6.7, 3.7 and 5.1, respectively. Upon multivariable analysis, mild psoriasis patients had a significantly higher risk of MI compared to matched control patients {hazard ratio (HR) = 1.31 [95% confidence interval (CI): 1.14, 1.51]} and severe psoriasis patients had a significantly higher risk of MI compared to matched control patients [HR = 1.28 (95% CI: 1.02, 1.60)]. CONCLUSION: Patients with psoriasis are at higher risk for MI compared to control patients.

Nadir CD4+ T cell count predicts response to subcutaneous recombinant interleukin-2.

Community Program for Clinical Research on AIDS 059 was a multicenter study conducted among human immunodeficiency virus (HIV)-infected individuals with CD4+ cell counts > or =300 cells/mm3 who were randomly assigned to receive antiretroviral therapy with or without intermittent subcutaneously administered recombinant interleukin-2 (rIL-2). To identify factors associated with a response to IL-2, a secondary analysis was performed that included the subset of rIL-2 recipients who were able to complete all 3 initial treatment cycles. Predictors of a change in CD4+ cell count between baseline and 1 month after the start of treatment cycle 3 were examined in a multivariate model that included sex, race, body surface area, rIL-2 dose, HIV load, and both baseline and nadir CD4+ cell count. The combination of race and sex (P=.027) and the nadir CD4+ cell count (P=.005) were significant predictors of mean CD4+ cell count response. Baseline CD4+ cell count had no significant effect. The strong association between nadir CD4+ cell count and CD4+ cell count response suggests that immunologic losses resulting from HIV-mediated CD4+ cell depletion may be irreversible.

Repeat midurethral sling compared with urethral bulking for recurrent stress urinary incontinence.

OBJECTIVE: To compare the effectiveness and safety of repeat midurethral sling with urethral bulking after failed midurethral sling. METHODS: This is a retrospective cohort study of patients within Kaiser Permanente Southern California Medical Group who underwent a midurethral sling for stress urinary incontinence (SUI) from 2008 to 2011 and subsequently had either a midurethral sling or urethral bulking for recurrent SUI. Current Procedural Terminology codes were used to identify patients and electronic medical records were queried for individual patient information. Our primary outcome was either subjective failure defined by SUI or objective failure defined as a positive cough stress test, urodynamic stress incontinence, or retreatment for SUI. Secondary outcomes included perioperative complications and adverse events. RESULTS: Of 6,914 midurethral slings performed, 165 patients underwent a repeat procedure for recurrent SUI, including 98 midurethral slings and 67 urethral bulking. Of the 165 patients who underwent repeat procedures, there were 11 failures (11.2%) in the midurethral sling group and 26 failures (38.8%) in the urethral bulking group (P=.004). There were no differences in perioperative complications or adverse events between the groups. In multivariable logistic regression, risk of failure was significantly higher in those undergoing urethral bulking compared with those undergoing midurethral sling (odds ratio 3.49, 95% confidence interval 1.34-9.09, P=.01). CONCLUSIONS: In a managed care population, urethral bulking was associated with higher risk of failure than repeat midurethral sling after primary midurethral sling failure with no differences in perioperative complications or adverse events. LEVEL OF EVIDENCE: II.

The demographics and epidemiology of osteochondritis dissecans of the knee in children and adolescents.

BACKGROUND: Osteochondritis dissecans (OCD) is a disorder of subchondral bone and articular cartilage whose incidence in children is not clearly known. PURPOSE: The purpose of this study was to assess the demographics and epidemiology of OCD of the knee in children. STUDY DESIGN: Descriptive epidemiology study. METHODS: A retrospective chart review of an integrated health system was performed on patients with OCD of the knee aged 2 to 19 years from 2007 to 2011, with over 1 million patients in this cohort. Lesion location, laterality, and all patient demographics were recorded. The incidence of OCD was determined for the group as a whole and by sex and age group (2-5 years, 6-11 years, and 12-19 years). Patient differences based on age, sex, and ethnicity were analyzed, and using multivariable logistic regression models, associations between age, sex, ethnicity, and diagnosis of OCD of the knee were evaluated. RESULTS: One hundred ninety-two patients with 206 OCD lesions of the knee fit the inclusion criteria. No OCD lesion of the knee was found in 2- to 5-year-old children. One hundred thirty-one (63.6%) lesions were in the medial femoral condyle, 67 (32.5%) were in the lateral femoral condyle, 96 (50.0%) lesions were right sided, 82 (42.7%) were left sided, and 14 (7.3%) were bilateral. The incidence of patients with OCD of the knee aged 6 to 19 years was 9.5 per 100,000 overall and 15.4 and 3.3 per 100,000 for male and female patients, respectively. Those aged 12 to 19 years represented the vast majority of OCD, with an incidence of 11.2 per 100,000 versus 6.8 per 100,000 for those aged 6 to 11 years. For those aged 6 to 11 and 12 to 19 years, female patients had an incidence of 2.3 and 3.9 per 100,000, respectively, while male patients had an incidence of 11.1 and 18.1 per 100,000, respectively. Multivariable logistic regression analysis revealed a 3.3-fold increased risk of OCD of the knee in patients aged 12 to 19 years compared with those aged 6 to 11 years (P < .001; 95% confidence interval [CI], 2.37-4.48), and male patients had 3.8 times a greater risk of OCD of the knee than female patients (P < .001; 95% CI, 2.71-5.41). Based on race and ethnicity, blacks had the highest odds ratio of OCD of the knee compared with all other ethnic groups. CONCLUSION: In this population-based cohort study of pediatric OCD of the knee, male patients had a much greater incidence of OCD and almost 4 times the risk of OCD compared with female patients. Also, patients aged 12 to 19 years had 3 times the risk of OCD of the knee as compared with 6- to 11-year-old children.