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© 2017 Elsevier Ltd. 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 × ULN and 2·0-5·0 × 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 × ULN, and at month 7, month 9, or month 12 if the mUFC concentration was greater than 1·0 × 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. Funding: Novartis Pharma AG.

Incidentally discovered adrenal masses are mostly benign, asymptomatic lesions, often arbitrarily considered as nonfunctioning tumors. Recent studies, however, have reported increasing evidence that subtle cortisol production and abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are more frequent than previously thought. The purpose of this study was to investigate the clinical and hormonal features of patients with incidentally discovered adrenal adenomas, in relation to their clinical outcome. Fifty consecutive patients with incidentally detected adrenal adenomas, selected from a total of 65 cases of adrenal incidentalomas, were prospectively evaluated. All of them underwent abdominal computed tomography scan and hormonal assays of the HPA axis function: circadian rhythm of plasma cortisol and ACTH, urinary cortisol excretion, 17-hydroxyprogesterone, androgens, corticotropin stimulation test and low-dose (2 mg) dexamethasone test. The patients were reevaluated at regular intervals (6, 12, and 24 months) for a median period of 38 months. Subtle hypercortisolism, defined as abnormal response to at least 2 standard tests of the HPA axis function in the absence of clinical signs of Cushing's syndrome (CS), was defined as subclinical CS. Mild-to-severe hypertension was found in 24 of 50 (48%) patients, type-2 diabetes in 12 of 50 (24%), and glucose intolerance in 6 of 50 (12%) patients. Moreover, 18 of 50 patients (36%) were diffusely obese (body mass index, determined as weight/height2, > 25), and 14 patients (28%) had serum lipid concentration abnormalities (cholesterol > or = 6.21 mmol/L, low-density lipoprotein cholesterol > or = 4.14 mmol/L and/or triglycerides > or = 1.8 mmol/L). Compared with a healthy population, bone mineral density Z-score, determined by the DEXA technique, tended to be slightly (but not significantly) lower in patients with adrenal adenoma (-0.41 SD). Endocrine data were compared with 107 sex- and age-matched controls, and patients with adenomas were found to have heterogeneous hormonal abnormalities. In particular, significantly higher serum cortisol values (P < 0.001), lower ACTH concentration (P < 0.05), and impaired cortisol suppression by dexamethasone (P < 0.001) were observed. Moreover, in patients with adenomas, cortisol, 17-OH progesterone, and androstenedione responses to corticotropin were significantly increased (P < 0.001, all), whereas dehydroepiandrosterone sulfate levels were significantly lower at baseline, with blunted response to corticotropin (P < 0.001, both). However, the criteria for subclinical CS were met by 12 of 50 (24%) patients. Of these, 6 (50%) were diffusely obese, 11 (91.6%) had mild-to-severe hypertension, 5 (41.6%) had type-2 diabetes mellitus, and 6 (50%) had abnormal serum lipids. The clinical and hormonal features improved in all patients treated by adrenalectomy, but seemed unchanged in all those who did not undergo surgery (follow-up, 9 to 73 months), except for one, who was previously found as having nonfunctioning adenoma and then revealed to have subclinical CS. In conclusion, an unexpectedly high prevalence of subtle autonomous cortisol secretion, associated with high occurrence of hypertension, diabetes mellitus, elevated lipids, and diffuse obesity, was found in incidentally discovered adrenal adenomas. Although the pathological entity of a subclinical hypercortisolism state remained mostly stable in time during follow-up, hypertension, metabolic disorders, and hormonal abnormalities improved in all patients treated by adrenalectomy. These findings support the hypothesis that clinically silent hypercortisolism is probably not completely asymptomatic.

BACKGROUND: Ovarian failure is a frequent complication occurring after haematopoietic stem cell transplantion (SCT), which is generally ascribed to radiation treatment and antiblastic alkylating agents. METHODS: Ovarian morphology and function were studied in reproductive age women 12-24 months after allogeneic SCT (n = 23) received from an HLA identical sibling, or autologous SCT (n = 22). Thirteen allo-transplanted women were suffering from chronic graft-versus-host disease (cGVHD). RESULTS: Menstrual cycles recovered in two and four women in the allo- and auto-SCT groups respectively, being associated with younger age and longer period elapsed from transplant. There was no difference in previous use of alkylating agents between allo- and auto-transplantation, while corticosteroid treatment was longer and more recent in the allo-SCT group. Significantly higher gonadotrophin levels and lower estradiol were seen in the combined group of patients than in controls. In allo-transplanted women, androgens were also significantly lower than in controls. Ovarian and uterine volumes were lower in patients than in controls, and in the allo- than in the auto-transplanted women. Within the allo-SCT group, endocrine function and ovarian and uterine volumes were significantly lower in the patients suffering from cGVHD. CONCLUSIONS: Ovarian failure in SCT recipients is likely to be caused principally by myelo-ablative treatments, but the condition of gonadal and androgen insufficiency can be worsened by an altered immunomodulation in allogeneic setting.

Background\ud \ud Cushing's disease is a rare endocrine disorder characterised by cortisol overproduction with severe complications. Therapies for cortisol reduction are often necessary. Here we report the outcomes from the pivotal phase III study of osilodrostat (a potent oral inhibitor of cytochrome P450 11B1, mitochondrial [11β-hydroxylase]; Novartis Pharma AG, Basel, Switzerland) in patients with Cushing's disease.\ud \ud \ud \ud Methods\ud \ud LINC 3 was a prospective, multicentre, open-label, phase III study with a double-blind randomised withdrawal period, that comprised four periods. Patients aged 18–75 years, with confirmed persistent or recurrent Cushing's disease (defined as mean 24-h urinary free cortisol [UFC] concentration >1·5 times the upper limit of normal [ULN] and morning plasma adrenocorticotropic hormone above the lower limit of normal) who had previously had pituitary surgery or irradiation, or were newly diagnosed and who refused surgery or were not surgical candidates, were recruited from 66 hospital sites and private clinical practices in 19 countries. In period 1, open-label osilodrostat was initiated in all participants and adjusted every 2 weeks (1–30 mg twice daily; film-coated tablets for oral administration) on the basis of mean 24-h UFC concentration and safety until week 12. In period 2, weeks 13–24, osilodrostat was continued at the therapeutic dose determined during period 1. In period 3, beginning at week 26, participants who had a mean 24-h UFC concentration of less than or equal to the ULN at week 24, without up-titration after week 12, were randomly assigned (1:1), via an interactive-response technology, stratified by osilodrostat dose at week 24 and history of pituitary irradiation, to continue osilodrostat or switch to placebo for 8 weeks. Participants and investigators were masked to treatment assignment. Ineligible participants continued open-label osilodrostat. In period 4, weeks 35–48, all participants were given open-label osilodrostat until core-study end. The primary objective was to compare the efficacy of osilodrostat versus placebo at the end of period 3. The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (ie, mean 24-h UFC concentration of ≤ULN) at the end of the randomised withdrawal period (week 34), without up-titration during this period. The key secondary endpoint was the proportion of participants with a complete response at the end of the single-arm, open-label period (ie, period 2, week 24) without up-titration during weeks 13–24. Analysis was by intention-to-treat for all patients who received at least one dose of osilodrostat (full analysis set; key secondary endpoint) or randomised treatment (randomised analysis set; primary endpoint) and safety was assessed in all enrolled patients who received at least one dose of osilodrostat and had at least one post-baseline safety assessment. LINC 3 is registered with ClinicalTrials.gov, NCT02180217, and is now complete.\ud \ud \ud \ud Findings\ud \ud Between Nov 12, 2014, and March 22, 2017, 202 patients were screened and 137 were enrolled. The median age was 40·0 years (31·0–49·0) and 106 (77%) participants were female. 72 (53%) participants were eligible for randomisation during the withdrawal phase, of whom 36 were assigned to continue osilodrostat and 35 were assigned to placebo; one patient was not randomly assigned due to investigator decision and continued open-label osilodrostat. More patients maintained a complete response with osilodrostat versus with placebo at week 34 (31 [86%] vs ten [29%]; odds ratio 13·7 [95% CI 3·7–53·4]; p25% of participants) were nausea (57 [42%]), headache (46 [34%]), fatigue (39 [28%]), and adrenal insufficiency (38 [28%]). Hypocortisolism occurred in 70 (51%) patients and adverse events related to adrenal hormone precursors occurred in 58 (42%) patients. One patient died, unrelated to study drug, after the core study phase.\ud \ud \ud \ud Interpretation\ud \ud Twice-daily osilodrostat rapidly reduced mean 24-h UFC and sustained this reduction alongside improvements in clinical signs of hypercortisolism; it was also generally well tolerated. Osilodrostat is an effective new treatment option that is approved in Europe for the treatment of endogenous Cushing's syndrome and in the USA for Cushing's disease.

Purpose Clinical trials have demonstrated the favorable efficacy/safety profile of pasireotide in patients with Cushing’s disease (CD). We report interim long-term results of an ongoing real-world evidence study of subcutaneous pasireotide in patients with CD. Methods Adults with CD receiving pasireotide, initiated before (prior-use) or at study entry (new-use), were monitored for ≤ 3 years during a multicenter observational study (http://clinicaltrials.gov identifier NCT02310269). Primary objective was to assess long-term safety of pasireotide alone or with other CD therapies. Results At the time of this interim analysis, 127 patients had received pasireotide (new-use, n = 31; prior-use, n = 96). Eight patients had completed the 3-year observation period, 53 were ongoing, and 66 had discontinued. Among 31 new-use and 92 prior-use patients with ≥ 1 safety assessment, respectively: 24 (77%) and 37 (40%) had drug-related adverse events (AEs); 7 (23%) and 10 (11%) had serious drug-related AEs. Most common drug-related AEs were nausea (14%), hyperglycemia (11%) and diarrhea (11%); these were more frequently reported in new users and mostly of mild-to-moderate severity. 14 (45%) new-use and 15 (16%) prior-use patients experienced hyperglycemia-related AEs. Mean urinary free cortisol (mUFC) was within normal range at baseline and months 1, 12 and 24, respectively, in: 1/16 (6%), 9/18 (50%), 1/3 (33%) and 0/0 new users; 28/43 (65%), 15/27 (56%), 27/33 (82%) and 12/19 (63%) prior users. Conclusions Pasireotide is well tolerated and provides sustained reductions in mUFC during real-world treatment of CD. The lower rate of hyperglycemia-related AEs in prior users suggests that hyperglycemia tends not to deteriorate if effectively managed soon after onset. Clinical Trial Registration Number: NCT02310269.

Objective Monitoring of patients with Cushing’s disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing’s disease. Design Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing’s disease (clinicaltrials.gov: NCT01374906). Methods Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time. Results At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman’s correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN. Conclusion mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing’s disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.

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 mgevery 4 weeks for 12 months (in the core phase). We stratified randomisation by screening mUFC concentration (1·5 to

Objective Baseline characteristics of the population enrolled in the ISSO study, designed to evaluate the incidence of vertebral and non-vertebral fractures in Italian patients with severe osteoporosis treated according to clinical practice over 24 months observation. Methods Prospective observational study in 783 post-menopausal women and men entering 18-month treatment with teriparatide in a community setting at 57 centres in Italy. Characterisation included demographics, fracture risk factors, hone mineral density, fracture status, Health-Related Quality of Life (HRQoL) measured by the European Quality of Life Questionnaire, EQ-5D, and back pain assessed by VAS. Results Most patients were elderly women (90.5%), mean age +/- SD was 72.9 +/- 8.8 years. Nearly all (91.3%) had experienced >= 1 vertebral fracture (mean +/- SD, 3.6 +/- 2.2 per patient), 37.5% had >= 1 non-vertebral fracture (mean +/- SD, 1.4 +/- 0.7 per patient). Nearly all patients were suffering from back pain (94.9%), which had significantly restricted their daily activities (51.7%) and had likely or very likely been caused by vertebral fractures (29.2% and 55.8%, respectively). Mean EuroQoL EQ-5D index value was 0.58 +/- 0.25 and VAS score 49.2 +/- 23.6. Non-vertebral fractures, back pain and multiple vertebral fractures were associated with lower HRQoL (EuroQoL-5D Index both p

Subclinical Cushing's syndrome (SCS) is increasingly being reported in incidentally discovered adrenal adenomas; its hallmark is mild autonomous cortisol hyperproduction without specific clinical signs of cortisol excess. Increased prevalence of hypertension, obesity, and impaired glucose tolerance have been described in SCS, but there is no specific study of the risk factors for cardiovascular diseases. In this cross-sectional study we assessed the cardiovascular profile in 28 consecutive SCS patients (19 women and 9 men; aged 56 +/- 10.6 yr) compared with 100 controls matched for age, gender, and body mass index. Systolic (P < 0.001) and diastolic (P < 0.005) blood pressures were higher in patients, as were fasting glucose, insulin, total cholesterol, triglycerides (all P < 0.001), and fibrinogen (P < 0.05). Moreover, the insulin resistance index was increased in patients as was the waist to hip ratio and mean carotid artery intima-media thickness (all P < 0.001). Of the patients, 60.7% had arterial hypertension, 71.4% had lipid abnormalities, 28.6% had impaired glucose tolerance, 35.7% type 2 diabetes mellitus, and 53.6% had abnormalities in hemostatic parameters. Atherosclerotic plaques were more frequent in patients (P < 0.0001). Only 4 (14.3%) patients did not have multiple risk factors for cardiovascular events. Six (21.3%) had clinical evidence of cardiovascular disease; another 11 (39.3%) had cardiovascular abnormalities as revealed by ultrasound scanning of carotid arteries and/or electrocardiogram records. These results strongly suggest that an increased cardiovascular risk profile, similar to that described in overt Cushing's syndrome, is present in SCS subjects. This finding supports the concept that chronic mild endogenous cortisol excess may have important systemic effects on the human body.