Context The MPOWERED core trial (NCT02685709) and open-label extension (OLE) phase investigated long-term efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly. Core... Show moreContext The MPOWERED core trial (NCT02685709) and open-label extension (OLE) phase investigated long-term efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly. Core trial primary endpoint data demonstrated noninferiority to injectable somatostatin receptor ligands (iSRLs). Core trial completers were invited to participate in the OLE phase. Objective To assess long-term efficacy and safety of OOC in patients with acromegaly who previously responded to and tolerated both OOC and injectable octreotide/lanreotide and completed the core phase. Methods The unique study design of transitioning between OOC and iSRLs allowed within-patient evaluations. The proportion of biochemical responders (insulin-like growth factor I < 1.3 x upper limit of normal) at end of each extension year who entered that year as responders was the main outcome measure. Results At year 1 extension end, 52/58 patients from both the monotherapy and the combination therapy groups were responders (89.7%; 95% CI 78.8-96.1), 36/41 (87.8%; 95% CI 73.8-95.9) in year 2, and 29/31 (93.5%; 95% CI 78.6-99.2) in year 3. No new or unexpected safety signals were detected; 1 patient withdrew owing to treatment failure. Patients who transitioned from iSRLs in the core trial to OOC in the OLE phase reported improved treatment convenience/satisfaction and symptom control. Conclusion Patient-reported outcome data support for the first time that transitioning patients randomized to iSRL (who previously responded to both OOC and iSRLs) back to OOC had a significant effect on patients' symptoms score in a prospective cohort. The MPOWERED OLE showed long-term maintenance of response and sustained safety with OOC. Show less
Fleseriu, M.; Molitch, M.; Dreval, A.; Biermasz, N.R.; Gordon, M.B.; Crosby, R.D.; ... ; Mathias, S.D. 2021
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... Show moreMedical 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(C)) 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 X 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. Show less
Background: Whereas biochemical response is often used as a primary study outcome, improvement in symptoms and health-related quality of life (HRQoL) is the relevant goal for patients to consider... Show moreBackground: Whereas biochemical response is often used as a primary study outcome, improvement in symptoms and health-related quality of life (HRQoL) is the relevant goal for patients to consider treatment successful. We performed a systematic review and meta-analysis to assess the effect of treatment on symptoms and HRQoL in acromegaly.Methods: Seven electronic databases were searched for longitudinal studies assessing patient-reported symptoms or HRQoL in acromegaly. Meta-analyses were performed to assess differences during treatment for the Acromegaly Quality of Life Questionnaire (AcroQoL) and Patient-Assessed Acromegaly Symptom Questionnaire (PASQ), and standardized mean difference (SMD) for individual symptoms (interpretation: 0.2 small, 0.5 moderate, and 0.8 large effect). Treatment-naive and previously treated patients were assessed separately.Results: Forty-six studies with 3301 patients were included; 24 contributed to quantitative analyses. Thirty-six studies used medication as main treatment, 1 transsphenoidal adenomectomy, and 9 various treatments. Symptoms and HRQoL both improved: AcroQoL increased 2.9 points (95% CI, 0.5 to 5.3 points), PASQ decreased -2.3 points (95% CI, -1.3 to -3.3 points), and individual symptom scores decreased for paresthesia -0.9 (95% CI, -0.6 to -1.2), hyperhidrosis -0.4 (95% CI, -0.1 to -0.6), fatigue -0.3 (95% CI, -0.1 to -0.6), arthralgia -0.3 (95% CI, -0.1 to -0.5), headache -0.3 (95% CI, 0.0 to -0.6), and soft-tissue swelling -0.2 (95% CI, 0.0 to -0.4).Conclusion: Symptoms and HRQoL improved during acromegaly treatment. Consensus is needed on which symptoms should be included in a potential core outcome set, taking into account symptom frequency, severity, and sensitivity to change, which can be used in clinical practice and as outcome in trials. Show less
Context: Joint complaints in patients with acromegaly are common, although the long-term disease course is largely unknown.Objective: This study aims to evaluate the long-term course of acromegalic... Show moreContext: Joint complaints in patients with acromegaly are common, although the long-term disease course is largely unknown.Objective: This study aims to evaluate the long-term course of acromegalic arthropathy.Design and Setting: A prospective longitudinal cohort study was conducted in controlled acromegaly patients followed at a tertial referral center, with 3 study visits: at baseline and after a median of 2.6 and 9.1 years.Patients: We included 31 patients with biochemically controlled acromegaly for 2 or more years (49% female; median age, 60 years) at baseline.Main Outcome Measures: Radiographic arthropathy of the knee, hip, hand, and cervical and lumbar spine were evaluated using Kellgren and Lawrence (KL) scores, developed for assessment of primary osteoarthritis (OA). Radiographic progression was defined as a KL increase above the smallest detectable change. Joint symptoms were assessed using self-reported questionnaires. Progression was defined using existing clinically important cutoff values. Risk factors for progression were investigated using a multivariable model.Results: All patients had definite radiographic OA at 1 or more joints at baseline. Radiographic progression was observed in 29%, 48%, 84%, and 94% of patients in the knees, hips, hands, and axial joints, respectively. Deterioration in hand-related pain and function was observed in 10 (32.3%) and 11 patients (35.5%), respectively. Solely baseline KL scores of the hip were associated with hip OA progression (OR 1.88; 95% CI, 1.09-3.16).Conclusions: Acromegalic arthropathy showed significant radiographic progression over 9.1 years of follow-up in patients in remission, whereas clinical progression was observed less frequently. Future studies should focus on adequate prevention and treatment strategies of acromegalic arthropathy. Show less
J. dal; Skov, B.G.; Andersen, M.; Feldt-Rasmussen, U.; Feltoft, C.L.; Karmisholt, J.; ... ; Jorgensen, J.O.L. 2020
Objective Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies.Design A nationwide cohort study including all incident cases of acromegaly (1978-2010, n ... Show moreObjective Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies.Design A nationwide cohort study including all incident cases of acromegaly (1978-2010, n = 596) and a meta-analysis on sex differences in active acromegaly (40 studies) were performed.Method Sex-dependent differences in prevalence, age at diagnosis, diagnostic delay, pituitary adenoma size, insulin-like growth factor 1 (IGF-I) and growth hormone (GH) concentrations were estimated.Results The cohort study identified a balanced gender distribution (49.6% females) and a comparable age (years) at diagnosis (48.2 CI95% 46.5-49.8 (males) vs. 47.2 CI95% 45.5-48.9 (females), p = 0.4). The incidence rate significantly increased during the study period (R-2 = 0.42, p < 0.01) and the gender ratio (F/M) changed from female predominance to an even ratio (SR: 1.4 vs. 0.9, p = 0.03). IGF-I-SDS was significantly lower in females compared to males, whereas neither nadir GH nor pituitary adenoma size differed between males and females.In the meta-analysis, the weighted percentage female was 53.3% (CI95% 51.5-55.2) with considerable heterogeneity (I-2 = 85%) among the studies. The mean age difference at diagnosis between genders was 3.1 years (CI95% 1.9-4.4), and the diagnostic delay was longer in females by 0.9 years (CI95% -0.4 to 2.1). Serum IGF-I levels were significantly lower in female patients, whereas nadir GH, and pituitary adenoma size were comparable.Conclusion There are only a minor sex differences in the epidemiology of acromegaly at the time of diagnosis except that female patients are slightly older and exhibit lower IGF-I concentrations and a longer diagnostic delay. Show less
Samson, S.L.; Nachtigall, L.B.; Fleseriu, M.; Gordon, M.B.; Bolanowski, M.; Labadzhyan, A.; ... ; Melmed, S. 2020
Purpose: The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control... Show morePurpose: The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs).Methods: In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] <= 1.0 x upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures.Results: Mean IGF-1 measurements were 0.80 and 0.97 x ULN for OOC and 0.84 and 1.69 x ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (<= 1.0 x ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (< 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 > 1.0 or >= 1.3 x ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P < .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience.Conclusions: OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs. Show less
Objective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013.Participants: The Consensus... Show moreObjective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013.Participants: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration.Evidence: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities.Consensus Process: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system.Conclusions: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality. Show less
Pituitary diseases are rare conditions with severe chronic multi-organ and multisystemic morbidity requiring complex multidisciplinary treatment and usually life-long drug treatment. Most cases are... Show morePituitary diseases are rare conditions with severe chronic multi-organ and multisystemic morbidity requiring complex multidisciplinary treatment and usually life-long drug treatment. Most cases are caused by functioning or non-functioning pituitary adenoma. From the patient's perspective, the burden of disease is caused by the tumour itself and associated compression symptoms, interventions, hormone excess and deficiencies, systemic manifestations of these endocrine abnormalities and general psychosocial issues that can manifest in patients with a chronic condition. In this review, patient burden is classified according to classic endocrine syndromes, with burden at diagnosis and after long-term remission, and also within the framework of value-based health care and the conceptual model of wellbeing. The recently developed patient-reported outcome measurement tool that helps to evaluate burden of patients is also discussed. (C) 2019 Elsevier Ltd. All rights reserved. Show less
