Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial.

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis.

BACKGROUND: An unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer-term treatment with sparsentan for FSGS are unknown. METHODS: In this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of ≤1.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated. RESULTS: A total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P = 0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 m2 of body-surface area per year (95% confidence interval [CI], -1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 m2 per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per minute per 1.73 m2 with sparsentan and -12.1 ml per minute per 1.73 m2 with irbesartan (difference, 1.8 ml per minute per 1.73 m2; 95% CI, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups. CONCLUSIONS: Among patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.).

Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial.

Introduction: Focal segmental glomerulosclerosis (FSGS) is a rare glomerular disease with high unmet clinical need. Interest in proteinuria as a surrogate end point for regulatory approval of novel treatments has increased. We assessed the relationship between achieving complete remission (CR) of proteinuria at least once during follow-up and long-term kidney outcomes. Methods: This post hoc analysis included all patients enrolled in the DUET trial of sparsentan in FSGS and the open-label extension (OLE). Evaluations occurred every 12 weeks, including blood pressure (BP), edema, proteinuria, and kidney function. CR was defined as a urine protein/creatinine ratio ≤0.3g/g in a first morning urine sample. Results: A total of 108 patients who received ≥1 sparsentan dose were included in this study. During a median follow-up of 47.0 months, 46 patients (43%) experienced ≥1 CR, 61% occurring within 12 months of starting sparsentan. There was an increased likelihood of CR with a higher sparsentan dose or baseline subnephrotic-range proteinuria. Achieving ≥1 CR was associated with significantly slower rate of estimated glomerular filtration rate (eGFR) decline versus non-CR patients (P < 0.05). Use of immunosuppressive agents was more frequent in patients who achieved a CR. However, the antiproteinuric effect of sparsentan was additive to that achieved with concomitant immunosuppressive treatment. No unanticipated adverse events occurred. Conclusion: We conclude that sparsentan can be safely administered for extended periods and exerts a sustained antiproteinuric effect. Achievement of CR at any time during follow-up, even if it is not sustained, may be an indicator of a favorable response to treatment and a predictor of improved kidney function outcomes.

Prevalence of cerebrotendinous xanthomatosis among patients diagnosed with early-onset idiopathic bilateral cataracts: final analysis.

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder caused by pathologic variants in CYP27A1, a gene involved in bile acid synthesis. Impaired function in this gene leads to accumulation of plasma cholestanol (PC) in various tissues, often in early childhood, resulting in such clinical signs as infantile diarrhea, early-onset bilateral cataracts, and neurological deterioration. The current study aimed to identify cases of CTX in a population of patients with a greater CTX prevalence than the general population, to facilitate early diagnosis. Patients diagnosed with early-onset, apparently idiopathic, bilateral cataracts between the ages of 2 and 21 years were enrolled. Genetic testing of patients with elevated PC and urinary bile alcohol (UBA) levels was used to confirm CTX diagnosis and determine CTX prevalence. Of 426 patients who completed the study, 26 met genetic testing criteria (PC ≥ 0.4 mg/dL and positive UBA test), and 4 were confirmed to have CTX. Prevalence was found to be 0.9% in enrolled patients, and 15.4% in patients who met the criteria for genetic testing.

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial.

BACKGROUND: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. METHODS: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m2 and ≥60 mL/min per 1·73 m2) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. INTERPRETATION: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. FUNDING: Travere Therapeutics.

Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis.

RATIONALE & OBJECTIVE: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. STUDY DESIGN: Individual patient-level meta-analysis. SETTING & STUDY POPULATIONS: Individual data of 1,037 patients from 12 randomized trials. SELECTION CRITERIA FOR STUDIES: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. ANALYTICAL APPROACH: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. RESULTS: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. LIMITATIONS: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. CONCLUSIONS: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.

Study Design of the Phase 3 Sparsentan Versus Irbesartan (DUPLEX) Study in Patients With Focal Segmental Glomerulosclerosis.

INTRODUCTION: Focal segmental glomerulosclerosis (FSGS), a histologic lesion in the kidney caused by varied pathophysiological processes, leads to end-stage kidney disease in a large proportion of patients. Sparsentan is a first-in-class orally active compound combining endothelin type A (ETA) receptor blockade with angiotensin II type 1 (AT1) receptor antagonism in a single molecule. A Randomized, Multicenter, Double-Blind, Parallel, Active-Control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS (DUPLEX) study evaluates the long-term antiproteinuric efficacy, nephroprotective potential, and safety profile of sparsentan compared with an AT1 receptor blocker alone in patients with FSGS. METHODS: DUPLEX is a multicenter, international, phase 3, randomized, double-blind, active-controlled study of sparsentan in patients with FSGS. Approximately 300 patients aged 8 to 75 years, inclusive (United States), and 18 to 75 years, inclusive (outside United States) will be randomized 1:1 to daily treatment with sparsentan or irbesartan. After renin-angiotensin-aldosterone system inhibitor washout, treatment will be administered for 108 weeks, with the final assessment at week 112, four weeks after withdrawal of study drug. RESULTS: The primary endpoint will be the slope of estimated glomerular filtration rate from week 6 to week 108. A novel surrogate efficacy endpoint, the proportion of patients achieving urinary protein-to-creatinine (UP/C) ratio of ≤1.5 g/g and >40% reduction from baseline in UP/C (FSGS partial remission endpoint: FPRE), will be evaluated at a planned interim analysis at week 36. Safety and tolerability of sparsentan will also be assessed. CONCLUSION: The phase 3 DUPLEX study will characterize the long-term antiproteinuric efficacy and nephroprotective potential of dual ETA and AT1 receptor blockade with sparsentan in patients with FSGS.

Cardiovascular Safety of the Selective µ-Opioid Receptor Antagonist Naloxegol: A Novel Therapy for Opioid-Induced Constipation.

BACKGROUND: Naloxegol is a novel selective, peripherally acting µ-opioid receptor antagonist for treating opioid-induced constipation (OIC) in patients with chronic pain syndromes. We analyzed the cardiovascular (CV) safety of naloxegol based on data from its development program prior to approval by the US Food and Drug Administration in 2015. METHODS: Comprehensive CV safety analyses were performed in 4 clinical studies of naloxegol (12.5 and/or 25 mg) in patients with noncancer pain and OIC: two 12-week, double-blind, randomized studies; a 12-week, double-blind, extension study; and a 52-week, randomized, open-label study versus usual care. Evaluations of baseline CV risk were obtained from medical histories and clinical findings at the time of study initiation. RESULTS: Across the 4 studies (N = 2135), 68% of patients had ≥1 CV risk factor and 41% had a history of CV disease, diabetes, or ≥2 other CV risk factors. There were no increases in blood pressure, heart rate, or the rate-pressure product with naloxegol versus placebo. The rates of major adverse cardiovascular events (MACE) per 100 patient-years of exposure were 1.13 (95% confidence interval [CI], 0.31-2.89) for placebo/usual care and 0.75 (95% CI, 0.24-1.75) for naloxegol. The relative risk of MACE for all doses of naloxegol versus placebo was 0.67 (95% CI, 0.14-3.36). CONCLUSION: These data demonstrate that naloxegol has a CV safety profile comparable to placebo/usual care in patients with OIC. Although the observed number of events was low, the data show no CV signal in patients with OIC treated with naloxegol.

Treatment with Naloxegol Versus Placebo: Pain Assessment in Patients with Noncancer Pain and Opioid-Induced Constipation.

OBJECTIVE: To summarize results from pain and opioid use assessments with naloxegol in adults with opioid-induced constipation (OIC) and chronic noncancer pain. METHODS: Two phase 3 randomized, double-blind, 12-week studies evaluated the efficacy and safety of oral naloxegol (12.5 or 25 mg daily) in adults (18 to < 85 years) with confirmed OIC and chronic noncancer pain: KODIAC-04 (NCT01309841) and KODIAC-05 (NCT01323790). Pain level was assessed daily (11-point numeric rating scale [NRS]; 0 = no pain, 10 = worst imaginable pain). Changes from baseline in mean weekly pain scores and opioid dose (weeks 1 through 12) were analyzed using mixed-model repeated measures. RESULTS: At baseline, mean daily NRS average pain scores ranged from 4.5 to 4.8 for all groups in KODIAC-04 (N = 652) and were 4.6 for each group in KODIAC-05 (N = 700). Respective mean ± SD changes from baseline average pain for placebo, naloxegol 12.5 mg, and naloxegol 25 mg were -0.2 ± 1.07, -0.3 ± 1.05 (P = 0.773 vs. placebo), and 0.2 ± 0.95 (P = 0.837 vs. placebo; KODIAC-04) and -0.1 ± 0.94, -0.1 ± 0.87 (P = 0.744), and 0.0 ± 1.18 (P = 0.572; KODIAC-05). At baseline, mean daily opioid doses ranged from 135.6 to 143.2 morphine equivalent units (MEUs)/day in KODIAC-04, and from 119.9 to 151.7 MEUs/day in KODIAC-05. Respective mean ± SD changes from baseline dose were -1.8 ± 30.19, -2.3 ± 20.52 (P = 0.724 vs. placebo), and 0.4 ± 13.01 (P = 0.188 vs. placebo; KODIAC-04) and -0.3 ± 17.14, -1.3 ± 17.11 (P = 0.669 vs. placebo), and 0.1 ± 8.54 (P = 0.863 vs. placebo; KODIAC-05). Changes in maintenance opioid dose were few; reasons for such changes were similar across treatment groups. CONCLUSION: Centrally mediated opioid analgesia was maintained during treatment with naloxegol in patients with noncancer pain and OIC.

An Open-Label, Randomized Bioavailability Study of Alternative Methods of Oral Administration of Naloxegol in Healthy Subjects.

Naloxegol is a peripherally acting µ-opioid receptor antagonist approved as an orally administered tablet for the treatment of opioid-induced constipation. Patients with swallowing difficulties may benefit from alternative approaches to the oral administration of the whole-tablet formulation of naloxegol. This open-label, randomized, 4-period, 4-treatment, crossover, single-dose study (NCT02446171) evaluated the pharmacokinetic (PK) characteristics of crushed naloxegol 25-mg tablets (suspended in water) administered orally or by nasogastric tube and a naloxegol solution compared with the commercially available 25-mg tablet formulation in healthy volunteers. The PK profiles for the crushed tablet, whether administered orally or by nasogastric tube, and the 25-mg oral solution were similar to that of the 25-mg tablet administered orally. Compared with naloxegol commercial tablets, the relative bioavailability of naloxegol using 3 alternative methods of administration was approximately 100%. For each pairwise treatment comparison of the 3 alternative methods with the approved whole tablet, the geometric least-squares mean ratio ranges were 94.37%-100.04%, 94.83%-100.44%, and 97.05%-102.05% for area under the curve (AUC), AUC0-t , and maximum plasma concentration, respectively, and their 90% confidence intervals were entirely within the predefined 80% to 125% bioequivalence limits. Naloxegol was well tolerated when administered in both liquid and solid form.

A 12-week extension study to assess the safety and tolerability of naloxegol in patients with noncancer pain and opioid-induced constipation.

OBJECTIVE: To compare the long-term safety and tolerability of naloxegol with placebo in patients with opioid-induced constipation (OIC) and noncancer pain. DESIGN: Twelve-week, multicenter, randomized, double-blind, parallel-group phase 3 extension study (KODIAC-07, NCT01395524). SETTING: Clinical investigation centers in the United States. PATIENTS: Adult outpatients (N = 302) with confirmed OIC who had completed a 12-week pivotal phase 3 study (KODIAC-04, NCT01309841). INTERVENTIONS: Daily oral administration of naloxegol (12.5 and 25 mg) or placebo. MAIN OUTCOME MEASURES: Adverse events (AEs), including treatment-related AEs, serious AEs, and AEs of special interest; changes from baseline to week 12 in pain scores, daily opioid dose, and symptoms and quality-of-life measurements. RESULTS: No important new AEs occurred during this extension study compared with KODIAC-04. AEs occurred more frequently with naloxegol 25 mg (41.2 percent) versus naloxegol 12.5 mg (34.0 percent) and placebo (33.0 percent). Treatment-emergent AEs occurring in >5 percent of patients in either naloxegol group during the treatment period were arthralgia (25 mg; 5.2 percent) and diarrhea (12.5 mg; 5.3 percent); two reported AEs attributable to opioid withdrawal syndrome in naloxegol groups were deemed unrelated to study medication. None of the gastrointestinal serious AEs was adjudicated as bowel perforation; one patient (naloxegol 12.5 mg) had an event adjudicated as a major cardiovascular event and was unrelated to study medication. Pain scores and daily opioid dose were unchanged, and improvements in symptoms and quality-of-life observed in KODIAC-04 were maintained throughout the extension study. CONCLUSION: Naloxegol was generally safe and well tolerated in this 12-week extension study in patients with noncancer pain and OIC.

Efficacy and safety of naloxegol in patients with opioid-induced constipation and laxative-inadequate response.

BACKGROUND: Treatment options for patients with opioid-induced constipation (OIC) and inadequate response to laxatives (LIR) are few. OBJECTIVE: Assess the efficacy and safety of orally administered naloxegol in patients with prospectively confirmed OIC and LIR. METHODS: We analyzed pooled data from two identical randomized, double-blind, placebo-controlled, Phase 3 trials of naloxegol in patients with non-cancer pain, OIC and LIR in which naloxegol (12.5 mg, n = 240; 25 mg, n = 241) or placebo (n = 239) were administered daily. We assessed the response rates, time to first post-dose laxation, spontaneous bowel movements (SBMs), OIC symptoms and patient-reported outcomes over 12 weeks. RESULTS: OIC response rates for the naloxegol 25-mg (p < 0.001) and the 12.5-mg (p = 0.005) LIR dose groups were higher than placebo. Median times to first post-dose SBM were 7.6, 19.2 and 41.1 hours for the naloxegol 25 mg, naloxegol 12.5 mg and placebo groups, respectively. Other SBM measures, daily symptoms of OIC, and both the Patient Assessment of Constipation - Symptoms and Patient Assessment of Constipation-Quality of Life scores improved from baseline with naloxegol treatment. Changes from baseline in opioid dose, pain scores and opioid withdrawal scores were similar among treatment groups. CONCLUSIONS: Naloxegol was efficacious, generally safe and well tolerated in the patients with OIC and LIR, while preserving opioid analgesia. ClinicalTrials.gov identifiers: NCT01309841; NCT01323790.

Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial.

BACKGROUND: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 µg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING: Bristol-Myers Squibb.

Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: A randomized international study of entecavir versus adefovir.

UNLABELLED: This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside-naïve adults with chronic hepatitis B (CHB). Sixty-nine nucleoside-naïve CHB patients with baseline HBV DNA of 10(8) copies/mL or more were randomized 1:1 to open-label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (-6.23 log(10) copies/mL versus -4.42 log(10) copies/mL, respectively; mean difference -1.58 log(10) copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV-ADV difference estimate: -0.66 log(10) copies/mL; 95% CI [-0.30, -0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir-treated than adefovir-treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV-treated versus 15 (47%) ADV-treated patients had HBV DNA of 10(5) copies/mL or more. Both antivirals were well tolerated. CONCLUSION: Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside-naïve HBeAg-positive patients with CHB.

The effect of different warming methods on sensory nerve conduction velocity in shipyard workers occupationally exposed to hand-arm vibration.

OBJECTIVES: Segmental sensory nerve conduction velocity (SNCV) was measured from the wrists to the hands and digits in a population of 134 (126 men and 8 women) vibration-exposed shipyard workers following systemic warming using a bicycle ergometer. Results were compared to earlier nerve conduction tests, identical in execution, except that the warming process was segmental and cutaneous. The study was designed to investigate whether SNCVs, which were selectively slow in the fingers after segmental cutaneous (skin surface) warming, would be affected differently by systemic warming. METHODS: Wrist-palm, palm-proximal digit, and digital sensory nerve segments were assessed antidromically by stimulating at the wrist with recording electrodes placed distally. The same subjects were cutaneously warmed in 2001 to >or=31 degrees C and were systemically warmed 28 months later in 2004 by ramped sustained exercise to 100 W for 12 min. Skin temperatures were measured by traditional thermistry and by infrared thermal images taken over the hand and wrist surfaces. RESULTS: When systemic warming was compared to segmental cutaneous warming, SNCVs were increased by 15.1% in the third digit and 20.4% in the fifth digit of the dominant hand. Respective increases in the non-dominant hand were 11.0% and 19.4%. A strong association between increased surface skin temperature and faster SNCV, which had been observed after segmental cutaneous warming, was largely eliminated for both digit and palmar anatomic segments after systemic warming. Significant differences in SNCV between vibration-exposed and non-exposed workers, which had been observed after segmental cutaneous warming, were eliminated after systemic warming. Systemic warming had only a small effect on the wrist-palm (transcarpal) segmental SNCVs. CONCLUSIONS: Reduced SNCV in the digits was observed in vibration-exposed and non-exposed workers. Substituting exercise-induced systemic warming for segmental cutaneous warming significantly increased SNCV in the digits and appeared to reduce differences in SNCV between vibration-exposed and non-exposed workers. These findings persisted despite a substantial time interval between tests, during which the subjects continued to work. There may be more general implications for diagnosing clinical conditions in industrial workers, such as the carpal tunnel syndrome and the hand-arm vibration syndrome.

Parametric models for spatially correlated survival data for individuals with multiple cancers.

Incorporating spatial variation could potentially enhance information coming from survival data. In addition, simultaneous (joint) modeling of time-to-event data from different diseases, such as cancers, from the same patient could provide useful insights as to how these diseases behave together. This paper proposes Bayesian hierarchical survival models for capturing spatial correlations within the proportional hazards (PH) and proportional odds (PO) frameworks. Parametric (Weibull for the PH and log-logistic for the PO) models were used for the baseline distribution while spatial correlation is introduced in the form of county-cancer-level frailties. We illustrate with data from the Surveillance Epidemiology and End Results database of the National Cancer Institute on patients in Iowa diagnosed with multiple gastrointestinal cancers. Model checking and comparison among competing models were performed and some implementation issues were presented. We recommend the use of the spatial PH model for this data set.

Syndromes from segmental vibration and nerve entrapment: observations on case definitions for carpal tunnel syndrome.

OBJECTIVES: The purpose of this paper is to assess the overlap and stability of two different case definitions of carpal tunnel syndrome CTS. The analysis considers the association between different case definitions and objective tests (sensory nerve conduction velocities, SNCVs and vibrotactile perception thresholds, TTS), and the natural history of CTS, in the context of two vibration-exposed cohorts. METHODS: Clinical CTS cases were defined in two ways: (1) by the study physician using fixed criteria, and; (2) by questionnaire and hand diagram. SNCV in median and ulnar nerves was measured for digital, transpalmar, and transcarpal segments, and conventionally as from wrist-digit. Skin temperature was assessed as a point measurement by thermistor and regionally by thermal imaging. VTTs were determined at the bilateral fingertips of the third and fifth digits using a tactometer meeting the requirements of ISO 13091-1 (ISO 2001). The subjects were cohorts of shipyard workers in 2001 and 2004, and dental hygienists in 2002 and 2004. RESULTS: Results are reported for 214 shipyard workers in 2001 and 135 in 2004, and for 94 dental hygienists in 2002 and 66 in 2004. In 2001, 50% of shipyard workers were diagnosed as CTS cases by at least one of the diagnostic schemes, but only 20% were positive by both criteria. Among study physician diagnosed cases, 64% were CTS negative in 2001, 76% were negative in 2004, 13% were positive in both years, 22% became negative after being positive, and 11% became positive after being negative. For only study physician diagnosed CTS did VTTs differ between cases differ and non-cases in digit 3; there was no such distinction in digit 5. The dental hygienists had little CTS. CONCLUSION: Clinical case definitions of CTS based on diagrams and self-assessment, and clinical evaluation have limited overlap. Combining clinical criteria to create a more narrow or specific case definition of CTS does not appear to predict SNCV. The natural history of CTS suggests a protean disorder with considerable flux in case status over time.

A population based survey of ergonomic risk factors in Connecticut: distribution by industry, occupation, and demographics.

BACKGROUND: Risk factors for upper-extremity musculoskeletal disorders (MSD) include biomechanical factors (force, repetition, posture) and psychosocial factors (job stress). A population-based telephone survey of workers in Connecticut characterized these risk factors by industry, occupation, gender, and age. FINDINGS: Risk factors were highly prevalent in the Connecticut workplace, but varied considerably by industry, occupation, gender, and age. Risk factors clustered based on (a) physically active occupations/industries (pushing/pulling, reaching, bent wrists, and tool use), (b) physically passive occupations/industries (static postures, stress, and computer use), and (c) repetitive motion exposures. Physically active patterns had the highest prevalence in construction/agriculture/mining, followed by (in order) wholesale/retail trade, utilities, manufacturing, services, government, and finance/insurance. Physically passive patterns tended to reverse this order, and repetitive motion followed a third pattern. Physically active risk factors were typically higher for males, though this varied by industry and occupation. All risk factors except for stress show a steady decrease with age. CONCLUSION: Almost 1,000,000 Connecticut workers are estimated to be exposed to repetitive work, bent wrists, and job stress. Workers in high exposure industries and occupations should be closely evaluated for risks, with outreach to industries for preventive ergonomic interventions as preferred to treatment for conditions that arise.

Musculoskeletal disorders of the neck and shoulder in dental hygienists and dental hygiene students.

PURPOSE: Dental hygienists have been found to have high rates of neck and shoulder disorders, but there is very limited information on risk factors associated with those disorders, the level of risk for students, and the relationship of prior work as dental assistants for dental hygiene students. This study examines self-reported and physician-diagnosed neck and shoulder pain. METHODS: A cohort consisting of 27 dental hygiene students with no prior dental occupation experience (mean age 24, 6.2 SD), and 39 dental hygiene students with prior experience as dental assistants (mean age 28, 6.0) and 94 experienced dental hygienists (mean age 46, 8.8) completed a questionnaire on risk factors and self reported pain, and were examined by a physician in reference to upper extremity findings and diagnoses. Analysis included tabular, trend, and logistic regression analysis. RESULTS: There were significant differences for risks, symptoms, and physician findings. Risk factors had a stepwise progression for students, student/assistants, and experienced dental hygienists, including working with a bent neck often or very often (79%, 89%, 96%, respectively, p<.001), static posture (39%, 50%, 63%, p<.001), precise motions (58%, 67%, 90%, p<.001), and repetition (79%, 86%, 98%, p<.001). Neck symptoms were reported by 37%, 43%, and 72%, respectively (p<.001), and 11%, 20%, and 35% for shoulder symptoms (p<.05). Similar patterns were demonstrated in physician findings, particularly for neck disorders (18%, 36%, 50%, p<.01). In regressions, self-reported shoulder pain was significantly associated with working above shoulder height (OR=1.5, CI 1.0-2.4), and neck symptoms with working with a bent neck (OR=2.1, CI 1.3-3.4), with a protective effect from high supervisor support (OR=0.5, CI 0.2-1.0). CONCLUSION: Risk factors and both self-reported and physician-diagnosed neck and shoulder symptoms increase in frequency from students to experienced hygienists, and students have higher prevalence if they are also dental assistants.