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In human beings, 5-HT6 receptors are almost exclusively expressed in the brain, particularly in areas relevant for cognition, such as the hippocampus and frontal cortex. We assessed the effect on cognitive performance of Lu AE58054 (idalopirdine), a selective 5-HT6 receptor antagonist, in donepezil-treated patients with moderate Alzheimer's disease. For this randomised, double-blind, placebo-controlled phase 2 trial (LADDER), we recruited patients from 48 outpatient clinical sites in seven countries. Patients were 50 years or older, had moderate Alzheimer's disease (a mini-mental state examination score of 12–19), and had been stably treated with donepezil 10 mg per day for 3 or more months. Using a computer-generated sequence, we randomly assigned patients (1:1, stratified by site) to receive either idalopirdine 90 mg per day (30 mg thrice daily) or placebo. The primary endpoint was change from baseline in the 11-item Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-cog) at week 24. We analysed all efficacy endpoints in the full-analysis set (modified intention-to-treat analysis). This trial is registered with ClinicalTrials.gov, number NCT01019421. Between Dec 8, 2009, and Dec 23, 2011, we randomly allocated 278 patients to treatment: 133 to placebo and 145 to idalopirdine. 132 patients in the placebo group and 140 in the experimental group were included in the final analysis. At week 24, the change from baseline in ADAS-cog total score was +1·38 (SD 0·53) in the placebo group and −0·77 (0·55) in the idalopirdine group (treatment difference of −2·16 points, 95% CI −3·62 to −0·69; p=0·0040). 25 patients (seven taking placebo and 18 taking idalopirdine) discontinued treatment because of adverse events, the difference between groups being mainly due to asymptomatic transient increases in transaminase concentrations in some idalopirdine-treated patients. The most common adverse events (occurring in >3% of patients) were increased γ-glutamyltransferase (14 [10%] patients in the idalopirdine group vs two [2%] in the placebo group), diarrhoea (six [4%] vs nine [7%]), urinary tract infection (three [2%] vs nine [7%]), fall (three [2%] vs eight [6%]), increased alanine aminotransferase (nine [6%] vs none), and benign prostatic hyperplasia (two [5%] vs none). Serious adverse events were reported by 14 (10%) patients in the idalopirdine group and 13 (10%) patients in the placebo group. One death occurred in each treatment group, neither were regarded as being related to treatment. Idalopirdine improved cognitive function in donepezil-treated patients with moderate Alzheimer's disease. Larger studies in a broader population of patients are ongoing to substantiate the effects reported here. H Lundbeck A/S.

Tisotumab vedotin is a first-in-human antibody–drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor. InnovaTV 201 is a phase 1–2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0–1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing. Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2–22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment. Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours. Genmab A/S.

In human beings, 5-HT6receptors are almost exclusively expressed in the brain, particularly in areas relevant for cognition, such as the hippocampus and frontal cortex. We assessed the effect on cognitive performance of Lu AE58054 (idalopirdine), a selective 5-HT6receptor antagonist, in donepezil-treated patients with moderate Alzheimer's disease. Methods For this randomised, double-blind, placebo-controlled phase 2 trial (LADDER), we recruited patients from 48 outpatient clinical sites in seven countries. Patients were 50 years or older, had moderate Alzheimer's disease (a mini-mental state examination score of 12-19), and had been stably treated with donepezil 10 mg per day for 3 or more months. Using a computer-generated sequence, we randomly assigned patients (1:1, stratified by site) to receive either idalopirdine 90 mg per day (30 mg thrice daily) or placebo. The primary endpoint was change from baseline in the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) at week 24. We analysed all efficacy endpoints in the full-analysis set (modified intention-to-treat analysis). This trial is registered withClinicalTrials.gov, numberNCT01019421. Findings Between Dec 8, 2009, and Dec 23, 2011, we randomly allocated 278 patients to treatment: 133 to placebo and 145 to idalopirdine. 132 patients in the placebo group and 140 in the experimental group were included in the final analysis. At week 24, the change from baseline in ADAS-cog total score was +1·38 (SD 0·53) in the placebo group and -0·77 (0·55) in the idalopirdine group (treatment difference of -2·16 points, 95% CI -3·62 to -0·69; p=0·0040). 25 patients (seven taking placebo and 18 taking idalopirdine) discontinued treatment because of adverse events, the difference between groups being mainly due to asymptomatic transient increases in transaminase concentrations in some idalopirdine-treated patients. The most common adverse events (occurring in >3% of patients) were increased γ-glutamyltransferase (14 [10%] patients in the idalopirdine group vs two [2%] in the placebo group), diarrhoea (six [4%] vs nine [7%]), urinary tract infection (three [2%] vs nine [7%]), fall (three [2%] vs eight [6%]), increased alanine aminotransferase (nine [6%] vs none), and benign prostatic hyperplasia (two [5%] vs none). Serious adverse events were reported by 14 (10%) patients in the idalopirdine group and 13 (10%) patients in the placebo group. One death occurred in each treatment group, neither were regarded as being related to treatment. Interpretation Idalopirdine improved cognitive function in donepezil-treated patients with moderate Alzheimer's disease. Larger studies in a broader population of patients are ongoing to substantiate the effects reported here. Funding H Lundbeck A/S.

A double-blind randomized comparison of meal-related glycemic control by repaglinide and glyburide in well-controlled type 2 diabetic patients. P Damsbo , P Clauson , T C Marbury and K Windfeld Novo Nordisk, Copenhagen, Denmark. Abstract OBJECTIVE: This study was designed to compare diurnal blood glucose excursions and the effects of accidental dietary noncompliance in type 2 diabetic patients who are well-controlled on either repaglinide or glyburide treatment. RESEARCH DESIGN AND METHODS: This single-center double-blind randomized study comprised type 2 diabetic patients whose mean fasting blood glucose value after repaglinide/glyburide titration and stabilization was in the range of 90-140 mg/dl. The study consisted of an initial screening day, a titration period of 3 weeks, a 1-week stabilization period, a study period, and an end-of-study day. During the 3-day study period, half the patients of each group received two meals on the first day and three meals on the next 2 days, and in the other half, this sequence was reversed. Repaglinide was administered preprandially with each meal, and glyburide was administered as recommended in current labeling, i.e., either one or two daily doses before breakfast and dinner, regardless of whether lunch had been omitted. The diurnal blood glucose excursions on a day in which three meals were eaten were compared between the two groups, and the minimum blood glucose concentration (BGmin) measurements were compared between lunch and dinner on days with three and two meals. RESULTS: Of the 83 randomized patients, 43 entered into the 3-day study period and completed the trial. The results showed no significant differences between the repaglinide and glyburide groups in average blood glucose excursions from fasting blood glucose (P = 0.44). The influence on the mean BGmin of omitting a meal differed significantly between the repaglinide and glyburide groups (P = 0.014). In the latter group, BGmin decreased from 77 to 61 mg/dl as a result of omitting lunch, whereas in the repaglinide group, BGmin was unchanged for the two-meal day (78 mg/dl) and the three-meal day (76 mg/dl). All hypoglycemic events (n = 6) occurred in the glyburide group on the two-meal day, in connection with omitting lunch. No hypoglycemic events were recorded in the repaglinide group. CONCLUSIONS: These results suggest that treatment with repaglinide in well-controlled type 2 diabetic patients who miss or delay a meal is superior to treatment with longer-acting sulfonylurea drugs (such as glyburide) with respect to the risk of hypoglycemic episodes.