MPOWERED Trial Open-Label Extension: Long-term Efficacy and Safety Data for Oral Octreotide Capsules in Acromegaly.

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 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 × 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.

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.

Assessment of muscle and fat mass in type 2 diabetes patients by dual-energy X-ray absorptiometry.

OBJECTIVES: The aim of this study was to assess the quantitative composition of muscle and adipose tissue in type 2 diabetes mellitus (T2DM) patients on the basis of dual-energy X-ray absorptiometry for the diagnosis of obesity and sarcopenia. METHODS: Dual-energy X-ray absorptiometry was administered to 50 patients with T2DM. Evaluation of the composition of muscle and adipose tissue was performed. RESULTS: The median of Appendicular Lean Mass Index (ALMI) in the general group was 8.04 [7.32; 8.97]. In general, there was a decrease in the appendicular muscle mass with increasing age. According to the results of T-score ALMI and Z-score ALMI, we did not identify patients with sarcopenia. However, the calculation of the T- and Z-criteria, adjusted for fat mass, led to a significant decrease of these parameters and in 98.0% it was possible to identify patients who meet the criteria of sarcopenia. CONCLUSION: We did not detect patients with sarcopenia on the basis of ALMI, T-ALMI. After revision of these criteria for fat mass, almost all patients started to meet the criteria of sarcopenia (98.0%).

Reduced microvascular reactivity in patients with diabetic neuropathy.

BACKGROUND: Neurogenic regulation is involved in the development of microcirculation response to local heating. We suggest that microvascular reactivity can be used to estimate the severity of diabetic polyneuropathy (DPN). OBJECTIVE: To evaluate the prospects for using the parameters of skin microvascular reactivity to determine the severity of DPN. METHODS: 26 patients with diabetes mellitus were included in the study (patients with retinopathy (n = 15), and without retinopathy (n = 11)). The severity of DPN was assessed using Michigan Neuropathy Screening Instrument (MNSI) and Norfolk QOL-DN (NQOLDN). Skin microcirculation was measured by laser Doppler flowmetry with local heating test. RESULTS: There were revealed moderate negative correlations between microvascular reactivity and the severity of DPN (for MNSI (Rs = -0.430), for NQOLDN (Rs = -0.396)). In patients with retinopathy, correlations were stronger than in the general group (for MNSI (Rs = -0.770) and NQOLDN (Rs = -0.636)). No such correlations were found in patients without retinopathy. CONCLUSION: Correlation of the microvascular reactivity and DPN was revealed in patients with registered structural disorders in microvessels (retinopathy). The lack of such correlation in patients without retinopathy may be explained by the intact compensatory mechanisms of microvessels without severe disorders.

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.

[Epidemiology, clinical manifestations and efficiency of different methods of treatment of acromegaly according to the United Russian Registry of Patients with Pituitary Tumors].

BACKGROUND: The registry is the main source of information about patients with acromegaly for assessing the quality of medical care, effectiveness of treatment, determining the compliance of real clinical practice with existing standards and patient management protocols. AIMS: To evaluate epidemiological, demographic and clinical characteristics of acromegaly in Russian Federation and effectiveness of treatment modalities. MATERIALS AND METHODS: The object of the study was the database of the united Russian registry of patients with pituitary tumors with specific analysis of patients with acromegaly only. We analyzed the data of 4114 patients with acromegaly stored on the online system in February 2019. RESULTS: Based on the data 32% of patients had complete clinical and laboratory remission of acromegaly; the percentage of patients with no remission was 68%, among them 22.5% had significant improvements in clinical symptoms and a decrease in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) without IGF-1 normalization. The average age of patients at the onset of the disease was 42.7 years and at diagnosis – 45.8 years. The ratio of men to women was 1:2.6. In patients with acromegaly hypopituitarism was registered in 14.7% of cases and among them hypothyroidism (66%) and hypogonadism (52%) were registered more often. Among other complications the leading were diabetes mellitus (15.7%) and acromegalic arthropathy (15%). The proportion of patients receiving neurosurgical treatment increased from 35.7% to 49.6% in 2012–2019; the portion of patients undergoing radiation therapy decreased significantly from 17.7% in 2012 to 0.8% in 2019. Remission was achieved in 40.47% after neurosurgery and 28.95% after medical treatment as a first line therapy p<0.01. The number of patients receiving medical treatment at the time of the study was 1209. Among them 51% of patients treated with long-acting lanreotide and 24% receiving long-acting octreotide achieved remission (p<0.0001) CONCLUSIONS: The remission rate of acromegaly remains suboptimal despite increased surgical activity, which corresponds to global trends. Long-acting lanreotide was significantly superior versus long-acting octreotide in the rate of acromegaly remission, which does not correspond with clinical trials.

Approaches to improve the predictive value of laser Doppler flowmetry in detection of microcirculation disorders in diabetes mellitus.

BACKGROUND: Laser Doppler flowmetry is widely used in scientific studies of blood microcirculation but constrained in clinical use due to the low diagnostic significance. OBJECTIVE: This research is aimed at creation of approaches to prognostic value increase in detection of microcirculation disorders in patients with type 2 diabetes mellitus. METHODS: The study included 10 volunteers and 10 patients with t2DM. Participants were observed using postural-heating test with LAKK-02 complex. We calculated median microcirculation for each period and then held a retroactive classification of the surveyed groups. RESULTS: Statistically significant differences between groups were found in the perfusion during the combination of postural and heating impacts. Conversion of this perfusion in the relative index (Irel) (relative to the baseline perfusion), allowed us to increase the significance of the differences. The value of AUC (95% CI) during the ROC-analysis in reverse classification was 0.81 (0,60-1,0) for the period of the impacts combination, and 0.93 (0,81-1,0) for Irel index. CONCLUSIONS: We demonstrated the possibility of using LDF method to achieve predictive value in the detection of microcirculatory disorders in an individual patient with diabetes. This extends the perspectives of the method beyond the purely scientific research.

A Randomized Controlled Trial to Assess the Impact of Proper Insulin Injection Technique Training on Glycemic Control.

INTRODUCTION: Improper injection technique can negatively affect glycemic control and treatment tolerability. We assessed the impact of structured insulin injection training on glycemic control. METHODS: We compared changes in glycated hemoglobin (A1C) and fasting plasma glucose following structured insulin injection training in a 6-month pilot study in patients with type 1 or 2 diabetes. Patients were recruited from mobile clinics in Moscow, Russia, and randomized into three groups. Groups 1 and 2 received structured injection training, and group 3 did not. Group 1 received 4-mm needles sufficient for each injection; groups 2 and 3 provided their own needle supply. Changes in insulin total daily dose (TDD), injection technique, needle reuse, and lipohypertrophy (LH) were assessed. RESULTS: Of 120 patients enrolled, 116 were included in all analyses (group 1, n = 43; group 2, n = 35; group 3, n = 38). At 6 months, mean [95% CI] reductions in A1C were significant in groups 1 and 2 (- 1.00% [10.9 mmol/mol (- 1.3 to - 0.6)] and - 1.00% [10.9 mmol/mol (- 1.4 to - 0.7)], respectively; P < 0.001 for both), but not in group 3 (- 0.02% [0.2 mmol/mol (- 1.2 to 1.6)]). Increases in insulin TDD, however, were similar and significant across groups (approximately 6 IU; P < 0.05). Injection technique improved, and needle reuse and LH declined in groups 1 and 2, but not in group 3. CONCLUSIONS: Little is known about the glycemic impact of insulin injection training. We found that structured training and the use of short pen needles can improve injection technique, leading to significant A1C reductions and decreased rates of LH.