Pregnancy outcomes in women receiving growth hormone replacement therapy enrolled in the NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program.

PURPOSE: Data on the safety of growth hormone (GH) replacement therapy during pregnancy are limited. We report a combined analysis of data from pregnant women treated with GH while enrolled in two non-interventional, multicenter studies: NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program. METHODS: Pregnancy data were pooled from NordiNet® IOS and the ANSWER Program. Data were collected during routine clinic visits by participating physicians using a web-based system. Patients exposed to GH replacement therapy during pregnancy were included in the analysis. RESULTS: The study population included 40 female patients with typical causes of adult GH deficiency (GHD). Overall, there were 54 pregnancies. Of these, 47 were exposed to GH between conception and delivery. In 48.9% of pregnancies exposed to GH, the dose was > 0.6 mg/day. GH was continued past conception and then stopped during the first, second, and third trimester, in 27.7%, 17.0%, and 2.1% of pregnancies, respectively. In 29.8%, GH was continued throughout pregnancy, with an unchanged dose in most cases. Of the 47 GH-exposed pregnancies, 37 (78.7%) progressed to normal delivery. There were three adverse events reported in two pregnancies. CONCLUSION: These real-world data suggest that there were no new safety signals related to GH exposure in women with GHD during pregnancy. These results are consistent with findings from previous studies reporting data in pregnancies exposed to GH at conception or throughout pregnancy. This observational study in additional pregnancies provides further evidence that GH exposure does not adversely affect pregnancy outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00960128 (date of registration: August 13, 2009) and NCT01009905 (date of registration: November 5, 2009).

An evaluation of the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ) in adult patients with acromegaly, including correlations with other patient-reported outcome measures: data from two large multicenter international studies.

PURPOSE: The Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ) is a new patient-reported outcome (PRO) measure for patients with acromegaly receiving injectable somatostatin analogs (SSAs) to assess clinical symptoms and adverse drug reaction interference, treatment satisfaction, and convenience. We evaluated its scale structure, reliability, validity, responsiveness, and what constitutes clinically meaningful change. METHODS: Data from two longitudinal studies (N = 79 and 82) of patients receiving a stable injectable SSA dose for ≥ 6 months who completed the Acro-TSQ and other collateral measures (e.g., AcroQoL, AIS, WPAI:SHP, EQ-5D-5L) were analyzed. RESULTS: The first study demonstrated internal consistency of the Acro-TSQ. However, several items had high ceiling effects, responsiveness could not be established, and the minimally important difference (MID) was not estimable. In the second study, factor analysis revealed six scales: Symptom Interference, Treatment Convenience, Injection Site Interference, GI Interference, Treatment Satisfaction, and Emotional Reaction. Internal consistency and test-retest reliability were confirmed; most scales demonstrated significant differences in mean scores by disease severity. Correlations between Acro-TSQ scales and other collateral measures exceeded 0.30 in absolute value, confirming convergent validity. Responsiveness in Acro-TSQ scale scores reflected improved disease control. The MID was estimated for Symptom Interference (10-12 points), Treatment Convenience (9-11) and GI Interference (8-10). CONCLUSIONS: The Acro-TSQ is a brief, yet comprehensive tool to monitor important outcomes associated with injectable acromegaly SSA treatments. Its content reflects both disease and treatment burden as well as patient satisfaction, and its relevant for use in clinical studies.

Development of a novel patient-reported measure for acromegaly: the Acro-TSQ.

PURPOSE: Somatostatin analogs (SSAs) represent a mainstay of medical treatment for acromegaly, currently available as either intramuscular or deep subcutaneous injections. Patient-reported outcomes (PROs) are increasingly common as relevant outcomes in studies of acromegaly and its treatment, but there are no validated PRO measures available that focus on the disease burden and the impact of treatment, specifically designed for use in patients with acromegaly. We sought to develop a new and unique PRO measure, the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ). METHODS: Concept elicitation (CE) interviews were conducted with acromegaly patients in the United States receiving SSA injections at a stable dose for ≥ 6 months. A questionnaire was drafted based on these interviews; combined CE and cognitive debriefing (CE/CD) interviews were then conducted to confirm the content, clarity, and relevance of the questionnaire. RESULTS: Nineteen subjects completed interviews [n = 9 CE, n = 10 CE/CD; n = 15 Lanreotide Depot/Autogel (Somatuline), n = 4 Octreotide LAR (Sandostatin LAR)]. Most subjects responded positively when asked about the effectiveness of their current treatment; however, breakthrough symptoms, injection site reactions, and side effects were commonly reported and had negative impacts on social and emotional well-being and daily activities. All 10 subjects involved in debriefing interviews found the questionnaire to be relevant, easy to complete, and found the response options to be clear. The resulting 26-item Acro-TSQ covers symptoms and symptom control, gastrointestinal side effects and their impact on daily activities, the emotional impact of treatment, convenience and ease of use, and overall satisfaction. CONCLUSIONS: The Acro-TSQ is a novel PRO, focused on both disease burden and impact of treatment; it was found to be comprehensive, clear, and relevant for patients with acromegaly receiving injectable SSA treatment.

A multicenter, observational study of lanreotide depot/autogel (LAN) in patients with acromegaly in the United States: 2-year experience from the SODA registry.

PURPOSE: This analysis evaluates the 2-year effectiveness and safety of lanreotide depot/autogel (LAN), as well as treatment convenience and acromegaly symptom relief, from the Somatuline® Depot for Acromegaly (SODA) registry, a post-marketing, open-label, observational, multicenter, United States registry study. METHODS: Patients with acromegaly treated with LAN were eligible for enrollment. Demographics, LAN dose, extended dosing interval (EDI) (interval of injections ≥42 days), insulin-like growth factor 1 (IGF-1), growth hormone (GH), glycated hemoglobin, adverse events (AEs), injection convenience, and symptom data were collected. RESULTS: As of September 29, 2014, 241 patients were enrolled in SODA. IGF-1 levels below age- and gender-adjusted upper normal limit (ULN) were achieved in 71.2% at month (M) 12 and 74.4% at M24; GH ≤2.5 µg/L in 83.3% at M12 and 80.0% at M24; GH <1.0 µg/L in 61.7% at M12 and 61.4% at M24. Both IGF-1 < ULN and GH ≤2.5 µg/L were achieved in 65.0% at M12 and 54.8% at M24; both IGF-1 < ULN and GH < 1.0 µg/L were achieved in 51.7 and 42.9% at M12 and M24, respectively. EDI regimen was 5.0% at baseline and 12.0% at M24. At M24, acromegaly symptoms appeared stable or improved. The most common AE was arthralgia (25.7%). Among 106 serious AEs reported by 42 patients, 10 were deemed related to therapy in 9 patients. At M24, 73.1% of patients rated LAN as convenient. CONCLUSIONS: SODA indicates 2-year biochemical control with majority of patients achieving both IGF-1 < ULN and GH ≤2.5 µg/L. LAN was generally well tolerated with no new or unexpected safety signals reported during the observation period. clinicaltrials.gov Clinical Trial Identifier: NCT00686348.

Follow-up intervals in patients with Cushing's disease: recommendations from a panel of experienced pituitary clinicians.

PURPOSE: Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes for patients with Cushing's disease (CD). The purpose of this study was to assess agreement by experts on recommended follow-up intervals for CD patients at different phases in their treatment course. METHODS: The RAND/UCLA modified Delphi process was used to assess expert consensus. Eleven clinicians who regularly manage CD patients rated 79 hypothetical patient scenarios before and after ("second round") an in-person panel discussion to clarify definitions. Scenarios described CD patients at various time points after treatment. For each scenario, panelists recommended follow-up intervals in weeks. Panel consensus was assigned as follows: "agreement" if no more than two responses were outside a 2 week window around the median response; "disagreement" if more than two responses were outside a 2 week window around the median response. Recommendations were developed based on second round results. RESULTS: Panel agreement was 65.9% before and 88.6% after the in-person discussion. The panel recommended follow-up within 8 weeks for patients in remission on glucocorticoid replacement and within 1 year of surgery; within 4 weeks for patients with uncontrolled persistent or recurrent disease; within 8-24 weeks in post-radiotherapy patients controlled on medical therapy; and within 24 weeks in asymptomatic patients with stable plasma ACTH concentrations after bilateral adrenalectomy. CONCLUSIONS: With a high level of consensus using the Delphi process, panelists recommended regular follow-up in most patient scenarios for this chronic condition. These recommendations may be useful for assessment of CD care both in research and clinical practice.

BIOCHEMICAL CONTROL DURING LONG-TERM FOLLOW-UP OF 230 ADULT PATIENTS WITH CUSHING DISEASE: A MULTICENTER RETROSPECTIVE STUDY.

OBJECTIVE: Cushing disease (CD) results from excessive exposure to glucocorticoids caused by an adrenocorticotropic hormone-secreting pituitary tumor. Inadequately treated CD is associated with significant morbidity and elevated mortality. Multicenter data on CD patients treated in routine clinical practice are needed to assess treatment outcomes in this rare disorder. The study purpose was to describe the burden of illness and treatment outcomes for CD patients. METHODS: Eight pituitary centers in four U.S. regions participated in this multicenter retrospective chart review study. Subjects were CD patients diagnosed at ≥18 years of age within the past 20 years. Descriptive statistical analyses were conducted to examine presenting signs, symptoms, comorbidities, and treatment outcomes. RESULTS: Of 230 patients, 79% were female (median age at diagnosis, 39 years; range, 18 to 78 years). Length of follow-up was 0 to 27.5 years (median, 1.9 years). Pituitary adenomas were 0 to 51 mm. The most common presenting comorbidities included hypertension (67.3%), polycystic ovary syndrome (43.5%), and hyperlipidemia (41.5%). Biochemical control was achieved with initial pituitary surgery in 41.4% patients (91 of 220), not achieved in 50.0% of patients (110 of 220), and undetermined in 8.6% of patients (19 of 220). At the end of follow-up, control had been achieved with a variety of treatment methods in 49.1% of patients (110 of 224), not achieved in 29.9% of patients (67 of 224), and undetermined in 21.0% of patients (47 of 224). CONCLUSION: Despite multiple treatments, at the end of follow-up, biochemical control was still not achieved in up to 30% of patients. These multicenter data demonstrate that in routine clinical practice, initial and long-term control is not achieved in a substantial number of patients with CD. ABBREVIATIONS: BLA = bilateral adrenalectomy CD = Cushing disease CS = Cushing syndrome eCRF = electronic case report form MRI = magnetic resonance imaging PCOS = polycystic ovary syndrome.

Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic-pituitary-adrenal axes in adults: results from a prospective randomized multicenter study.

CONTEXT: Recent studies suggest using lower GH cut-points for the glucagon stimulation test (GST) in diagnosing adult GH deficiency (GHD), especially in obese patients. There are limited data on evaluating GH and hypothalamic-pituitary-adrenal (HPA) axes using weight-based dosing for the GST. OBJECTIVE: To define GH and cortisol cut-points to diagnose adult GHD and secondary adrenal insufficiency (SAI) using the GST, and to compare fixed-dose (FD: 1 or 1.5 mg in patients >90 kg) with weight-based dosing (WB: 0.03 mg/kg). Response to the insulin tolerance test (ITT) was considered the gold standard, using GH and cortisol cut-points of ≥3 ng/ml and ≥18 µg/dL, respectively. DESIGN: 28 Patients with hypothalamic-pituitary disease and 1-2 (n = 14) or ≥3 (n = 14) pituitary hormone deficiencies, and 14 control subjects matched for age, sex, estrogen status and body mass index (BMI) underwent the ITT, FD- and WB-GST in random order. RESULTS: Age, sex ratio and BMI were comparable between the three groups. The best GH cut-point for diagnosis of GHD was 1.0 (92 % sensitivity, 100 % specificity) and 2.0 ng/mL (96 % sensitivity and 100 % specificity) for FD- and WB-GST, respectively. Age negatively correlated with peak GH during FD-GST (r = -0.32, P = 0.04), but not WB-GST. The best cortisol cut-point for diagnosis of SAI was 8.8 µg/dL (92 % sensitivity, 100 % specificity) and 11.2 µg/dL (92 % sensitivity and 100 % specificity) for FD-GST and WB-GST, respectively. Nausea was the most common side effect, and one patient had a seizure during the FD-GST. CONCLUSION: The GST correctly classified GHD using GH cut-points of 1 ng/ml for FD-GST and 2 ng/ml for WB-GST, hence using 3 ng/ml as the GH cut-point will misclassify some GH-sufficient adults. The GST may also be an acceptable alternative to the ITT for evaluating the HPA axis utilizing cortisol cut-points of 9 µg/dL for FD-GST and 11 µg/dL for WB-GST.

TRENDS IN GROWTH HORMONE STIMULATION TESTING AND GROWTH HORMONE DOSING IN ADULT GROWTH HORMONE DEFICIENCY PATIENTS: RESULTS FROM THE ANSWER PROGRAM.

OBJECTIVE: Adult growth hormone deficiency (AGHD) results in physiologic impairments that may reduce quality of life and negatively impact body composition. AGHD can be treated with recombinant human growth hormone (GH). This study analyzes AGHD patients enrolled in the American Norditropin(®) STUDIES: Web-Enabled-Research (ANSWER) Program/NovoNet, a U.S. observational noninterventional study of patients treated with Norditropin(®) (somatropin [recombinant DNA origin] injection) at the discretion of their physicians. METHODS: Data were evaluated for GH stimulation test (GHST) usage and Norditropin(®) doses over 4 years. RESULTS: Adults (N = 468) with isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) were evaluated. The most commonly used GHSTs were arginine + L-dopa (27%; mostly a single center) and glucagon (25%; most frequent test after 2009). The percent of patients meeting recommended test-specific cut points varied from 32 to 100%, depending on the GHST used. Mean baseline GH doses were higher for MPHD patients and for younger patients in both IGHD and MPHD groups. CONCLUSION: MPHD was more common than IGHD. Mean GH doses were higher in younger patients, consistent with a transition from higher pediatric to lower adult dosing. Over time, glucagon became the most popular GHST. The use, in some patients, of other GHSTs with cut points, as well as starting doses not consistent with current recommendations, highlights the need for continued education regarding treatment guidelines for AGHD.

Long-term treatment with pegvisomant as monotherapy in patients with acromegaly: experience from ACROSTUDY.

OBJECTIVE: To evaluate use of pegvisomant, a growth hormone (GH) receptor antagonist, as monotherapy in ACROSTUDY, a global safety surveillance study set in 14 countries (373 sites). METHODS: A descriptive analysis of safety, magnetic resonance imaging (MRI) reading, and treatment outcomes in 710 subjects who received at least 1 pegvisomant dose as monotherapy during and up to 5 years follow-up in ACROSTUDY. RESULTS: Subjects received a mean of 5.4 years of pegvisomant and were followed in ACROSTUDY for a mean of 3.8 years. A total of 1,255 adverse events (AEs) were reported in 345 subjects (48.6%). Serious AEs (SAEs) were reported in 133 (18.7%) subjects, including 22 deaths, none of which were attributed to pegvisomant use. Of 670 (94%) subjects with at least 1 liver function test (LFT) reported in ACROSTUDY, 8 (1.2%) had reported increases in transaminases >3 times the upper limit of normal (ULN). No liver failure was reported. Based on central MRI reading, 12 of 542 subjects (2.2%) had a confirmed increase or increase/decrease in tumor size. Injection-site reactions were reported in 2.3%. At 5 years of therapy, insulin-like growth factor 1 (IGF-1) level was reported normal in 67.5% (mean dose 17.2 mg/day) and elevated in 29.9% (mean dose 19.8 mg/day). Subjects on 20 mg per day or more rose from 36% at 3 years to 41% at 5 years of therapy. CONCLUSIONS: ACROSTUDY data indicate that pegvisomant used as sole medical therapy is safe and effective for patients with acromegaly. The reported low incidence of pituitary tumor size increase and liver enzyme elevations are reassuring and support the positive benefit-risk of pegvisomant therapy.

Lanreotide extended-release aqueous-gel formulation, injected by patient, partner or healthcare provider in patients with acromegaly in the United States: 1-year data from the SODA registry.

Lanreotide depot (LD; commercial name Somatuline(®) Depot) is an injectable, extended-release formulation of the synthetic somatostatin analog (SSA) lanreotide. In recent clinical trials, LD was found to be suitable for self or partner administration, avoiding the need to travel to a medical facility. The Somatuline(®) Depot for Acromegaly (SODA) study is an ongoing, multicenter, observational study in the US investigating the efficacy, safety, convenience and symptom relief provided by LD in patients with acromegaly. Sub-analyses explore outcomes according to who administered the injection: patient, partner, healthcare provider (HCP) or a combination. Data reported here reflect one year of patient experience. Patients are eligible for inclusion if they have a diagnosis of acromegaly, are treated with LD and can give signed informed consent. Baseline data include patient demographics, previous acromegaly treatment and investigations, GH and IGF-I levels, LD dose and dose adjustment frequency. Symptom frequency, injection pain and treatment convenience are assessed using patient-reported questionnaires. As of 18 April 2012, 166 patients had enrolled in SODA. Most (72 %) achieved normal IGF-I levels after 12 months of LD treatment. Disease control was similar in self or partner injectors and in patients who received injections from their HCP, although self or partner injecting was deemed more convenient. LD was well-tolerated irrespective of who performed the injection. Self injection led to more injection-site reactions, but this did not increase the rate of treatment interruption. Acromegaly symptoms remained stable. Biochemical, safety and convenience data support the clinical validity of injecting LD at home.

Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults.

Weight-based (WB: 0.03 mg/kg) and fixed dose (FD: 1-1.5 mg) regimens of the glucagon stimulation test (GST) have been used to evaluate GH and cortisol secretion in children and adults, respectively. However, experience of the WB regimen in assessing GH and cortisol secretion in adults are limited. We describe a multicenter experience using WB and FD regimens in evaluating GH and cortisol secretion in adults suspected of GH deficiency and central adrenal insufficiency. Retrospective case series of GSTs (n = 515) performed at five tertiary centers. Peak and nadir glucose, and peak GH and peak cortisol responses occurred later with WB (mean dose: 2.77 mg) compared to FD (mean dose: 1.20 mg) regimens. Main side-effects were nausea and vomiting, particularly in younger females. Nausea was comparable but vomiting was more frequent in the WB regimen (WB: 10.0 % vs FD: 2.4 %; P < 0.05). Peak and nadir glucose, ΔGH, and peak and Δcortisol were higher in the WB regimen. In both regimens, age correlated negatively with peak cortisol levels, and body mass index (BMI), fasting, peak and nadir glucose correlated negatively with peak GH levels. WB and FD regimens can induce adult GH and cortisol secretion, but peak responses occur later in the WB regimen. Both regimens are relatively safe, and vomiting was more prevalent in the WB regimen. As age, BMI, and glucose tolerance negatively correlated with peak GH and cortisol levels, the WB regimen may be more effective than the FD regimen in older overweight glucose intolerant patients.

Reduced CV risk with long-term GH replacement in AGHD: data from two large observational studies.

Adult growth hormone deficiency (AGHD) is associated with an increased risk of cardiovascular (CV) disease. Long-term growth hormone (GH) treatment could improve CV outcomes. The objective of this study was to evaluate CV disease risk in patients with AGHD who received GH replacement therapy for up to 10 years as part of NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905). The studies were observational, non-interventional and multicentre, monitoring long-term effectiveness and safety of GH treatment. NordiNet® IOS involved 23 countries (469 sites) across Europe and the Middle East. The ANSWER Program was conducted in the USA (207 sites). This analysis included patients aged 18-75 years who were GH naïve at study entry, who had ≤10 years of GH treatment data and who could be assessed for CV risk for at least 1 follow-up year. The main outcome measure was risk of CV disease by age 75 years, as calculated with the Multinational Cardiovascular Risk Consortium model (Brunner score) using non-high-density lipoprotein cholesterol adjusted for age, sex and CV risk factors. The results of this analysis showed that CV risk decreased gradually over the 10-year period for GH-treated patients. The risk was lower for patients treated for 2 and 7 years vs age- and sex-matched control groups (not yet started treatment) (14.51% vs 16.15%; P = 0.0105 and 13.53% vs 16.81%; P = 0.0001, respectively). This suggests that GH treatment in people with AGHD may reduce the risk of CV disease by age 75 years compared with matched controls.

Long-term Effectiveness and Safety of GH Replacement Therapy in Adults ≥60 Years: Data From NordiNet® IOS and ANSWER.

Context: Effectiveness and safety data on GH replacement therapy (GHRT) in older adults with adult GH deficiency (AGHD) are limited. Objective: To compare GHRT safety and clinical outcomes in older (≥60 years and, for some outcomes, ≥75 years) and middle-aged (35-<60 years) patients with AGHD. Design/setting: Ten-year follow-up, real-world data from 2 large noninterventional studies-NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program-were analyzed. Patients: GH-naïve and non-naïve patients with AGHD. Intervention: Norditropin® (somatropin). Main outcome measures: Outcomes included GH exposure, IGF-I standard deviation scores (SDS), body mass index (BMI), glycated hemoglobin (HbA1c), serious and nonserious adverse reactions (SARs and NSARs, respectively), and serious adverse events (SAEs). Adverse reactions were events with possible/probable causal relationship to GHRT. Results: The effectiveness analysis set comprised 545 middle-aged and 214 older patients (19 aged ≥75 years) from NordiNet® IOS. The full analysis set comprised 1696 middle-aged and 652 older patients (59 aged ≥75 years) from both studies. Mean GH doses were higher in middle-aged vs older patients. For both age groups and sexes, mean IGF-I SDS increased following GHRT, while BMI and HbA1c changes were similar and small.Incidence rate ratios (IRRs) did not differ statistically between older and middle-aged patients for NSARs [IRR (mean, 95% confidence interval) 1.05 (.60; 1.83)] or SARs [.40 (.12; 1.32)]. SAEs were more frequent in older than middle-aged patients [IRR 1.84 (1.29; 2.62)]. Conclusion: Clinical outcomes of GHRT in AGHD were similar in middle-aged and older patients, with no significantly increased risk of GHRT-related adverse reactions in older patients.

ACROBAT Edge: Safety and Efficacy of Switching Injected SRLs to Oral Paltusotine in Patients With Acromegaly.

CONTEXT: Paltusotine is a once-daily, oral, nonpeptide small-molecule somatostatin receptor type 2 (SST2) agonist in clinical development for treatment of acromegaly. OBJECTIVE: This work aimed to evaluate change in insulin-like growth factor I (IGF-I) levels in patients switched from octreotide long-acting release or lanreotide depot monotherapy to paltusotine. METHODS: A phase 2, open-label, prospective, multicenter, multinational, nonrandomized, single-arm exploratory study was conducted in which dosage uptitrations were performed in a double-blinded manner. At 26 global sites, patients with acromegaly switched to paltusotine from injected somatostatin receptor ligand (SRL)-based therapy. Patients received 13-week treatment with once-daily oral paltusotine (10-40 mg/d). The primary end point was change from baseline to week 13 in IGF-I for patients who switched from long-acting octreotide or lanreotide depot monotherapy to paltusotine (group 1). All patients underwent a 4-week paltusotine washout at end of treatment period (wk 13-17). IGF-I, growth hormone (GH), patient-reported outcome, and safety data were collected. RESULTS: Forty-seven patients enrolled. In group 1 (n = 25), IGF-I and GH showed no significant change between SRL baseline and end of paltusotine treatment at week 13 (median change in IGF-I = -0.03×upper limit of normal [ULN]; P = .6285; GH = -0.05 ng/mL; P = .6285). IGF-I and GH rose significantly in the 4 weeks after withdrawing paltusotine (median change in IGF-I = 0.55×ULN; P < .0001 [median increase 39%]; GH = 0.72 ng/mL; P < .0001 [109.1% increase]). No patients discontinued because of adverse events (AE); no treatment-related serious AEs were reported. CONCLUSION: These results suggest once-daily oral paltusotine was effective in maintaining IGF-I values in patients with acromegaly who switched from injected SRLs. Paltusotine was well tolerated with a safety profile consistent with other SRLs.

Corrigendum: Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

[This corrects the article DOI: 10.3389/fendo.2021.662865.].

Maintenance of response to oral octreotide compared with injectable somatostatin receptor ligands in patients with acromegaly: a phase 3, multicentre, randomised controlled trial.

BACKGROUND: Despite biochemically responding to injectable somatostatin receptor ligands (iSRLs), many patients with acromegaly experience treatment burdens. We aimed to assess maintenance of biochemical response and symptomatic control with oral octreotide capsules versus iSRLs in patients with acromegaly who previously tolerated and responded to both. METHODS: This global, open-label, randomised controlled phase 3 trial was done in 29 clinical sites in Austria, France, Germany, Hungary, Italy, Lithuania, Russia, Serbia, Spain, and the USA. Eligible patients were adults aged 18-75 years with acromegaly who were receiving iSRLs (long-acting octreotide or lanreotide autogel) for at least 6 months before baseline with a stable dose for at least 4 months, and were deemed to be biochemically responding (insulin-like growth factor I [IGF-I] <1·3 × upper limit of normal [ULN] and mean integrated growth hormone <2·5 ng/mL). In the 26-week run-in phase, all patients received oral octreotide (40 mg a day, optional titration to 60 or 80 mg a day). Eligibility for the randomised treatment phase was completion of the run-in phase as a biochemical responder (IGF-I <1·3 × ULN and mean integrated growth hormone <2·5 ng/mL at week 24) and investigator assessment of acromegaly being adequately controlled. Patients were randomly assigned (3:2) to oral octreotide capsules or iSRL at the same dose and interval as before enrolment. Randomisation and drug dispensing were conducted through a qualified randomisation service provider (eg, interactive web or voice response system). The primary endpoint was a non-inferiority assessment (margin -20 percentage points) of proportion of participants maintaining biochemical response throughout the randomised treatment phase (IGF-I <1·3 × ULN using time-weighted average; assessed by comparing the lower bound of the 2-sided 95% CI for the difference in biochemical response between groups). IGF-I was assessed once a month during the run-in and randomised treatment phases (single sample). Efficacy and safety assessments were performed on the randomised population. This trial is registered with ClinicalTrials.gov, NCT02685709. FINDINGS: Between Feb 11, 2016, and Aug 20, 2020, 218 patients were assessed for eligibility. 72 patients were excluded, and 146 participants were enrolled into the run-in phase. 116 patients completed the run-in phase and 30 participants discontinued treatment. 92 participants were randomly assigned to oral octreotide (n=55) or iSRL (n=37). 50 (91%) of 55 participants who received oral octreotide (95% CI 44-53) and 37 (100%) of 37 participants who received iSRLs (34-37) maintained biochemical response. The lower bound of the 2-sided 95% CI for the adjusted difference in proportions between the two treatment groups achieved the prespecified non-inferiority criterion of -20% (95% CI -19·9 to 0·5). 19 (35%) of 55 participants in the oral octreotide group and 15 (41%) of 37 participants in the iSRL group had treatment-related adverse events; the most common of which in both groups were gastrointestinal. INTERPRETATION: Oral octreotide was non-inferior to iSRL treatment, and might be a favourable alternative to iSRLs for many patients with acromegaly. FUNDING: Chiasma. TRANSLATION: For the Russian translation of the abstract see Supplementary Materials section.

Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

Introduction/Purpose: Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS). Materials and Methods: A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%). Results: 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred. Conclusions: The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.

Disease and Treatment-Related Burden in Patients With Acromegaly Who Are Biochemically Controlled on Injectable Somatostatin Receptor Ligands.

Medical treatment for acromegaly commonly involves receiving intramuscular or deep subcutaneous injections of somatostatin receptor ligands (SRLs) in most patients. In addition to side effects of treatment, acromegaly patients often still experience disease symptoms even when therapy is successful in controlling GH and IGF-1 levels. Symptoms and side effects can negatively impact patients' health-related quality of life. In this study, we examine the disease- and treatment-related burden associated with SRL injections as reported through the use of the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ ©) and clinician-reported symptom severity through the Acromegaly Index of Severity (AIS). Patients included in this analysis were enrolled in a randomized phase 3 study, were biochemically-controlled (an IGF-1 < 1.3 × the upper limit of normal [ULN] and average GH < 2.5 ng/ml) and receiving SRL injections for ≥6 months with a stable dose of either long-acting octreotide or lanreotide monotherapy for ≥4 months. The sample (N = 91) was 65% female, 91% Caucasian, with a mean [standard deviation (SD)] age of 53 (1) years. Two-thirds of patients reported that they still experience acromegaly symptoms; 82% of these said they experience symptoms all of the time. Three-fourths experienced gastrointestinal (GI) side effects after injections, and 77% experienced treatment-related injection site reactions (ISRs). Patients commonly reported that these interfered with their daily life, leisure, and work activities. Those with higher symptom severity, as measured by the AIS, scored significantly worse on several Acro-TSQ domains: Symptom Interference, GI Interference, Treatment Satisfaction, and Emotional Reaction. Despite being biochemically controlled with injectable SRLs, most patients reported experiencing acromegaly symptoms that interfere with daily life, leisure, and work. GI side effects and ISRs were also common. This study highlights the significant disease burden that still persists for patients with acromegaly that have achieved biochemical control with the use of injectable SRLs.

RECURRENT INVASIVE DUCTAL BREAST CARCINOMA PRESENTING AS PRIMARY ADRENAL INSUFFICIENCY WITH ADRENAL CRISIS.

OBJECTIVE: We report the first case of recurrent ductal breast carcinoma presenting as primary adrenal insufficiency. METHODS: We describe a patient who developed a recurrence of invasive ductal breast carcinoma which went undetected until the patient presented with fulminant adrenal crisis. We describe here an overview of the clinical presentation, work-up, diagnosis, and treatment of adrenal crisis. RESULTS: Adrenal crisis due to bilateral adrenal metastases secondary to invasive ductal breast carcinoma is an exceedingly rare occurrence. To our knowledge, this is the first case of recurrent breast carcinoma in which the presenting feature is primary adrenal insufficiency. CONCLUSION: Patients with a history of breast carcinoma and bilateral adrenal enlargement should be evaluated for the presence of primary adrenal insufficiency.

Clinical management of patients with Cushing syndrome treated with mifepristone: consensus recommendations.

BACKGROUND: While surgery is the first-line treatment for patients with endogenous hypercortisolism (Cushing syndrome [CS]), mifepristone has been shown to be a beneficial medical treatment option, as demonstrated in the SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome) trial. Mifepristone is a competitive glucocorticoid receptor antagonist and progesterone receptor antagonist that is associated with several treatment effects and adverse events that clinicians need to be aware of when considering its use. The objective of this review was to provide updated clinical management recommendations for patients with CS treated with mifepristone. METHODS: A panel of endocrinologists from the US with extensive experience in treating patients with CS, including with mifepristone, convened as part of a clinical advisory board to develop a consensus on the practical, real-world clinical management of patients on mifepristone. RESULTS: Comprehensive considerations and recommendations are provided for managing mifepristone-associated effects, including symptoms of cortisol withdrawal, hypokalemia, and change in thyroid function; effects related to its antiprogesterone activity; and rash. Additional management strategies to address concomitant medications and special clinical situations, such as surgery and use in specific populations, are also provided. CONCLUSION: Safe and effective use of mifepristone requires clinical judgment and close patient monitoring to ensure optimal clinical outcomes. These consensus recommendations provide useful, practical guidance to clinicians using mifepristone.