IGF-I variability and its association with demographic and clinical characteristics in patients with acromegaly treated with injectable somatostatin receptor ligands (SRLs); results from OPTIMAL, an international prospective phase 3 study

2020 ◽  
Author(s):  
Susan Samson ◽  
Lisa Nachtigall ◽  
Maria Fleseriu ◽  
Ehud Ur ◽  
Molitch Mark E ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Somatostatin Receptor ◽  
Receptor Ligands ◽  
Phase 3 ◽  
Somatostatin Receptor Ligands ◽  
Igf I ◽  
Prospective Phase

scholarly journals A Phase 3 Large International Noninferiority Trial (MPOWERED): Assessing Maintenance of Response to Oral Octreotide Capsules in Comparison to Injectable Somatostatin Receptor Ligands

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A517-A517
Author(s):  
Maria Fleseriu ◽  
Alexander V Dreval ◽  
Yulia Pokramovich ◽  
Irina Bondar ◽  
Elena Isaeva ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Safety Data ◽  
Biochemical Response ◽  
Receptor Ligands ◽  
Phase 3 ◽  
Landmark Analysis ◽  
End Point ◽  
Noninferiority Trial ◽  
Somatostatin Receptor Ligands ◽  
Igf I

Abstract Background: MPOWERED, a large phase 3 trial, assessed maintenance of response to oral octreotide capsules (OOC; MYCAPSSA®) compared to injectable somatostatin receptor ligands (iSRLs) in patients with acromegaly who responded to OOC and iSRLs (octreotide or lanreotide). OOC were recently approved in the US for patients with acromegaly who responded to and tolerated iSRLs. Methods: Eligibility criteria included age 18-75 years at screening, acromegaly diagnosis, disease evidence, biochemical control (insulin-like growth factor I [IGF-I] <1.3 × upper limit of normal [ULN] and mean integrated growth hormone [GH] <2.5 ng/mL) at screening, and ≥6 months’ iSRL treatment. Effective OOC dose was determined in a 26-week Run-in phase. Eligible patients (IGF-I <1.3 × ULN and mean integrated GH <2.5 ng/mL, week 24) were randomized to a 36-week controlled treatment phase (RCT), receiving OOC or iSRLs starting at week 26. The primary end point was a noninferiority assessment of proportion of patients biochemically controlled in the RCT (IGF-I <1.3 × ULN using time-weighted average). Other end points included nonresponse imputation of the primary end point, landmark analysis using proportion of responders based on average of last 2 IGF-I values at end of RCT, and change from baseline RCT (week 26) IGF-I and GH levels. Results: Of 146 enrolled patients, 92 entered the RCT (OOC, n=55; iSRLs, n=37). Both arms were well balanced for age, sex, and acromegaly duration. OOC demonstrated noninferiority to iSRLs in maintaining biochemical response, with 91% (CI, 80%-97%) of OOC and 100% (CI, 91%-100%) of iSRL groups maintaining control during the RCT. Of those responding at end of Run-in, 96% of patients on OOC maintained response during RCT. Using nonresponse imputation, 89% of OOC and 95% of iSRL groups were biochemically controlled in RCT. Landmark analysis of those respnding at end of Run-in showed that 94% of patients in each group maintained response at RCT end. In both groups, IGF-I levels were stable in the RCT, average IGF-I at baseline and RCT end being 0.9 × ULN (OOC) and 0.8 × ULN (iSRL). Mean change in GH from RCT start to RCT end was -0.03 ng/mL (OOC) and +0.29 ng/mL (iSRL). Safety data were mostly similar between groups; the OOC group did not experience injection site reactions. Conclusion: In this noninferiority trial in patients with acromegaly, OOC demonstrated maintenance of biochemical response compared to iSRLs. Results support the efficacy of OOC as a possible iSRL alternative.

scholarly journals Maintenance of Acromegaly Control in Patients Switching From Injectable Somatostatin Receptor Ligands to Oral Octreotide

2020 ◽  
Vol 105 (10) ◽  
pp. e3785-e3797 ◽  
Author(s):  
Susan L Samson ◽  
Lisa B Nachtigall ◽  
Maria Fleseriu ◽  
Murray B Gordon ◽  
Marek Bolanowski ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Control Measures ◽  
Double Blind Study ◽  
Efficacy And Safety ◽  
Receptor Ligands ◽  
Biochemical Control ◽  
Phase 3 ◽  
Double Blind ◽  
Somatostatin Receptor Ligands ◽  
End Of Treatment

Abstract 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 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 × 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 × ULN for OOC and 0.84 and 1.69 × 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 × 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 × 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.

scholarly journals Oral Octreotide Capsules Lowered Incidence and Improved Severity of Acromegaly Symptoms Compared to Injectable Somatostatin Receptor Ligands—Results From the MPOWERED Trial

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A522-A523
Author(s):  
Nienke Biermasz ◽  
Maria Fleseriu ◽  
Akexander V Dreval ◽  
Yulia Pokramovich ◽  
Irina Bondar ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Symptom Burden ◽  
Receptor Ligands ◽  
Phase 3 ◽  
Eligibility Criteria ◽  
Somatostatin Receptor Ligands ◽  
Severity Scores ◽  
The Us ◽  
Normal Mean ◽  
Index Of Severity

Abstract Background: Patients with acromegaly may have high symptom burden. The phase 3 MPOWERED trial assessed control of acromegaly by oral octreotide capsules (OOC; MYCAPSSA®) in comparison to injectable somatostatin receptor ligands (iSRLs) in patients responding to both OOC and iSRLs. iSRLs have been first-line medical treatment for patients with acromegaly for decades. OOC are newly approved in the US for patients previously controlled on iSRLs. Methods: Eligibility criteria for MPOWERED included acromegaly diagnosis, biochemical control of acromegaly (insulin-like growth factor I <1.3 × upper limit of normal; mean integrated growth hormone, <2.5 ng/mL) and ≥6 months’ iSRL (octreotide, lanreotide) treatment. Eligible patients entered a 26-week Run-in phase to determine the effective OOC dose; responders at week 24 then entered a 36-week randomized controlled treatment (RCT) phase receiving OOC or iSRLs. Acromegaly symptom number and severity (mild to severe, 1-3) were collected. Total score was calculated by summating all severity scores (Acromegaly Index of Severity [AIS]). Symptom results were assessed using total AIS score and proportion of patients experiencing individual symptoms. Results: At beginning of Run-in, average AIS score of 92 randomized patients was 4.52, representative of symptoms experienced while previously receiving iSRLs. After 26 weeks’ OOC treatment at end of Run-in, average AIS score was significantly reduced to 3.46 (P<0.001). More than 80% of patients on OOC improved or maintained AIS score during Run-in compared to baseline. Over this 26-week period, there was a significant reduction in extremity swelling (P=0.01) and fatigue (P=0.03). During the RCT, of patients randomized to OOC (n=55), 73% maintained or improved AIS score, and 75% maintained or reduced overall number of active symptoms. In comparison, 68% of those randomized to iSRLs (n=37) maintained or improved AIS score, and 70% maintained or reduced overall number of active symptoms. Conclusion: Results from MPOWERED show that patients receiving OOC had significant improvement in number and severity of acromegaly symptoms after switching from iSRLs. These findings validate previous results from a phase 3 study of OOC in acromegaly in which patients switching to OOC from iSRLs showed significant reduction in joint pain, extremity swelling, and fatigue.1 1Melmed S, et al. JCEM. 2015;100(4):1699-1708.

Machine Learning-based Prediction Model for Treatment of Acromegaly With First-generation Somatostatin Receptor Ligands

2021 ◽  
Author(s):  
Luiz Eduardo Wildemberg ◽  
Aline Helen da Silva Camacho ◽  
Renan Lyra Miranda ◽  
Paula C L Elias ◽  
Nina R de Castro Musolino ◽  
...  
Keyword(s):  
Machine Learning ◽  
Support Vector Machine ◽  
Prediction Model ◽  
Predictive Value ◽  
First Generation ◽  
Somatostatin Receptor ◽  
Support Vector ◽  
Receptor Ligands ◽  
Somatostatin Receptor Ligands ◽  
Igf I

Abstract Context Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. Objective To develop a prediction model of therapeutic response of acromegaly to fg-SRL. Methods Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). Results A total of 153 patients were analyzed. Controlled patients were older (P = .002), had lower GH at diagnosis (P = .01), had lower pretreatment GH and IGF-I (P < .001), and more frequently harbored tumors that were densely granulated (P = .014) or highly expressed SST2 (P < .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. Conclusion We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.

scholarly journals MON-LB55 Biochemical Control of Most Patients Reverting to Injectable Long-Acting Somatostatin Receptor Ligands Is Achieved After One Dose: Results From the Phase 3, Randomized, Double Blind, Placebo-Controlled Optimal Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Maria Fleseriu ◽  
Susan Leanne Samson ◽  
Lisa B Nachtigall ◽  
Artak Labadzhyan ◽  
Atanaska Elenkova ◽  
...  
Keyword(s):  
Rescue Therapy ◽  
Somatostatin Receptor ◽  
Clinical Signs ◽  
Placebo Treatment ◽  
Receptor Ligands ◽  
Biochemical Control ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Somatostatin Receptor Ligands ◽  
Igf I

Abstract Background: Injectable somatostatin receptor ligands (SRLs) are currently the most widely used medical therapy for acromegaly worldwide. Oral octreotide capsules (OOC) have been formulated as a potential therapy for this disorder and the safety and efficacy were evaluated in the CHIASMA OPTIMAL pivotal study (Samson et al. ENDO 2020). As reported, mean IGF-I levels of the OOC treatment group were maintained within normal range at the end of treatment in all patients. However, some patients may not respond to OOC treatment (25% of OOC group and 68% of placebo groups required rescue, P=0.003). This analysis describes the degree and rapidity with which patients achieve biochemical control (IGF-I ≤1.0 x ULN) when reverted to their prior injectable SRL treatment. Methods: Patients with confirmed acromegaly and receiving a stable dose of injectable SRL (≥3 months) were randomized to OOC (40mg/day; N=28) or placebo (N=28) for 36 weeks. Patients were dose titrated to 60 or 80mg of OOC (or placebo) through week 24 at investigator discretion based on increased IGF-I levels and/or worsening acromegaly signs/symptoms. Patients could be rescued via reversion to prior injectable SRL therapy if they met the predefined withdrawal criteria (i.e., IGF-I ≥1.3 x upper limit of normal [ULN] for 2 consecutive visits on the highest dose, and exacerbation of clinical signs/symptoms) or discontinued treatment early for any other reason. In the study, 7 patients in the OOC group and 19 in the placebo group required rescue. The change in IGF-I from Baseline was compared to the end of the Double-blind Placebo Controlled period. Results: In patients rescued up to week 32 and in whom there were at least 4 weeks of follow up, baseline IGF-I levels (mean of Screening Visit 2 and Baseline) were 0.80 and 0.87 x ULN in the OOC and placebo groups, respectively. In patients receiving rescue therapy, the end of study IGF-I levels (mean of week 34 and 36) were 0.80 and 0.89 x ULN in the OOC and placebo groups, respectively, virtually unchanged. The median time to return to normal baseline IGF-I values following loss of response was 4.0 weeks after discontinuing OOC and 4.0 weeks after discontinuing placebo treatment. Therefore, most patients who required rescue following a short trial of therapy with OOC returned to their baseline values following a single SRL injection. Conclusion: Most treatment failures in the CHIASMA OPTIMAL trial (on either OOC or placebo) rescued with injectable SRL re-established their baseline response levels after a single injectable SRL administration (at pre-study dose). Based on this data, patients may potentially be treated with OOC and for those not responding, either not biochemically controlled or who have adverse effects, they may be able to return to injectable SRLs with immediate IGF-I control after one SRL injection.

scholarly journals Biliary adverse events in acromegaly during somatostatin receptor ligands: predictors of onset and response to ursodeoxycholic acid treatment

Pituitary ◽  
2020 ◽  
Author(s):  
N. Prencipe ◽  
C. Bona ◽  
D. Cuboni ◽  
M. Parasiliti-Caprino ◽  
A. M. Berton ◽  
...  
Keyword(s):  
Adverse Events ◽  
Ursodeoxycholic Acid ◽  
Somatostatin Receptor ◽  
Stone Disease ◽  
Receptor Ligands ◽  
First Line ◽  
Metabolic Markers ◽  
Somatostatin Receptor Ligands ◽  
Igf I

Abstract Purpose Somatostatin receptor ligands (SRL) are the first-line medical treatment for acromegaly. Gallbladder alterations are one of most important SRL side effect, but according to some authors growth hormone hypersecretion itself is a risk factor for gallstones. This single center, longitudinal retrospective study evaluated the incidence and the predictors of biliary adverse events (BAE) in acromegaly during SRL therapy and their response to ursodeoxycholic acid (UDCA). Methods 91 acromegaly patients with indication to SRL were enrolled. Evaluations of acromegaly activity (GH, IGF-I, IGF-I/ULN) and metabolic profile were collected before starting treatment, yearly during follow-up and at BAE onset. In patients developing BAE we searched for predictors of UDCA effectiveness. Results 61.5% of patients developed BAE (58.9% cholelithiasis; 41.1% only sludge). IGF-I and IGF-I/ULN proved to be positive predictor of BAE, which occur about 5 years after SRL starting. None of metabolic markers proved to be associated with BAE. Only five patients (5.5%) underwent cholecystectomy for symptomatic cholelithiasis. 71% of patients started UDCA treatment, achieving regression of BAE in 60% of cases (88% in patients developing only sludge and 30% in patients affected by cholelithiasis, p < 0.001). BMI and obesity were negative predictors of UDCA efficacy. In 50% of the subjects BAE resolved after 36 months of therapy with a lower rate if cholelithiasis was present. Conclusion Biliary stone disease is a frequent SRL adverse event, although it is often symptomless. Ultrasound follow-up mainly in the first 5 years of therapy, early UDCA starting and proper lifestyle represent a valid strategy in their detection and management.

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