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Introduction Migraine is a debilitating neurological condition, affecting up to 15% of Americans. Recent estimates from a long-term safety study of rimegepant showed evidence of decreased monthly migraine days (MMD) in people with episodic migraine treated with rimegepant 75 mg. The objective of this study was to characterize migraine-specific quality of life version 2.1 (MSQv2) scores and corresponding mapped EuroQol-5 Dimensions-3 Level (EQ-5D-3L) utility values. Methods Study participants were randomized into two treatment regimens: individuals with 2–14 MMD received rimegepant 75 mg as needed (PRN), and those with 4–14 MMD at baseline who received rimegepant on a fixed every-other-day schedule plus an as needed dose on days they did not treat (QOD + PRN). MSQv2 was mapped to EQ-5D-3L utilities using a validated algorithm. Outcomes were assessed for the PRN arm at baseline weeks 12, 24, 36, and 52 and for the QOD + PRN arm at baseline and week 12. Results At baseline, MSQv2 data were available for 1,800 patients: 1,033 with 2–8 MMD in the PRN group, 481 with 9–14 MMD in the PRN group, and 286 with 4–14 MMD in the QOD + PRN group. For all MSQv2 domains as well as mapped utility values, outcomes improved over each study visit. At baseline, EQ-5D-3L utilities were 0.66, 0.63, and 0.65 for the 2–8 MMD PRN, 9–14 MMD PRN, and 4–14 MMD QOD + PRN groups, respectively. At end-of-study, utilities had increased by + 0.09, + 0.10, and + 0.12 for the three groups, respectively (p

Objective In the absence of head-to-head comparisons, the objective of this study was to conduct a network meta-analysis (NMA) to indirectly compare the relative efficacy and safety of rimegepant, ubrogepant, and lasmiditan for the acute treatment of migraine. Methods A systematic literature review was conducted to identify randomized controlled trials (RCTs) of rimegepant, ubrogepant, and lasmiditan in adults with acute migraine. Outcomes included sustained pain freedom and -relief 2-48 hours post-dose, and adverse events. No RCTs were identified that directly compared these interventions. Therefore, a fixed-effects Bayesian NMA was conducted by identifying a connected (via comparison to placebo) network of RCTs. Results Five RCTs were identified as follows: rimegepant study 303 (n = 1,466), ubrogepant ACHIEVE I and II (n = 1,672 and n = 1,686, respectively), and lasmiditan SAMURAI and SPARTAN (n = 2,231 and n = 3,005, respectively). Efficacy outcomes (pain freedom and relief at 2, 24, 48 hours) tended to be highest for lasmiditan 200 mg and rimegepant followed lower doses of lasmiditan and all doses of ubrogepant. However, lasmiditan 200 mg was also associated with higher rates of adverse events, particularly somnolence and dizziness. Conclusions Lasmiditan, rimegepant, and ubrogepant all performed significantly better than placebo with respect to pain freedom and pain relief. Efficacy results were similar for rimegepant and lasmiditan with rimegepant having higher rates of pain freedom and relief than lower doses of lasmiditan, while somnolence and dizziness outcomes were lower for rimegepant than higher doses of lasmiditan.

Objective Rimegepant is an orally administered small‐molecule calcitonin gene‐related peptide (CGRP) receptor antagonist, with demonstrated efficacy in the acute treatment of migraine. Recent estimates from a single‐arm trial (BHV3000‐201) have also shown evidence of long‐term preventive effects in monthly migraine days (MMDs) and health‐related quality of life (HRQoL). This study aimed to compare MMDs and HRQoL data for oral rimegepant to those obtained in placebo‐controlled trials for injectable anti‐CGRP monoclonal antibodies (mAbs) galcanezumab and erenumab. Methods Matching‐adjusted indirect comparisons (MAICs) were conducted using rimegepant subject‐level data and published aggregate‐level results from mAb trials. Rimegepant baseline characteristics were matched to the pooled subject characteristics from EVOLVE‐I/II (galcanezumab vs. placebo; n = 1773) and STRIVE (ereumab vs. placebo; n = 955) by reweighting the rimegepant subjects to more closely match the distributions observed in these trials. To align with inclusion criteria of the mAb trials, only the subset of rimegepant subjects with a history of 4–14 MMDs were included (n = 257). Weighted mean differences were used to calculate adjusted change in MMDs, Migraine Disability Assessment Test (MIDAS) score, and Migraine‐Specific Quality of Life Questionnaire version 2 (MSQv2) scores from baseline to week 12. Results When matched to the EVOLVE trials, rimegepant was superior to placebo with a mean difference in MMD change from baseline [95% confidence interval] of −1.16 [−1.80, −0.52] and was not statistically significantly different from galcanezumab 0.59 [−0.13, 1.32]. When matched to the STRIVE trial, rimegepant was superior to placebo −1.59 [−2.15, −1.03] and was not statistically significantly different from erenumab −0.06 [−0.61, 0.50]. Rimegepant showed superior MIDAS and MSQv2 results compared with placebo in both EVOLVE trials and in the STRIVE trial, no statistically significant differences from galcanezumab and erenumab regarding MIDAS, and favorable results compared with erenumab across all MSQv2 domains, while being generally similar to galcanezumab across all MSQv2 domains. Conclusions When adjustments were made to reflect baseline characteristics in published literature, supporting data from BHV3000‐201 suggest that rimegepant every other day is an effective therapy in reducing disability and MMDs and enhancing migraine‐specific HRQoL. These data support the preventive benefit observed in randomized trials of rimegepant and further validate its efficacy for both acute and preventive treatment of migraine.

Objective Evaluate the safety and tolerability of oral rimegepant when used for acute treatment concomitantly with a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the preventive treatment of migraine. Background The efficacy of CGRP mAbs for the preventive treatment of migraine and the small molecule CGRP receptor antagonist rimegepant for acute treatment has been demonstrated in randomized controlled clinical trials. Over the past few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the preventive treatment of migraine and 2 small molecule CGRP receptor antagonists for the acute treatment of migraine. A previous case report of 2 patients receiving concomitant treatment with rimegepant and erenumab suggested that rimegepant may be safely used as acute treatment in patients who are also receiving a preventive regimen involving CGRP mAbs. We report here 13 additional patients with migraine who simultaneously used rimegepant and either erenumab, fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events (AEs). Methods This was a substudy nested within a multicenter, open-label, long-term safety study in adults with 2-14 monthly migraine attacks of moderate to severe pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for acute treatment for 12 weeks. Results The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab [n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5) doses; a total of 224 doses were taken. Five (38%) patients reported ≥1 on-treatment AE. Of these, 2 (15%) patients had mild or moderate nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of mild or moderate severity that were considered potentially treatment-related. No patients had serious AEs, AEs leading to discontinuation, or aminotransferase levels >3× the upper limit of normal. Conclusion Rimegepant, when used as an oral acute treatment in patients receiving CGRP mAbs as preventive treatment, was well tolerated; no safety issues were identified. Studies involving larger patient populations are needed to confirm these findings.

This ongoing, randomized phase III study assesses the safety and efficacy of entecavir versus placebo in nucleos(t)ide-naïve children (2 to18 years) with hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B (CHB). Blinded treatment was administered for a minimum of 48 weeks. After week 48, patients with HBeAg seroconversion continued blinded treatment; those without switched to open-label entecavir. The primary endpoint was HBeAg seroconversion and HBV DNA50 IU/mL at week 48. A total of 180 patients were randomized (2:1) and treated. Baseline median age was 12 years, with approximately 50% of children ages12 to18, and 25% each ages ≥2 to ≤6 and6 to ≤12. Rates for the primary endpoint at week 48 were significantly higher with entecavir than placebo (24.2% [29 of 120] vs. 3.3% [2 of 60]; P = 0.0008). Furthermore, higher response rates were observed with entecavir compared with placebo for the key week 48 secondary endpoints: HBV DNA50 IU/mL (49.2% [59 of 120] vs. 3.3% [2 of 60]; P0.0001); alanine aminotransferase normalization (67.5% [81 of 120] vs. 23.3% [14 of 60]; P0.0001); and HBeAg seroconversion (24.2% [29 of 120] vs. 10.0% [6 of 60]; P = 0.0210). Among entecavir-randomized patients, there was an increase in all efficacy endpoints between weeks 48 and 96, including an increase from 49% to 64% in virological suppression. The cumulative probability of emergent entecavir resistance through years 1 and 2 of entecavir was 0.6% and 2.6%, respectively. Entecavir was well tolerated with no observed differences in adverse events or changes in growth compared with placebo.In childhood CHB, entecavir demonstrated superior antiviral efficacy to placebo with a favorable safety profile. These results support the use of entecavir as a therapeutic option in children and adolescents with CHB.

Protease inhibitor (PI) treatment can result in dyslipidemia in a significant proportion of patients. Atazanavir (ATV) is a once-daily PI that has not been associated with clinically relevant increases in total cholesterol (TC), fasting low-density lipoprotein cholesterol (LDL-C), or fasting triglyceride (TG) concentrations. The objectives of this paper were to evaluate lipid profiles in untreated patients, and investigate the frequency and severity of dyslipidemia in the same individuals after treatment with ATV or nelfinavir (NFV) for 48 weeks. Two multinational, randomized, active-controlled, blinded trials compared the safety and efficacy of ATV and NFV in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral (ARV)-naive patients. Serum lipid concentrations were analyzed in patients who had available measurements both at baseline and at week 48. Patients who had missing data at either time point were not included. Lipid levels remained within baseline ranges at week 48 with ATV treatment, whereas clinically relevant elevations in TC, fasting LDL-C, and fasting TG concentrations occurred with NFV treatment. Mean changes from pre-treatment baseline in fasting LDL-C ranged from -6 percent to +6 percent in the ATV-treatment groups, and from +27 percent to +31 percent in the NFV-treatment groups. After 48 weeks, there was a substantive increase in the proportion of NFV-treated patients who would be recommended for lipid-lowering treatment by National Cholesterol Education Program (NCEP) guidelines, whereas a lesser proportion of ATV-treated patients would be recommended for lipid-lowering treatment. Atazanavir does not lead to dyslipidemia in ARV-naive patients, and may limit the need for lipid-lowering strategies to reduce the risk of cardiovascular disease.

Efficacy in HIV clinical trials is measured by changes in HIV RNA levels over time as well as the proportion of subjects with HIV RNA levels below an assay’s threshold of reliable quantification at a single time point. Missing data arise naturally due to missed visits and premature discontinuations of treatment. The available data are then analyzed using repeated measures models and univariate comparisons of proportions, assuming missing data occur at random or considering missing values as treatment failures (worst case scenario). These and other methods recently proposed by regulatory authorities are presented along with alternative approaches. Advantages and disadvantages of each method are discussed. Data from a recent comparison of ’ standard-of-care’ triple combination regimens are used for illustration.

Summary Background Atazanavir/ritonavir is as effective as lopinavir/ritonavir, with a more favourable lipid profile and less gastrointestinal toxicity, in treatment-experienced HIV-1-infected patients. We compared these two combinations directly in treatment-naive patients. Methods In this open-label, international non-inferiority study, 883 antiretroviral-naive, HIV-1-infected patients were randomly assigned to receive atazanavir/ritonavir 300/100 mg once daily (n=440) or lopinavir/ritonavir 400/100 mg twice daily (n=443), in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily. Randomisation was done with a computer-generated centralised randomisation schedule and was stratified by baseline levels of HIV RNA (viral load) and geographic region. The primary endpoint was the proportion of patients with viral load less than 50 copies per mL at week 48. The main efficacy analysis was done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00272779. Findings At week 48, 343 (78%) of 440 patients receiving atazanavir/ritonavir and 338 (76%) of 443 patients receiving lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL (difference 1·7%, 95% CI −3·8 to 7·1). Mean increases from baseline in CD4 cell count were similar (203 cells per μL in the atazanavir/ritonavir group vs 219 cells per μL in the lopinavir/ritonavir group). 25 (6%) patients in the atazanavir/ritonavir group and 26 (6%) in the lopinavir/ritonavir group were virological failures by week 48. Only two patients, both in the atazanavir/ritonavir group, had non-polymorphic protease inhibitor resistance mutations emerge on treatment, which conferred phenotypic resistance to atazanavir in one patient. Serious adverse events were noted in 51 (12%) of 441 patients in the atazanavir/ritonavir group and in 42 (10%) of 437 patients in the lopinavir/ritonavir group. Fewer patients in the atazanavir/ritonavir group than in the lopinavir/ritonavir group experienced grade 2–4 treatment-related diarrhoea (10 [2%] vs 50 [11%]) and nausea (17 [4%] vs 33 [8%]). Grade 2–4 jaundice was seen in 16 (4%) of 441 patients in the atazanavir/ritonavir group versus none of 437 patients in the lopinavir/ritonavir group; grade 3–4 increases in total bilirubin were seen in 146 (34%) of 435 patients on atazanavir/ritonavir and in one ( Interpretation In treatment-naive patients, atazanavir/ritonavir once-daily demonstrated similar antiviral efficacy to lopinavir/ritonavir twice-daily, with less gastrointestinal toxicity but with a higher rate of hyperbilirubinaemia. Funding Bristol-Myers Squibb.

Protease inhibitor treatment of human immunodeficiency virus (HIV)-infected individuals has been linked to the development of lipodystrophy. The effects of atazanavir on body fat distribution and related metabolic parameters were examined in antiretroviral-naive patients.HIV-positive patients with CD4 cell countsor = 100 cells/mm3 were randomized to 1 of 2 treatment arms: (1) atazanavir, 400 mg given once daily, plus efavirenz placebo; or (2) efavirenz, 600 mg given once daily, plus atazanavir placebo; each drug was administered with fixed-dose zidovudine (300 mg) and lamivudine (150 mg) given twice daily, and patients were treated for at least 48 weeks. Fat distribution measurements (visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], and total adipose tissue [TAT], as measured by computed tomography; and appendicular fat, truncal fat, and total fat levels, as measured by dual-energy x-ray absorptiometry), metabolic measurements (cholesterol and fasting triglyceride levels), and measurements of insulin resistance (fasting glucose and fasting insulin levels) were made at baseline and at week 48 of treatment for a subgroup of 111 atazanavir recipients and 100 efavirenz recipients.Atazanavir and efavirenz treatments resulted in minimal to modest increases in fat accumulation, as measured by VAT, SAT, TAT, appendicular fat, truncal fat, and total fat levels; results were comparable in both arms. In addition, atazanavir was associated with none of the metabolic abnormalities seen with many other protease inhibitors.Use of atazanavir for 48 weeks neither resulted in abnormal fat redistribution in antiretroviral-naive patients nor induced other metabolic disturbances commonly associated with HIV-related lipodystrophy. Longer-term assessments (e.g., at 96 weeks) will be important to confirm these findings.

Entecavir is a nucleoside analogue with potent in vitro activity against lamivudine-resistant hepatitis B virus (HBV). This randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients.Hepatitis B e antigen (HBeAg)-positive and -negative patients (n = 182), viremic despite lamivudine treatment foror =24 weeks or having documented lamivudine resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks.At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV DNA levels by branched chain DNA assay compared with lamivudine (13%; P.0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (P.01). After 48 weeks, mean reductions in HBV DNA levels were 5.06, 4.46, and 2.85 log(10) copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log(10) copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virologic rebound due to resistance occurred (in the 0.5-mg group).In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels. One milligram of entecavir was more effective than 0.5 mg in this population.

Background: Atazanavir, an azapeptide protease inhibitor (PI), has pharmacokinetics that allow once-daily dosing, and it is not associated with significant Pl-associated dyslipidemia. Methods: A randomized, double-blind, double-dummy, active-controlled, 2-arm study comparing the antiviral efficacy and safety of atazanavir 400 mg administered once daily with efavirenz 600 mg administered once daily in combination with open-label fixed-dose zidovudine plus lamivudine twice daily. The 810 treatment-naive patients were stratified by HIV RNA level. The primary efficacy end point was the proportion of treated patients with HIV RNA levels

Three dose levels of the protease inhibitor (PI) atazanavir (200, 400, and 500 mg once daily) were compared with nelfinavir (750 mg three times daily) when given both as monotherapy and in combination with didanosine and stavudine in 420 antiretroviral-naive subjects infected with HIV-1. Subjects received monotherapy for 2 weeks, followed by combination therapy for 46 weeks. After 48 weeks, mean change from baseline in HIV RNA (-2.57 to -2.33 log 10 copies/mL), the proportion of subjects with HIV RNA

3. PR plus BOC for 44 weeks (BOC/PR48). Primary endpoint was SVR 24 wks post-therapy (Roche TaqMan LLD = 9.3 IU/mL). Results: SVR was numerically higher in patients with G1a (66–73%) compared to G1b (59–64%) in the BOC arms of both studies. Similarly, the number of patients with RAVs was higher with G1a infection and the rate of detectable RAVs in all patients for whom RAV testing was performed was higher in G1a infected subjects in both studies (Table). Conclusions: BOC/PR therapy is associated with a small but consistently higher SVR rate and lower rate of development of RAVs in patients infected with G1b compared to G1a.