Efficacy and safety of switching to dolutegravir/lamivudine in virologically suppressed people with HIV-1 aged ≥ 50 years: week 48 pooled results from the TANGO and SALSA studies.

BACKGROUND: As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years). METHODS: Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis. RESULTS: Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years. CONCLUSIONS: Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities. TRIAL REGISTRATION NUMBER: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019).

Efficacy, safety, and pharmacokinetics by BMI category in Phase 3/3b cabotegravir + rilpivirine long-acting trials.

BACKGROUND: Cabotegravir + rilpivirine (CAB + RPV) is a guideline-recommended long-acting (LA) injectable regimen for the maintenance of HIV-1 virologic suppression. This post hoc analysis summarizes CAB + RPV LA results by baseline body mass index (BMI) category among Phase 3/3b trial participants. METHODS: Data from CAB + RPV-naive participants receiving every 4 or 8 week dosing in FLAIR, ATLAS, and ATLAS-2 M were pooled through Week (W) 48. Data beyond W48 were summarized by study (FLAIR through W96 and ATLAS-2 M through W152). HIV 1 RNA <50 and ≥50 copies/mL, confirmed virologic failure (CVF; two consecutive HIV-1 RNA ≥200 copies/mL), safety and tolerability, and plasma CAB and RPV trough concentrations were evaluated by baseline BMI (<30 kg/m2 [lower]; ≥ 30 kg/m2 [higher]). RESULTS: Among 1245 CAB + RPV LA participants, 213 (17%) had a baseline BMI ≥30 kg/m2. At W48, 92% vs. 93% of participants with lower vs. higher BMI had HIV-1 RNA <50 copies/mL, respectively. Including data beyond W48, 18 participants had CVF; those in the higher BMI group (n = 8) all had at least one other baseline factor associated with CVF (archived RPV resistance-associated mutations or HIV 1 subtype A6/A1). Safety and pharmacokinetic profiles were comparable between BMI categories. CONCLUSION: CAB + RPV LA was efficacious and well tolerated, regardless of baseline BMI category.Main point summary: CAB + RPV LA is effective in the maintenance of HIV-1 virologic suppression in adults regardless of BMI category, with longer-length needles (≥2 inches) recommend for those with BMI ≥30 kg/m2 to accommodate individual body habitus and ensure appropriate administration.

An indirect comparison of 144-week efficacy, safety, and tolerability of dolutegravir plus lamivudine and second-generation integrase inhibitor-based, 3-drug, single-tablet regimens in therapy-naive people with HIV-1.

BACKGROUND: The long-term efficacy and safety of the 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) and 3-drug single-tablet regimens recommended for antiretroviral therapy (ART)-naive people with HIV-1 (PWH) have yet to be compared directly in clinical trials. This indirect treatment comparison (ITC) was conducted to compare the durability of efficacy and long-term safety of DTG + 3TC vs second-generation, integrase strand transfer inhibitor (INSTI)-based, 3-drug, single-tablet regimens bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) and DTG/abacavir/3TC (DTG/ABC/3TC) at Week 144 after treatment initiation. METHODS: A systematic literature review identified 4 trials evaluating the treatment regimens of interest in ART-naive PWH (GEMINI-1, GEMINI-2, GS-US-380-1489, and GS-US-380-1490). Safety, efficacy, and tolerability results were compared using fixed-effects Bucher ITC methodology to calculate relative outcomes. RESULTS: Rates of virologic suppression (HIV-1 RNA < 50 copies/mL, US Food and Drug Administration Snapshot analysis) and virologic failure (HIV-1 RNA ≥ 50 copies/mL) as well as mean change in CD4 + cell count were similar with DTG + 3TC, BIC/FTC/TAF, and DTG/ABC/3TC at Week 144. Serious adverse events occurred less frequently with DTG + 3TC compared with both BIC/FTC/TAF (odds ratio [OR], 0.51; 95% CI 0.29-0.87; P = 0.014) and DTG/ABC/3TC (OR, 0.38; 95% CI 0.19-0.75; P = 0.006). Discontinuations and overall adverse events were similar across all 3 regimens. CONCLUSIONS: These results suggest that the 2-drug regimen DTG + 3TC offers comparable and durable efficacy with fewer serious adverse events vs BIC/FTC/TAF and DTG/ABC/3TC through 144 weeks of treatment in ART-naive PWH. These long-term comparative data support the therapeutic value of DTG + 3TC for PWH.

Comparative efficacy and safety of dolutegravir relative to common core agents in treatment-naïve patients infected with HIV-1: a systematic review and network meta-analysis.

BACKGROUND: Network meta-analyses (NMAs) provide comparative treatment effects estimates in the absence of head-to-head randomized controlled trials (RCTs). This NMA compared the efficacy and safety of dolutegravir (DTG) with other recommended or commonly used core antiretroviral agents. METHODS: A systematic review identified phase 3/4 RCTs in treatment-naïve patients with HIV-1 receiving core agents: ritonavir-boosted protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), or integrase strand inhibitors (INSTIs). Efficacy (virologic suppression [VS], CD4+ cell count change from baseline) and safety (adverse events [AEs], discontinuations, discontinuation due to AEs, lipid changes) were analyzed at Week 48 using Bayesian NMA methodology, which allowed calculation of probabilistic results. Subgroup analyses were conducted for VS (baseline viral load [VL] ≤/> 100,000copies/mL, ≤/> 500,000copies/mL; baseline CD4+ ≤/>200cells/µL). Results were adjusted for the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) combined with the core agent (except subgroup analyses). RESULTS: The NMA included 36 studies; 2 additional studies were included in subgroup analyses only. Odds of achieving VS with DTG were statistically superior to PIs (odds ratios [ORs] 1.78-2.59) and NNRTIs (ORs 1.51-1.86), and similar but numerically higher than other INSTIs. CD4+ count increase was significantly greater with DTG than PIs (difference: 23.63-31.47 cells/µL) and efavirenz (difference: 34.54 cells/µL), and similar to other core agents. INSTIs were more likely to result in patients achieving VS versus PIs (probability: 76-100%) and NNRTIs (probability: 50-100%), and a greater CD4+ count increase versus PIs (probability: 72-100%) and NNRTIs (probability: 60-100%). DTG was more likely to result in patients achieving VS (probability: 94-100%), and a greater CD4+ count increase (probability: 53-100%) versus other core agents, including INSTIs (probability: 94-97% and 53-93%, respectively). Safety outcomes with DTG were generally similar to other core agents. In patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/µL (18 studies), odds of achieving VS with DTG were superior or similar to other core agents. CONCLUSION: INSTI core agents had superior efficacy and similar safety to PIs and NNRTIs at Week 48 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious, including in patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/µL, who can be difficult to treat.

Automated identification of brain new lesions in multiple sclerosis using subtraction images.

PURPOSE: To propose and evaluate a new automated method for the identification of new/enlarging multiple sclerosis (MS) lesions on subtracted images (SI). The subtraction of serially acquired images has shown great potential in assessing new/enlarging brain magnetic resonance imaging (MRI) lesions in MS patients. However, this approach relies on the manual definition of lesions, which is labor-intensive and subject to operator-dependent variability. MATERIALS AND METHODS: An overestimated mask of candidate SI lesions was created and then these hyperintense voxel clusters were filtered using specific constraints for extent, shape, and intensity. The method was tested on normal and pathological MRI datasets. RESULTS: The automated method did not detect hyperintense voxels on SI of healthy controls. SI lesions were identified manually and automatically in a multicenter MS dataset of 19 patients with paired MRI over 36 weeks. Sensitivity of the method was high (0.91) and in agreement with the results of manually defined SI lesions (Cohen's k=0.82,95% confidence interval [CI]: 0.77­0.87). On a second multicenter MS dataset of 103 patients with paired MRI over 76 weeks, the number of SI lesions detected automatically correlated with the number of gadolinium-enhancing lesions(r=0.74). CONCLUSION: The proposed method is robust, accurate,and sensitive and may be used with confidence in Phase II MS trials.

Dolutegravir/Lamivudine Efficacy and Safety Outcomes in People With HIV-1 With or Without Historical Resistance Results at Screening: 48-Week Pooled Analysis.

Background: Drug resistance testing aids in appropriate antiretroviral therapy selection to improve treatment success but may not be readily available. We evaluated the impact of switching to dolutegravir/lamivudine (DTG/3TC) using pooled data from the TANGO and SALSA trials in adults who were virologically suppressed with or without historical resistance results at screening. Methods: Adults who were virologically suppressed (HIV-1 RNA <50 copies/mL for >6 months) with no prior virologic failure were randomized to switch to DTG/3TC (TANGO, n = 369; SALSA, n = 246) or continue their current antiretroviral regimen (CAR; TANGO, n = 372; SALSA, n = 247). Week 48 HIV-1 RNA ≥50 and <50 copies/mL (Snapshot algorithm, Food and Drug Administration; intention-to-treat exposed), CD4+ cell count, and safety were analyzed by availability of historical resistance results. Results: Overall, 294 of 615 (48%) participants in the DTG/3TC group and 277 of 619 (45%) participants in the CAR group had no historical resistance results at screening. At week 48, proportions with Snapshot HIV-1 RNA ≥50 copies/mL were low (≤1.1%) and similar across treatment groups and by historical resistance results availability. High proportions (91%-95%) maintained virologic suppression through week 48, regardless of results availability. Across both subgroups of results availability, greater increases in CD4+ cell count from baseline to week 48 occurred with DTG/3TC vs CAR. No participants taking DTG/3TC had confirmed virologic withdrawal, regardless of historical resistance results availability. One participant undergoing CAR without historical resistance results had confirmed virologic withdrawal; no resistance was detected. Overall, DTG/3TC was well tolerated; few adverse events led to withdrawal. Conclusions: Findings support DTG/3TC as a robust switch option for adults who are virologically suppressed with HIV-1 and no prior virologic failure, regardless of historical resistance results availability. Clinical trial registration: TANGO: NCT03446573, https://clinicaltrials.gov/study/NCT03446573. SALSA: NCT04021290, https://clinicaltrials.gov/study/NCT04021290.

Switching to dolutegravir plus rilpivirine versus maintaining current antiretroviral therapy regimen in virologically suppressed people with HIV-1 and the Lys103Asn (K103N) mutation: 48-week results from a randomised, open-label pilot clinical trial.

BACKGROUND: The combination of dolutegravir plus rilpivirine has been studied in people with virologically suppressed HIV with no previous history of treatment failure or resistance. We investigated the potential to maintain viral suppression with dolutegravir plus rilpivirine in people with Lys103Asn mutations whose HIV was previously managed with other treatment regimens. METHODS: In this open-label pilot trial at 32 clinical sites in seven European countries, virologically suppressed, HBsAg-negative adults aged 18 years or older with HIV-1 and Lys103Asn mutations were randomly assigned (2:1) to switch to 50 mg dolutegravir plus 25 mg rilpivirine (given as a single tablet) once daily or to continue their current antiretroviral therapy regimen (control group). After 48 weeks, participants in the control group also switched to dolutegravir plus rilpivirine. Randomisation was stratified by country, and a computer-generated randomisation list with permuted blocks within strata was used to assign participants to treatment groups. The primary endpoints were virological failure (ie, two consecutive measurements of 50 copies or more of HIV RNA per mL at least 2 weeks apart) and virological suppression (the proportion of participants with fewer than 50 copies of HIV RNA per mL) at week 48 (week 96 data will be reported separately). Analyses were done in the modified intention-to-treat population, which included all participants who received at least one dose of the study medication. This trial is registered with ClinicalTrials.gov, NCT05349838, and EudraCT, 2017-004040-38. FINDINGS: Between Nov 5, 2018, and Dec 9, 2020, 140 participants were enrolled and randomly assigned, 95 to the dolutegravir plus rilpivirine group and 45 to the control group. Virological failure was recorded in three participants (3·2%, 95% CI 0·7 to 9·0) in the the dolutegravir plus rilpivirine group and one (2·2%, 0·1 to 11·8) in the control group. The proportion of participants in whom virological suppression was maintained at week 48 was 88·4% (80·2 to 94·1) in the dolutegravir plus rilpivirine group versus 88·9% (75·9 to 96·3) in the control group (difference -0·5, -11·7 to 10·7). Significantly more adverse events were recorded in the dolutegravir plus rilpivirine group than in the control group (234 vs 72; p=0·0034), but the proportion of participants who reported at least one adverse event was similar between groups (76 [80%] of 95 vs 33 [73%] of 45; p=0·39). The frequency of serious adverse events was low and similar between groups. INTERPRETATION: Virological suppression was maintained at week 48 in most participants with Lys103Asn mutations when they switched from standard regimens to dolutegravir plus rilpivirine. The results of this pilot study, if maintained when the week 96 data are reported, support conduct of a large, well-powered trial of dolutegravir plus rilpivirine. FUNDING: ViiV Healthcare.

Cabotegravir + Rilpivirine Long-Acting: Overview of Injection Guidance, Injection Site Reactions, and Best Practices for Intramuscular Injection Administration.

Background: Cabotegravir (CAB) + rilpivirine (RPV) dosed monthly or every 2 months is a complete long-acting (LA) regimen for the maintenance of human immunodeficiency virus type 1 virologic suppression. Across the phase 3/3b trials, the most frequently reported adverse events were injection site reactions (ISRs). Methods: We present pooled ISR characteristics and outcomes for participants receiving CAB + RPV LA through week 96 of the FLAIR and ATLAS-2M studies, and survey results from healthcare providers (HCPs) giving injections (eg, injectors) in the ATLAS, FLAIR, and ATLAS-2M studies to determine optimal injection techniques. Surveys were anonymous, self-administered online questionnaires that queried provider demographics, injection experience, and techniques to minimize pre-/postinjection discomfort. Data were summarized using descriptive statistics. Results: Overall, 8453 ISRs were reported by 801 participants receiving ≥1 injection of CAB LA/RPV LA. Most ISRs were mild to moderate in severity (grade 1-2, 99%), with a median duration of 3 days (interquartile range, 2-4 days), and rarely led to withdrawal (2%). Surveys were completed by 181 HCPs across 113 sites. Pushing the intramuscular injection at slow speed (66%), bringing the medication to room temperature (58%), and relaxing the gluteus muscle before injecting (53%) were ranked as effective preinjection/injection procedure practices for minimizing pain. Most injectors (60%) indicated that a prone position provided optimal patient comfort, and 41% had no preference on injection medication order. Conclusions: Taken together, the data demonstrate favorable tolerability with CAB + RPV LA injections over the long term and simple techniques routinely used by injectors to help optimize the administration of CAB + RPV LA injections.

Evaluating Diversity in Randomized Clinical Trials of Dolutegravir-Based Antiretroviral Therapy Regimens: Pooled 48-Week Analyses by Race, Sex, and Regional Subgroups.

Background: In HIV clinical trials, proportions of Black and female participants achieving virologic suppression (VS) are often lower compared with White and male participants. As the antiretroviral therapy (ART) landscape continues to evolve, addressing existing challenges in clinical trial diversity will be critical to effectively translate results into clinical practice. Here, we pooled data to evaluate the efficacy and safety of dolutegravir (DTG)-containing regimens by race, sex, and regional subgroups. Methods: Three pooled analyses were conducted using 48-week results from phase 3/3b trials: DTG 3-drug vs non-DTG-containing 3- or 4-drug regimens in ART-naive participants (ARIA, FLAMINGO, SINGLE, SPRING-2), DTG-containing 2-drug vs 3-drug regimens in ART-naive participants (GEMINI-1, GEMINI-2), and DTG 3-drug vs non-DTG-containing 3- or 4-drug regimens in ART-experienced participants (SAILING, DAWNING). Proportions of participants with VS, safety, and change from baseline in CD4+ cell count were analyzed. Results: Proportions of participants achieving VS were high among those receiving DTG vs comparator regimens. Proportions of participants achieving VS were generally lower in Black (vs non-Black), female (vs male), and US (vs non-US) subgroups. No new safety signals emerged from any subgroup in pooled analyses. Conclusions: These analyses confirm that, across subgroups, DTG has robust efficacy and a good safety profile at week 48 relative to comparator regimens. Achieving VS may vary by participant characteristics, highlighting the urgent need for enrollment to reflect the demographics of global HIV populations more accurately. Future studies should strive to support participants throughout the trial to ensure optimal representation, inclusion, and retention.

Dolutegravir-based regimens in treatment-naive and treatment-experienced aging populations: analyses of 6 phase III clinical trials.

Background: Older adults living with HIV (OALWH) are a growing population facing unique challenges to successful antiretroviral therapy.Objective: To assess efficacy and safety profiles of antiretroviral regimens, including those containing dolutegravir, in OALWH.Methods: Combined data from 6 phase III/IIIb trials in treatment-naive (ARIA, FLAMINGO, SINGLE, SPRING-2; N = 2634) and treatment-experienced (DAWNING, SAILING; N = 1339) participants receiving dolutegravir- or non-dolutegravir-based regimens were analyzed by age (<50, ≥50 to <65, and ≥65 years). Baseline data included comorbidities and numbers of concomitant medications. Week 48 efficacy outcomes included virologic response (HIV-1 RNA <50 copies/mL) and CD4+ cell count change from baseline. Safety outcomes included incidence of adverse events (AEs), serious AEs, and AE-related withdrawals.Results: Use of ≥5 concomitant medications was more frequently reported among treatment-naive and treatment-experienced participants aged ≥50 to <65 (30% [90/296] and 25% [57/227], respectively) and ≥65 years (43% [10/23] and 29% [4/14]) than among those aged <50 years (13% [310/2315] and 11% [118/1098]). Comorbidities were more prevalent in the older age groups. For dolutegravir-based regimens, Week 48 rates of virologic response and change in CD4+ cell count were similar across age groups (treatment naive, 80-87% and 234-251 cells/mm3; treatment experienced, 70-100% and 105-156 cells/mm3, respectively). There were no major differences in safety outcomes in each age group.Conclusions: In these analyses of combined phase III/IIIb trial data, efficacy and safety of dolutegravir-based regimens were generally similar across age groups in treatment-naive or treatment-experienced participants. Polypharmacy and comorbidities were more common among OALWH than those aged <50 years.

Impact of treatment adherence on efficacy of dolutegravir plus lamivudine and dolutegravir plus tenofovir disoproxil fumarate/emtricitabine: pooled analysis of the GEMINI-1 and GEMINI-2 clinical studies.

Background: GEMINI-1 and GEMINI-2 (ClinicalTrials.gov, NCT02831673 and NCT02831764, respectively) are double-blind, multicenter, phase III studies that demonstrated the non-inferiority of once-daily dolutegravir + lamivudine to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL at 48, 96, and 144 weeks in treatment-naive adults with HIV-1 infection.Objective: We present a post hoc analysis of the impact of treatment adherence on Week 48 virologic response.Methods: Adherence was estimated using pill counts and categorized as ≥90% vs <90%. Unadjusted treatment differences with exact 95% CIs were derived for the proportion of participants with HIV-1 RNA <50 copies/mL within each adherence category, using Snapshot algorithm and last available on-treatment viral load through Week 48.Results: In each treatment group, 5% of participants had <90% adherence (dolutegravir + lamivudine group, 35/716; dolutegravir + tenofovir disoproxil fumarate/emtricitabine group, 34/717). The proportion of participants with HIV-1 RNA <50 copies/mL (Snapshot) at Week 48 in the <90% adherence group was 69% in the dolutegravir + lamivudine group and 65% in the dolutegravir + tenofovir disoproxil fumarate/emtricitabine group (analysis by last on-treatment viral load: 91% and 85%, respectively). Corresponding proportions in the ≥90% adherence group were 93% and 96% (analysis by last on-treatment viral load: 97% and 99%, respectively).Conclusions: Decreased adherence resulted in lower Week 48 virologic efficacy outcomes that were comparable between treatment groups. These results indicate that the robust antiviral activity and regimen forgiveness of dolutegravir + lamivudine is similar to dolutegravir-containing 3-drug regimens (see graphical abstract).

Impact of colour on the bioreceptivity of granite to the green alga Apatococcus lobatus: Laboratory and field testing.

Recent work has demonstrated that surface colour affects the formation of cyanobacterial subaerial biofilms on polycarbonate coupons and, in turn, influences their bioreceptivity. To explore whether colour is important on other substrates, the influence of colour on the primary bioreceptivity of granite to the terrestrial green alga Apatococcus lobatus (Trebouxiophyceae, Chlorophyta) has been assessed. Two granitoids (Grissal and Rosa Porriño) with the same texture, and very similar chemical composition, open porosity and surface roughness, but different coloration related to feldspars (i.e. greyish and reddish) were used to conduct bioreceptivity studies in parallel field and laboratory tests. Light microscopy, colour spectrophotometry, PAM fluorometry, and optical profilometry were used to evaluate colonisation and its impacts. Short-term results (after 7 and 10 weeks of colonisation by a mono-species biofilm) from both lab and field trials, showed significantly more algae growth on reddish granite (Rosa Porriño) than on greyish granite (Grissal). Also, optical profilometry and light microscopy demonstrated that on both granites algal aggregates developed in hollows. We attribute the roughly double levels of A. lobatus growth on reddish vs greyish granite to differences in the amount of radiant energy absorbed and the higher levels of red wavelength light (known to encourage algal growth) reflected from the reddish surface.

Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis.

OBJECTIVE: To investigate the efficacy and safety of belimumab, a fully human immunoglobulin G1λ monoclonal antibody against B-lymphocyte stimulator, in participants with generalized myasthenia gravis (MG) who remained symptomatic despite standard of care (SoC) therapy. METHODS: Eligible participants with MG were randomized 1:1 to receive IV belimumab 10 mg/kg or placebo in this phase II, placebo-controlled, multicenter, double-blind study (NCT01480596; BEL115123). Participants received SoC therapies throughout the 24-week treatment phase and 12-week follow-up period. The primary efficacy endpoint was mean change from baseline in the Quantitative Myasthenia Gravis (QMG) scale at week 24; safety assessments included the frequency and severity of adverse events (AEs) and serious AEs. RESULTS: Forty participants were randomized (placebo n = 22; belimumab n = 18). The mean change in QMG score from baseline at week 24 was not significantly different for belimumab vs placebo (p = 0.256). There were no statistically significant differences between treatment groups for secondary endpoints, including the MG Composite and MG-Activity of Daily Living scores. Acetylcholine receptor antibody levels decreased over time in both treatment groups. No unexpected AEs were identified and occurrence was similar in the belimumab (78%) and placebo (91%) groups. One participant receiving placebo died (severe sepsis) during the treatment phase. CONCLUSIONS: The primary endpoint was not met for belimumab in participants with generalized MG receiving SoC. There was no significant difference in mean change in the QMG score at week 24 for belimumab vs placebo. The safety profile of belimumab was consistent with previous systemic lupus erythematosus studies. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for participants with generalized MG, belimumab did not significantly improve QMG score compared with placebo.

Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study.

OBJECTIVE: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS). METHODS: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion. RESULTS: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing. CONCLUSION: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.

Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study.

Histamine H3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18-50 with RRMS, receiving intramuscular interferon-ß1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4-5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI -0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS.

A Phase II study of a histamine H3 receptor antagonist GSK239512 for cognitive impairment in stable schizophrenia subjects on antipsychotic therapy.

This Phase II exploratory study assessed GSK239512, a brain penetrant histamine H3 receptor antagonist, versus placebo on cognitive impairment in 50 stable outpatients with schizophrenia. Subjects were randomized to placebo or GSK239512 for 7 weeks (4 weeks titration). GSK239512 was associated with a small positive effect size (ES) on the CogState Schizophrenia Battery (CSSB) Composite Score (ES=0.29, CI=-0.40, 0.99) relative to placebo (primary endpoint). GSK239512's ES on CSSB domains were generally positive or neutral except Processing Speed, which favored placebo (ES=-0.46). Effects on the MATRICS Consensus Cognitive Battery were mostly neutral or favored placebo. GSK239512 was generally well tolerated with an adverse event profile consistent with the known class pharmacology. There was no evidence of overall beneficial effects of GSK239512 for CIAS in this population.

Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study.

OBJECTIVES: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple sclerosis (RRMS). METHODS: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed. RESULTS: Thirty-eight patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19(+) expression. New brain MRI lesion activity was suppressed (>99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions. CONCLUSIONS: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with RRMS, ofatumumab compared with placebo does not increase the number of serious adverse events and decreases the number of new MRI lesions.

Patterns of responding on a balloon analogue task reveal individual differences in overall risk-taking: choice between guaranteed and uncertain cash.

We explored the utility of analyzing within- and between-balloon response patterns on a balloon analogue task (BAT) in relation to overall risk scores, and to a choice between a small guaranteed cash reward and an uncertain reward of the same expected value. Young adults (n = 61) played a BAT, and then were offered a choice between $5 in cash and betting to win $0 to $15. Between groups, pumping was differentially influenced by explosions and by the number of successive unexploded balloons, with risk takers responding increasingly on successive balloons after an explosion. Within-balloons, risk takers showed a characteristic pattern of constant high rate, while non-risk takers showed a characteristic variable lower rate. Overall, results show that the higher number of pumps and explosions that characterize risk takers at a molar level, result from particular forms of adaptation to the positive and negative outcomes of choices seen at a molecular level.