18 research outputs found
Late-night salivary cortisol may be valuable for assessing treatment response in patients with Cushingâs disease: 12-month, Phase III pasireotide study
Measuring salivary cortisol is a simple, convenient
and accurate technique with potential value in monitoring
patients with hypercortisolism. This analysis reports
changes in late-night salivary cortisol (LNSC) during a
12-month, multicentre, Phase III study of patients with
Cushingâs disease who were randomized to pasireotide 600
or 900 lg sc bid. LNSC assessment was an exploratory
objective based on a single, optional measurement at
midnight ± 1 h on the same day as one of the 24-h urinary
free cortisol (UFC) measurements. Of 162 enrolled
patients, baseline LNSC was measured in 93. Sixty-seven
patients had levels above the upper limit of normal (ULN);
median baseline levels were 19.7 and 20.7 nmol/L in the
groups subsequently randomized to 600 lg (n = 40) and
900 lg (n = 27), respectively. Median LNSC levels
decreased from baseline to month 12; median changes in
patients who had baseline LNSC [ULN in the 600 and
900 lg groups were -13.4 nmol/L (â52.6 %; n = 19) and
-11.8 nmol/L (â56.1 %; n = 14), respectively. LNSC
normalized at months 6 and 12 in 25/67 (37.3 %) and 13/67
(19.4 %) patients, respectively; 10/25 and 8/13 patients
also had normalized UFC, and 7/25 and 4/13 had partial
UFC control (UFC [ULN and C50 % decrease from
baseline). There was a moderate correlation (r = 0.55) on
the log scale between individual patient LNSC and UFC
values when all time points were pooled. Pasireotide
decreased LNSC levels during 12 months of treatment.
Salivary cortisol may be a simple, convenient biomarker
for assessing treatment response in patients with Cushingâs disease
Use of late-night salivary cortisol to monitor response to medical treatment in Cushingâs disease
Objective
Monitoring of patients with Cushingâs 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 Cushingâs disease.
Design
Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushingâs 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 (nâ=â92), 17.4% had both mLNSC â€ULN and mUFC â€ULN; 22.8% had mLNSC â€ULN, and 45.7% had mUFC â€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 (Spearmanâs correlation: Ïâ=â0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC â€ULN and mUFC â€ULN.
Conclusion
mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushingâs disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled
Longâterm efficacy and safety of onceâmonthly pasireotide in Cushing's disease: A Phase III extension study
Objectives
Many patients with Cushing's disease (CD) require chronic pharmacotherapy to control their hypercortisolism. We evaluated the efficacy and safety of longâacting pasireotide during a longâterm extension study in patients with CD.
Design
Openâlabel extension to a 12âmonth Phase III study of longâacting pasireotide in CD (N = 150; NCT01374906).
Patients
Patients with mean urinary free cortisol (mUFC) †upper limit of normal (ULN) or receiving clinical benefit at core study end could continue longâacting pasireotide during the extension.
Results
Eightyâone of 150 (54.0%) enrolled patients entered the extension. Median overall exposure to pasireotide at study end was 23.9 months; 39/81 (48.1%) patients completed the extension (received â„ 12 monthsâ treatment during the extension and could transit to a separate pasireotide safety study). mUFC was â€ULN in 42/81 (51.9%), 13/81 (16.0%) and 43/81 (53.1%) patients at extension baseline, month (M) 36 and last assessment. Median mUFC remained within normal limits. Median lateânight salivary cortisol was 2.6 Ă ULN at core baseline and 1.3 Ă ULN at M36. Clinical improvements were sustained over time. Fortyâtwo (51.9%) patients discontinued during the extension: 25 (30.9%) before M24 and 17 (21.0%) after M24. Hyperglycaemiaârelated AEs occurred in 39.5% of patients. Mean fasting glucose (FPG) and glycated haemoglobin (HbA1c) were stable during the extension, with antidiabetic medication initiated/escalated in some patients. Sixtyâsix (81.5%) and 71 (88.9%) patients were classified as having diabetes (HbA1c â„ 6.5%, FPG â„ 7.0 mmol/L, antidiabetic medication use, or history of diabetes) at extension baseline and last assessment.
Conclusions
Longâacting pasireotide provided sustained biochemical and clinical improvements, with no new safety signals emerging, supporting its use as an effective longâterm therapy for CD
Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing's disease: results from a Phase III study
Objective
Signs and symptoms of Cushing\u27s disease are associated with high burden of illness. In this analysis, we evaluated the effect of pasireotide treatment on signs and symptoms in patients with Cushing\u27s disease.
Design
Phase III study with double-blind randomization of two pasireotide doses.
Methods
Patients (n = 162) with persistent/recurrent or de novo Cushing\u27s disease and urinary free cortisol (UFC) levels â„1·5Ă upper limit of normal (ULN) were randomized to receive subcutaneous pasireotide (600/900 Όg bid). At month 3, patients with UFC â€2 Ă ULN and not exceeding the baseline value continued their randomized dose; all others received 300 Όg bid uptitration. At month 6, patients could enter an open-label phase until month 12 with a maximal dose of 1200 Όg bid. Changes in signs and symptoms of hypercortisolism over 12 months\u27 treatment in patients still enroled in the study and with evaluable measurements were assessed in relation to degree of UFC control.
Results
Reductions in blood pressure were observed even without full UFC control and were greatest in patients who did not receive antihypertensive medications during the study. Significant reductions in total cholesterol and low-density lipoprotein (LDL)-cholesterol were observed in patients who achieved UFC control. Reductions in BMI, weight and waist circumference occurred during the study even without full UFC control. Adverse effects were typical of somatostatin analogues except for hyperglycaemia-related events, which were experienced by 72·8% of patients.
Conclusions
In the largest Phase III study of medical therapy in Cushing\u27s disease, significant improvements in signs and symptoms were seen during 12Â months of pasireotide treatment, as UFC levels decreased
Hypertension in Acromegaly in Relationship to Biochemical Control and Mortality: Global ACROSTUDY Outcomes
Context: Hypertension is a major cardiovascular risk factor related to increased mortality in acromegaly. Surgical cure of acromegaly is associated with improvement in blood pressure levels, however little is known about the effect of pegvisomant (PEGV) treatment in patients with hypertension. This analysis evaluates outcomes in patients with hypertension and acromegaly included in ACROSTUDY. Methods: ACROSTUDY is a global non-interventional surveillance study of long-term treatment with PEGV, monitoring its safety and efficacy. The cohort was retrospectively divided in two subgroups: patients with and without hypertension. Stepwise logistic regression and Kaplan-Meyer analyses were performed for testing predictors of mortality. Results: The tota
Long-term outcomes of osilodrostat in Cushingâs disease: LINC 3 study extension
Objective
To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11ÎČ-hydroxylase inhibitor, for treating Cushingâs disease (CD).
Design/methods
A total of 137 adults with CD and mean 24-h urinary free cortisol (mUFC) >â1.5âĂ upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received â„â72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from the core study baseline.
Results
Median osilodrostat exposure from the core study baseline to study end was 130 weeks (range 1â245) and median average dose was 7.4 mg/day (range 0.8â46.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained â€âULN. Of 106 patients, 86 (81%) patients who entered the extension had mUFC â€âULN at week 72. Improvements in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15/137 (10.9%) and 12/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension.
Conclusions
Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated
Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushingâs syndrome
Purpose: The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushingâs syndrome (CS) and baseline mean urinary free cortisol (mUFC) â„ 1.5Ă ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. Methods: Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). Results: Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; â â 1.9; P < 0.0001), end of Month 1 for acne (mean baseline score, 2.8; â â 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; â â 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; â + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; â â 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. Conclusions: Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551
GH safety workshop position paper: A critical appraisal of recombinant human GH therapy in children and adults
Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-Term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-Term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement
Growth Hormone Research Society perspective on biomarkers of GH action in children and adults
Objective
The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly.
Participants
GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry.
Evidence
Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs.
Consensus process
Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process.
Conclusions
The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly