Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trial.

Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, -3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; -9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols.

Randomized Double-Blind Placebo-Controlled Trial of the Corticosteroid-Sparing Effects of Immunoglobulin in Myasthenia Gravis.

BACKGROUND AND OBJECTIVES: Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction at the neuromuscular junction. Treatment frequently includes corticosteroids (CSs) and IV immunoglobulin (IVIG). This study was conducted to determine whether immune globulin (human), 10% caprylate/chromatography purified (IGIV-C) could facilitate CS dose reduction in CS-dependent patients with MG. METHODS: In this randomized double-blind placebo-controlled trial, CS-dependent patients with MG (Myasthenia Gravis Foundation of America Class II-Iva; AChR+) received a loading dose of 2 g/kg IGIV-C over 2 days (maximum 80 g/d) or placebo at week 0 (baseline). Maintenance doses (1 g/kg IGIV-C or placebo) were administered every 3 weeks through week 36. Tapering of CS was initiated at week 9 and continued through week 36 unless the patient worsened (quantitative MG score ≥4 points from baseline). CS doses were increased (based on the current CS dose) in patients who worsened. Patients were withdrawn if worsening failed to improve within 6 weeks or if a second CS increase was required. The primary efficacy end point (at week 39) was a ≥50% reduction in CS dose. Secondary and safety end points were assessed throughout the study and follow-up (weeks 42 and 45). The study results and full protocol are available at clinicaltrials.gov/ct2/show/NCT02473965. RESULTS: The primary end point (≥50% reduction in CS dose) showed no significant difference between the IGIV-C treatment (60.0% of patients) and placebo (63.3%). There were no significant differences for secondary end points. Safety data indicated that IGIV-C was well tolerated. DISCUSSION: In this study, IGIV-C was not more effective than placebo in reducing daily CS dose. These results suggest that the effects of IGIV-C and CS are not synergistic and may be mechanistically different. TRIAL REGISTRATION INFORMATION: The trial was registered on clinicaltrialsregister.eu (EudraCT #: 2013-005099-17) and clinicaltrials.gov (identifier NCT02473965). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVIG infusions in adult patients with MG do not increase the percentage of patients achieving a ≥50% reduction in corticosteroid dose compared with placebo.

Pharmacokinetics, efficacy and safety of a novel fibrinogen concentrate in pediatric patients with congenital afibrinogenemia.

INTRODUCTION: Congenital afibrinogenemia treatment with plasma-derived fibrinogen concentrates in pediatric patients is limited. This study investigated the pharmacokinetics, surrogate efficacy, and safety of a plasma-derived fibrinogen concentrate (FIB Grifols) in pediatric patients with congenital afibrinogenemia. METHODS: Patients aged <18 years old diagnosed with congenital afibrinogenemia were included in this prospective, multinational, phase 1-2, single-arm study. After a single dose of a plasma-derived fibrinogen concentrate (70 mg/kg body weight), pharmacokinetic parameters were determined from plasma fibrinogen activity (Clauss method) and antigen method (ELISA), and calculated by noncompartmental and population pharmacokinetic (popPK) models. Patients were followed up over 14 days. Efficacy variables were the mean change on thromboelastographic variables (maximum clot firmness [MCF], alpha angle [ α ]) and coagulation tests (prothrombin time, activated partial thromboplastin time, and thrombin time) 1 h postinfusion. Safety parameters were assessed. RESULTS: Eleven patients with a median (range) age 8.80 (3.7-12.7) years were treated with the plasma-derived fibrinogen concentrate. Using the popPK modeling, fibrinogen activity reached a mean (standard deviation) Cmax of 1.3 (0.225) g/l, half-life ( t1/2 ) of 60.6 (4.48) h and incremental in vivo recovery (IVR) of 1.86 (0.322) (mg/dl)/(mg/kg). Surrogate efficacy was demonstrated by significant increase in MCF (9.23 [3.94] mm; P  < 0.001; 95% confidence interval 6.58, 11.87). All coagulation times were significantly shortened after fibrinogen concentrate infusion. Adverse events were mild or moderate in severity, and unrelated to fibrinogen concentrate. CONCLUSIONS: In pediatric patients with congenital afibrinogenemia, plasma-derived fibrinogen concentrate revealed a favorable and specific pharmacokinetic profile, demonstrated efficacy in coagulation and was safe and well tolerated.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery.

BACKGROUND: Antithrombin (AT) activity is reduced during cardiac operations with cardiopulmonary bypass (CPB), which is associated with adverse outcomes. Preoperative AT supplementation, to achieve >58% and <100% AT activity, may potentially reduce postoperative morbidity and mortality in cardiac operations with CPB. This prospective, multicenter, randomized, double-blind, placebo-controlled study was designed to evaluate the safety and efficacy of preoperative treatment with AT supplementation in patients at risk for low AT activity after undergoing cardiac surgery with CPB. METHODS: A total of 425 adult patients were randomized (1:1) to receive either a single dose of AT (n = 213) to achieve an absolute increase of 20% above pretreatment AT activity or placebo (n = 212) before surgery. The study duration was approximately 7 weeks. The primary efficacy end point was the percentage of patients with any component of a major morbidity composite (postoperative mortality, stroke, acute kidney injury [AKI], surgical reexploration, arterial or venous thromboembolic events, prolonged mechanical ventilation, and infection) in the 2 groups. Secondary end points included AT activity, blood loss, transfusion requirements, duration of intensive care unit (ICU), and hospital stays. Safety was also assessed. RESULTS: Overall, 399 patients (men, n = 300, 75.2%) with a mean (standard deviation [SD]) age of 66.1 (11.7) years, with the majority undergoing complex surgical procedures (n = 266, 67.9%), were analyzed. No differences in the percentage of patients experiencing morbidity composite outcomes between groups were observed (AT-treated 68/198 [34.3%] versus placebo 58/194 [29.9%]; P = .332; relative risk, 1.15). After AT infusion, AT activity was significantly higher in the AT group (108% [42-143]) versus placebo group (76% [40-110]), and lasted up to postoperative day 2. At ICU, the frequency of patients with AT activity ≥58% in the AT group (81.5%) was significantly higher ( P < .001) versus placebo group (43.2%). Secondary end point analysis did not show any advantage of AT over placebo group. There were significantly more patients with AKI ( P < .001) in the AT group (23/198; 11.6%) than in the placebo group (5/194, 2.6%). Safety results showed no differences in treatment-emergent adverse events nor bleeding events between groups. CONCLUSIONS: AT supplementation did not attenuate adverse postoperative outcomes in our cohort of patients undergoing cardiac surgery with CPB.

Pharmacokinetic modeling and simulation of subcutaneous and intravenous IgG dosing in patients with primary immunodeficiency diseases.

A population pharmacokinetic (PK) model for comparing the PK of subcutaneously administered immunoglobulin G (IgG) replacement therapy (SCIG) with Gamunex-C 10% or SCIG 20% formulations in patients with primary immunodeficiency diseases was developed using data from 3 clinical trials (N = 95, 69.5% adults, 30.5% <18 years) of intravenous IG (IVIG) 10% and SCIG 10% or SCIG 20%. Serum IgG exposure following switches from IVIG 10% every 3 or 4 weeks to biweekly SCIG 20% (dose adjustment factor 1.0 or 1.37) and from weekly SCIG 20% to biweekly SCIG 20% or SCIG 20% 2-7 times/week was simulated. The PK of IVIG 10% and SCIG 20% were adequately described by a 2-compartment model with first-order absorption rate constant of exogenous IgG from an SC depot compartment into the central compartment and first-order elimination from the central compartment. Switching from IVIG 10% every 4 weeks to biweekly SCIG 20% produced similar serum IgG exposure, with lower peak and higher trough serum IgG concentrations. Switching from IVIG 10% every 3 or 4 weeks to weekly and biweekly SCIG 20% yielded comparable IgG exposure and clinically effective trough IgG concentrations.

A Multi­Center, Open­Label, Single­Arm Trial to Evaluate the Efficacy, Pharmacokinetics, and Safety and Tolerability of IGSC 20% in Subjects with Primary Immunodeficiency.

PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

Myasthenia gravis: Historical achievements and the "golden age" of clinical trials.

Since the death of Chief Opechankanough >350 years ago, the myasthenia gravis (MG) community has gained extensive knowledge about MG and how to treat it. This review highlights key milestones in the history of treatment and discusses the current "golden age" of clinical trials. Although originally thought by many clinicians to be a disorder of hysteria and fluctuating weakness without observable cause, MG is one the most understood autoimmune neurologic disorders. However, studying it in clinical trials has been challenging due to the fluctuating nature of the medical condition which impacts MG clinical outcomes. Clinical trials must also account for the possibility of a placebo effect. Because MG is a rare incurable autoimmune disorder, it limits the number of potential patients available to participate in clinical trials. In the last 15 years, however, significant progress has been made with MG randomized clinical trials, resulting in a new drug (eculizumab) for physicians' treatment repertoire and an old technique (thymectomy) confirmed effective for MG. Some of the therapies (eg, thymectomy, corticosteroids, plasma exchange, and intravenous immunoglobulin [IVIg]) have survived the test of time. Others (eg, eculizumab and neonatal Fc receptor inhibitor) are novel and hold promise.

Immune globulin subcutaneous, human - klhw 20% for primary humoral immunodeficiency: an open-label, Phase III study.

Aim: This prospective, Phase III study assessed the pharmacokinetics (PK), safety and tolerability of immune globulin subcutaneous, human - klhw 20% solution (IGSC-C 20%) in participants with primary humoral immunodeficiency (PI), compared with immune globulin injection (human), 10% caprylate/chromatography purified (IGIV-C 10%). Patients & methods: About 53 participants enrolled. Total 44 received IGIV-C 10% in the run-in phase and then entered the IV phase (with an additional nine who were already receiving IGIV-C 10% and entered the IV phase directly) for steady-state IV PK assessments. Total 49 entered the SC phase (weekly doses of IGSC-C 20% for ∼24 weeks). The PK profiles of IGIV-C 10% and IGSC-C 20% and their safety and tolerability parameters were compared. Results: At a dose adjustment factor of 1.37, IGSC-C 20% provided comparable (noninferior and bioequivalent) overall total immunoglobulin G exposure to IGIV-C 10% over an equal time interval. About 33 participants reported 79 adverse events during run-in + IV phases; 41 participants reported 141 adverse events during the SC phase, with most being local infusion site reactions. The majority of infusion site reactions were mild to moderate in severity. Conclusion: IGSC-C 20% was bioequivalent to IGIV-C 10% and was well tolerated, with a safety profile comparable with IGIV-C 10%, in this study. Trial registration: ClinicalTrials.gov identifier: NCT02604810.

A Phase 3 Multicenter, Prospective, Open-Label Efficacy and Safety Study of Immune Globulin (Human) 10% Caprylate/Chromatography Purified in Patients with Myasthenia Gravis Exacerbations.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Exacerbations may involve increasing bulbar weakness and/or sudden respiratory failure, both of which can be critically disabling. Management of MG exacerbations includes plasma exchange and intravenous immunoglobulin (IVIG); they are equally effective, but patients experience fewer side effects with IVIG. The objective of this study was to assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with MG exacerbations. METHODS: This prospective, open-label, non-controlled 28-day clinical trial was conducted in adults with MG Foundation of America class IVb or V status. Subjects received IGIV-C 2 g/kg over 2 consecutive days (1 g/kg/day) and were assessed for efficacy/safety on Days 7, 14, 21, and 28. The primary efficacy endpoint was the change from Baseline in quantitative MG (QMG) score to Day 14. Secondary endpoints of clinical response, Baseline to Day 14, included at least a 3-point decrease in QMG and MG Composite and a 2-point decrease in MG-activities of daily living (MG-ADL). RESULTS: Forty-nine subjects enrolled. The change in QMG score at Day 14 was significant (p < 0.001) in the Evaluable (-6.4, n = 43) and Safety (-6.7, n = 49) populations. Among evaluable subjects, Day 14 response rates were 77, 86, and 88% for QMG, MG Composite, and MG-ADL, respectively. IGIV-C showed good tolerability with no serious adverse events. CONCLUSIONS: The results of this study show that IGIV-C was effective, safe, and well tolerated in the treatment of MG exacerbations.

Safety and neutralizing rabies antibody in healthy subjects given a single dose of rabies immune globulin caprylate/chromatography purified.

BACKGROUND: Rabies immune globulin (RIG) and vaccination series are necessary for postexposure prophylaxis. A new formulation of RIG (human) purified by caprylate/chromatography (RIG-C) was evaluated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02139657. MATERIALS AND METHODS: This open-label, single-arm study in healthy subjects evaluated neutralizing rabies antibody concentrations produced from a single 20 IU/kg intramuscular (IM) dose of RIG-C as measured by rapid fluorescent focus inhibition test (50% neutralization endpoint) 1-hour postdose and on days 1, 2, 4, 6, 8, 10, 14, 18, and 21. RESULTS: Twelve subjects were enrolled into the study. No discontinuations, serious adverse events (AEs), or treatment-emergent clinically significant changes in laboratory parameters were observed. All AEs resolved and were mild except 1 moderate AE of oropharyngeal pain. Injection site pain (4 subjects) was most commonly reported. RIG-C produced a rapid increase in neutralizing rabies antibody: mean value 0.113 IU/mL at 24 hours after IM injection, peak on day 4 (0.132 IU/mL), persisting through day 21 (0.116 IU/mL). The mean reciprocal titer was 11.5 by day 2; the peak value of 12.1 was achieved on day 4; and a mean value ≥10.6 was maintained through day 21. CONCLUSION: RIG-C was well tolerated and provided neutralizing rabies antibodies, which combined with vaccine series after rabies exposure, should result in effective prophylaxis per World Health Organization/Centers for Disease Control and Prevention guidelines.

Gamunex® in Guillain-Barré Syndrome: A Postmarketing, Retrospective, Observational Study.

BACKGROUND: The objective of this retrospective study was to evaluate the effectiveness and safety of Gamunex® (immune globulin [human] 10%; hereinafter "Gamunex") when administered intravenously in the initial treatment of Guillain-Barré syndrome (GBS). The study was conducted as a postapproval commitment for Health Canada. METHODS: A medical chart review for hospitalized patients diagnosed with GBS and treated with Gamunex (Gamunex 10% and IGIVnex® 10%; N=109; n=69 evaluable) was conducted at seven Canadian study centers in reverse chronological order. The primary endpoint for assessing effectiveness was the proportion of patients with treatment success compared with a prospectively defined historical effectiveness threshold for plasma exchange (PE) treatment (55.05%). Treatment success was assessed as ≥1 point improvement from baseline on the GBS Disability Scale or abbreviated GBS Disability Scale. Cases were not evaluable if treatment success, relapse, or treatment failure could not be determined by the available chart data. RESULTS: Applying a conservative estimate with all nonevaluable patients (n= 40) classified as treatment failures, Gamunex treatment success was estimated at 57.8% (63 of 109 patients), which exceeded the predefined historical PE effectiveness threshold. In the evaluable population of this study, Gamunex treatment was successful in 91.3% of patients (63/69). Some 23 (21.1%) of 109 Gamunex-treated patients experienced ≥1 adverse event; the profile and frequency were consistent with the adverse events reported for Gamunex in the product's labeling and with the natural clinical course of GBS. CONCLUSIONS: The effectiveness of Gamunex for treatment of GBS was comparable to PE therapy. Gamunex was observed to have an acceptable safety profile in this study population.

Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection.

A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.

Safety and efficacy of ulimorelin administered postoperatively to accelerate recovery of gastrointestinal motility following partial bowel resection: results of two randomized, placebo-controlled phase 3 trials.

BACKGROUND: Gastrointestinal recovery is a critical milestone after bowel resection with postoperative ileus resulting in increased risk of complications and prolonged hospitalization. OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of ulimorelin, a ghrelin receptor agonist given postoperatively in 2 identically designed phase 3 studies (ClinicalTrials.gov NCT01285570 and NCT01296620). DESIGN: This investigation is designed as a multicenter, double-blind, randomized, parallel-group study. SETTINGS: This study involves hospital inpatients. PATIENTS: Adult patients undergoing partial bowel resection were included. INTERVENTION: Thirty-minute intravenous infusions (160 µg/kg, 480 µg/kg ulimorelin, or placebo) once daily were started within 60 minutes after the end of surgery and ended at the first of the following: primary efficacy end point fulfilled (defined below), hospital discharge, or 7 days treatment. MAIN OUTCOME MEASURES: The primary efficacy end point was the time from the end of surgery to the composite end point of the later of first bowel movement and tolerance of solid food. Safety was assessed with the use of standard assessments including adverse events and laboratory tests. RESULTS: Ulimorelin Study of Efficacy and Safety 007, n = 332 patients; Ulimorelin Study of Efficacy and Safety 008, n = 330 patients: in both studies, the primary efficacy end point and the secondary efficacy outcomes, which included postsurgical time to first bowel movement, tolerance of solid food, and discharge eligibility, did not differ significantly among patients treated with either dose of ulimorelin versus placebo. Rates of serious adverse events were comparable across all treatment groups. There was no statistically significant difference from placebo in regard to events of interest, namely nausea, vomiting, ileus as an adverse event, nasogastric tube reinsertion, anastomotic complications, and infections. LIMITATIONS: A possible limitation is the variance inherent in surgery and comorbidities. CONCLUSIONS: Although the efficacy of ulimorelin in reducing the duration of postoperative ileus was not demonstrated in these studies, intravenous ulimorelin at doses of 160 µg/kg and 480 µg/kg was generally well tolerated in postcolectomy patients. Similar to other promotility agents, ulimorelin may find an application in other indications better suited to its attributes.

Efficacy and safety of long-term adefovir dipivoxil therapy in children with chronic hepatitis B infection.

BACKGROUND: The safety and efficacy of adefovir dipivoxil (ADV) for chronic hepatitis B infection in children was demonstrated in a randomized, placebo-controlled trial. Those children were followed for 4 more years, and many continued to receive ADV for all or part of this time. OBJECTIVES: To examine the therapeutic effects and safety of prolonged ADV therapy in children with chronic hepatitis B infection. METHODS: After 48 weeks of double-blind treatment, all placebo-treated subjects who did not exhibit HBeAg seroconversion at week 44, and all ADV-treated subjects, were offered open-label ADV for up to 192 additional weeks. Treatment was discontinued if there was no virologic effect, except for adolescents with previous lamivudine exposure, in whom lamivudine was added to ADV. Durability of HBeAg seroconversion was assessed. Annual resistance surveillance was conducted in subjects who had detectable hepatitis B virus DNA. RESULTS: Of the 170 subjects who completed the 48-week study, 162 participated in the open-label study. ADV was discontinued in 61 subjects due to virologic failure. In subjects who continued treatment, either as monotherapy or with lamivudine, continued viral suppression and alanine aminotransferase normalization were noted. HBeAg seroconversions were observed in 55 subjects, and hepatitis B surface antigen seroconversion in 5. Mean duration of HBeAg seroconversion at last observation was 762 ± 371.2 days in the ADV-ADV group and 643 ± 291.5 days in the PLB-ADV group. ADV was safe and well-tolerated. Resistance to ADV was observed in 1 child on ADV monotherapy. Nine treatment-experienced subjects entered the study with mutations associated with lamivudine resistance. All responded to ADV therapy. CONCLUSIONS: Prolonged ADV treatment is safe in children. If reserved only for those with virologic response within 6 months, viral resistance was minimal.

A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis.

UNLABELLED: In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase-3-cleaved cytokeratin (CK)-18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK-18 fragment levels had decreased to 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group. CONCLUSION: GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH.

Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease.

UNLABELLED: Data are limited on the safety and effectiveness of oral antivirals other than lamivudine and adefovir dipivoxil for treatment of chronic hepatitis B (CHB) in patients with decompensated liver disease. This Phase 2, double-blind study randomized 112 patients with CHB and decompensated liver disease to receive either tenofovir disoproxil fumarate (TDF; n = 45), emtricitabine (FTC)/TDF (fixed-dose combination; n = 45), or entecavir (ETV; n = 22). The primary endpoint was safety; more specifically, tolerability failure (adverse events resulting in permanent treatment discontinuation) and confirmed serum creatinine increase ≥ 0.5 mg/dL from baseline or confirmed serum phosphorus <2 mg/dL. Patients with insufficient viral suppression (e.g., confirmed HBV DNA ≥ 400 copies/mL at week 8 or 24) could begin open-label FTC/TDF but were considered failures in this interim week 48 analysis for efficacy endpoints. Tolerability failure was infrequent across arms: 6.7% TDF, 4.4% FTC/TDF, and 9.1% ETV (P = 0.622) as were confirmed renal parameters meeting threshold 8.9%, 6.7%, and 4.5% (P = 1.000), respectively. Six patients died (none considered related to study drug) and six received liver transplants (none had HBV recurrence). The adverse event and laboratory profiles were consistent with advanced liver disease and complications, with no unexpected safety signals. At week 48, HBV DNA was <400 copies/mL (69 IU/mL) in 70.5% (TDF), 87.8% (FTC/TDF), and 72.7% (ETV) of patients. Proportions with normal alanine aminotransferase were: 57% (TDF), 76% (FTC/TDF), and 55% (ETV). Hepatitis B e antigen (HBeAg) loss/seroconversion occurred in 21%/21% (TDF), 27%/13% (FTC/TDF), and 0%/0% (ETV). Child-Turcotte-Pugh and Modification for End-stage Liver Disease scores improved in all groups. CONCLUSION: All treatments were well tolerated in patients with decompensated liver disease due to CHB with improvement in virologic, biochemical, and clinical parameters.

Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF), a nucleotide analogue and potent inhibitor of hepatitis B virus (HBV) polymerase, showed superior efficacy to adefovir dipivoxil in treatment of chronic hepatitis B through 48 weeks. We evaluated long-term efficacy and safety of TDF monotherapy in patients with chronic hepatitis B who were positive or negative for hepatitis B e antigen (HBeAg(+) or HBeAg(-)). METHODS: After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, patients who underwent liver biopsy were eligible to continue the study on open-label TDF for 7 additional years; data presented were collected up to 3 years (week 144) from 85% of participants. Primary efficacy end points at week 144 included levels of HBV DNA and alanine aminotransferase, development of resistance mutations, and presence of HBeAg or hepatitis B surface antigen (HBsAg). RESULTS: At week 144, 87% of HBeAg(-) and 72% of HBeAg(+) patients treated with TDF had levels of HBV DNA <400 copies/mL. Among patients who had previously received adefovir dipivoxil and then received TDF, 88% of the HBeAg(-) and 71% of the HBeAg(+) patients had levels of HBV DNA <400 copies/mL; overall, 81% and 74%, respectively, maintained normalized levels of alanine aminotransferase and 34% had lost HBeAg. Amino acid substitutions in HBV DNA polymerase that are associated with resistance to tenofovir were not detected in any patient. Cumulatively, 8% of HBeAg(+) patients lost HBsAg. TDF maintained a favorable safety profile for up to 3 years. CONCLUSIONS: TDF was safe and effective in the long-term management of HBeAg(+) and HBeAg(-) patients with chronic hepatitis B.

Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.

BACKGROUND: Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. METHODS: In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. RESULTS: At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. CONCLUSIONS: Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)