Background Cushing's disease is a rare debilitating endocrine disorder for which few prospective interventional studies have been done. We report results of the first phase 3 trial assessing long-acting intramuscular pasireotide in patients with Cushing's disease. Methods In this phase 3 clinical trial we recruited patients aged 18 years or older with persistent, recurrent, or de-novo (non-surgical candidates) Cushing's disease who had a mean urinary free cortisol (mUFC) concentration (from three 24 h samples) of 1.5-5.0 times the upper limit of normal (ULN), a normal or greater than normal morning plasma adrenocorticotropic hormone concentration, and a pituitary source of Cushing's syndrome, from 57 sites across 19 countries. Exclusion criteria included previous pasireotide treatment, mitotane therapy within 6 months, and pituitary irradiation within 10 years. We randomly allocated patients 1: 1 (block size of four) using an interactive-response-technology system to intramuscular pasireotide 10 mg or 30 mg every 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1.5 to < 2.0 x ULN and 2.0-5.0 x ULN). The dose could be uptitrated (from 10 mg to 30 mg or from 30 mg to 40 mg) at month 4 if the mUFC concentration was greater than 1.5 x ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1.0 x ULN. Investigators, patients, site personnel, and those assessing outcomes were masked to dose group allocation. The primary endpoint was the proportion of patients in each group with an mUFC concentration of less than or equal to the ULN at month 7. Efficacy analyses were based on intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01374906. Findings Between Dec 28, 2011, and Dec 9, 2014, we randomly allocated 150 patients to receive pasireotide 10 mg (74 [49%] patients) or 30 mg (76 [51%] patients). The primary efficacy endpoint was met by 31 (41.9% [95% CI 30.5-53.9]) of 74 patients in the 10 mg group and 31 (40.8% [29.7-52.7]) of 76 in the 30 mg group. The most common adverse events were hyperglycaemia (36 [49%] in the 10 mg group and 36 [47%] in the 30 mg group), diarrhoea (26 [35%] and 33 [43%]), cholelithiasis (15 [20%] and 34 [45%]), diabetes mellitus (14 [19%] and 18 [24%]), and nausea (15 [20%] and 16 [21%]). Serious adverse events suspected to be study drug related were reported in eight (11%) patients in the 10 mg group and four (5%) in the 30 mg group. Two (3%) patients in the 30 mg group died during the study (pulmonary artery thrombosis and cardiorespiratory failure); neither death was judged to be related to the study drug. Interpretation Long-acting pasireotide normalised mUFC concentration in about 40% of patients with Cushing's disease at month 7 and had a similar safety profile to that of twice-daily subcutaneous pasireotide. Long-acting pasireotide is an efficacious treatment option for some patients with Cushing's disease who have persistent or recurrent disease after initial surgery or are not surgical candidates, and provides a convenient monthly administration schedule.
Background Glucokinase acts as a glucose sensor in the pancreas and a glucose processor in the liver, and has a central role in glucose homoeostasis. Dorzagliatin is a new, dual-acting, allosteric glucokinase activator that targets both pancreatic and hepatic glucokinases. Dorzagliatin has good pharmacokinetic and pharmacodynamic properties in humans, and provides effective 24-h glycaemic control and improves glucose sensitivity in patients with type 2 diabetes. We aimed to assess the efficacy and safety of dorzagliatin monotherapy at different doses in Chinese patients with type 2 diabetes. Methods In this multicentre, randomised, double-blind, placebo-controlled, phase 2 study, we randomly assigned (1:1:1:1:1) patients to receive oral placebo or one of four doses of oral dorzagliatin (75 mg once a day, 100 mg once a day, 50 mg twice a day, or 75 mg twice a day) using permuted-block randomisation, with a block size of ten and without stratification. Eligible patients were men or non-fertile women (aged 40-75 years) with type 2 diabetes who had a BMI of 19.0-30.0 kg/m(2), were on a diet and exercise regimen, and were previously untreated or treated with metformin or a-glucosidase inhibitor monotherapy. The study started with a 4-week placebo run-in period followed by a 12-week treatment period. The primary endpoint was the change in HbA(1c) from baseline to week 12, which was assessed in all patients who received at least one dose of study drug and had both baseline and at least one post-baseline HbA(1c) value. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02561338. Findings Between Sept 29, 2015, and Aug 17, 2016, we randomly assigned 258 patients to one of the five study groups. At the end of 12 weeks, the least squares mean change in Hb(1c) from baseline was -0.35% (95% CI -0.60 to -0.10) in the placebo group, -0.39% (-0.64 to -0.14) in the 75 mg once daily group, -0.65% (-0.92 to -0.38) in the 100 mg once daily group, -0.79% (-1.06 to -0.52) in the 50 mg twice daily group, and -1.12% (-1.39 to -0.86) in the 75 mg twice daily group. Compared with the placebo group, the change in HbA(1c) between baseline and 12 weeks was significant in the 50 mg twice daily (p=0.0104) and the 75 mg twice daily (p<0.0001) groups. The number of adverse events was similar between the treatment groups and the placebo group. There were no reports of drug-related serious adverse events or severe hypoglycaemia. Interpretation Dorzagliatin had a beneficial effect on glycaemic control and was safe and well tolerated over 12 weeks in Chinese patients with type 2 diabetes. Copyright (C) 2018 Elsevier Ltd. All rights reserved.