Comparison of Oral Octreotide Capsules to Injectable Somatostatin Analogs in Acromegaly (MPOWERED)

A Phase 3, Randomized, Active Controlled Study to Evaluate Maintenance of Response, Safety and Patient Reported Outcomes in Acromegaly Patients Treated With Octreotide Capsules vs. Parenteral Somatostatin Receptor Ligands

Octreotide capsule is a novel, orally-administered formulation of the commercially-available injectable drug octreotide. In a recent phase 3 trial (OPTMAL; NCT03252353), oral octreotide capsules demonstrated sustained biochemical response up to 13 months in patients with acromegaly previously managed with somatostatin analog injections (ref).

The objective of this study was to compare the efficacy, safety, and patient reported outcomes (PROs) between oral octreotide capsules and injectable somatostatin receptor ligands (SRLs).

Study Overview

• Status: Completed
• Conditions: Acromegaly
• Intervention / Treatment: Drug: Octreotide capsules

Detailed Description

This was phase 3, randomized, open-label, active controlled, multicenter study to evaluate the maintenance of response, safety and patient reported outcomes (PROs) in acromegaly patients treated with octreotide capsules and in patients treated with standard of care parenteral somatostatin receptor ligands (SRLs), who previously tolerated and demonstrated biochemical control on both treatments.

The core study consisted of three phases: a Screening phase, Run-in phase and a Randomized Controlled Treatment (RCT) phase.

Eligible patients who were biochemically controlled on parenteral SRLs were switched to octreotide capsules for a 26-week period Run-in phase. During this phase the effective dose for each patient was determined through dose titration.

Patients whose acromegaly has been controlled biochemically on octreotide capsules at the end of the Run-in phase entered a 36-week open-label RCT phase, where they randomized to continue on octreotide capsules or switch back to their injectable SRL treatment (as received prior to Screening).

Following the completion of the core study (Screening, Run-in and RCT phases), eligible patients were offered to enter the Study Extension phase and receive octreotide capsules until product marketing or study termination.

A Sub-study, performed in selected non-European sites, allowed patients with inadequate biochemical control on octreotide capsules during the Run-in phase to enter a Combination phase and receive co-administration of octreotide capsules with cabergoline tablets for a total of 36 weeks.

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, A-8036
    • Universitätsklinik für Innere Medizin Klinische Abteilung für Endokrinologie und Diabetologie
  • Wien, Austria, A-1090
    • Medizinische Universität Wien
• France
  • Bron, France, 69677
    • Hospices Civils de Lyon
  • Le Kremlin-Bicêtre, France, 94275
    • Hôpital Bicêtre APHP
• Germany
  • Oldenburg, Germany, 26122
    • Praxis für Endokrinologie und Diabetologie Dr M Droste
• Hungary
  • Budapest, Hungary, H-1062
    • Magyar Honvedseg Egeszsegugyi Kozpont
  • Pecs, Hungary, H-7624
    • University of Pecs
  • Szeged, Hungary, H-6720
    • Szegedi Tudományegyetem, I. Belgyógyászati Klinika
• Italy
  • Monserrato, Italy, 09042
    • Policlinico di Monserrato U.O.C. Endocrinologia e Diabetologia
  • Pisa, Italy, 56124
    • Università di Pisa Dipartimento di Medicina Clinica e Sperimentale
  • Rome, Italy, 00168
    • Fondazione Policlinico Universitario A. Gemelli Università Cattolica del S.Cuore S.C. Endocrinologia e Malattie del Metabolismo
• Lithuania
  • Kaunas, Lithuania, LT-50009
    • Hospital of LUHS Kauno Klinikos
  • Vilnius, Lithuania, LT-10207
    • Vaidotas Urbanavicius Individuali Imonė
• Poland
  • Gdańsk, Poland, 80-211
    • Katedra i Klinika Endokrynologii i Chorob Wewnetrznych Gdanski Uniwersytet Medyczny
  • Wroclaw, Poland, 50-367
    • Samodzielny Publiczny Szpital Kliniczny nr 1 we Wroclawiu, Klinika Endokrynologii, Diabetologii i Leczenia Izotopami
• Romania
  • Bucharest, Romania, 011863
    • "C.I. Parhon" National Institute of Endocrinology I Clinical Endocrinology Department - Endemic goitier and its complications
• Russian Federation
  • Barnaul, Russian Federation, 656043
    • Antrium Multidisciplinary Medical Clinic
  • Kazan, Russian Federation, 420101
    • Interregional Clinical Diagnostic Center
  • Krasnoyarsk, Russian Federation, 660022
    • Regional State Budgetary Healthcare Institution Regional State Hospital
  • Moscow, Russian Federation, 119881
    • Sechenov Moscow First State Medical University
  • Moscow, Russian Federation, 121170
    • "Atlas" Medical Center
  • Moscow, Russian Federation, 129110
    • Vladimirsky Moscow Regional Research Clinical Institute
  • Novosibirsk, Russian Federation, 630087
    • Novosibirsk State Regional Clinical Hospital
  • Saint-Petersburg, Russian Federation, 194156
    • Federal State Budgetary Institution "V. A. Almazov Federal North-West Medical Research Centre" of the Ministry of Health of the Russian Federation
  • Samara, Russian Federation, 443041
    • "Centre Diabetes" LLC
• Serbia
  • Belgrade, Serbia, 11 000
    • Clinical Centre of Serbia, Clinic for Endocrinology Diabetes and Metabolic Diseases
• Spain
  • Alzira, Spain, 46600
    • Hospital Universitario de La Ribera
  • Barcelona, Spain, 08916
    • Hospital Universitari Germans Trias i Pujol
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Santiago de Compostela, Spain, 15706
    • Complejo Hospitalario Universitario de Santiago de Compostela
  • Sevilla, Spain, 46013
    • Campus Del Hospital Universitario Virgen del Rocio
• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital
  • Manchester, United Kingdom, M13 9WL
    • Central Manchester University Hospitals NHS Foundation Trust, Manchester Royal Infirmary
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • Royal Victoria Infirmary
  • Sheffield, United Kingdom, S10 2JF
    • Royal Hallamshire Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90033
      • Keck Medical Center of University of Southern California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • John H. Stroger, Jr. Hospital of Cook County
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers - Robert Wood Johnson Medical School
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43203
      • The Ohio State University Wexner Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Endocrinology Associates
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Houston Methodist Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed diagnosis of acromegaly
• Treatment with Somatostatin analogs injections (octreotide or lanreotide) for at least 6 months
• Biochemical control (IGF -1 < 1.3 x ULN and GH < 2.5ng/mL)

Exclusion Criteria:

• Injections of long-acting somatostatin analogs, at a dosing interval > 8 weeks.
• Pituitary radiotherapy within 5 years
• Pituitary surgery within six months
• Patients who previously participated in CH-ACM-01 study
• Any clinically significant uncontrolled concomitant disease
• Symptomatic cholelithiasis
• Previous treatment with:
• Pegvisomant, within 12 weeks
• Dopamine agonists, within 6 weeks
• Pasireotide, within 12 weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Run-in phase; Oral octreotide capsules	Drug: Octreotide capsules; Other Names: Injection SRLs
Experimental: RCT phase - Oral; Oral octreotide capsules	Drug: Octreotide capsules; Other Names: Injection SRLs
Active Comparator: RCT phase - Injectables; Injectable somatostatin analogs (octreotide or lanreotide)	Drug: Octreotide capsules; Other Names: Injection SRLs
Experimental: Combination phase (sub-study); Octreotide capsules plus cabergoline	Drug: Octreotide capsules; Other Names: Injection SRLs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Who Are Biochemically Controlled Throughout the RCT Phase	Proportion of patients who are biochemically controlled throughout the RCT phase. A patient was considered biochemically controlled if IGF-1 Time Weighted Average (TWA) during the RCT phase is <1.3 ULN	62 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With Clinical and Biochemical Control at the End of the RCT Phase	Proportion of patients with clinical and biochemical control at the end of the RCT phase. Patients were considered biochemically and clinically controlled if they met both of the following criteria: Their IGF-1 TWA during the RCT phase was <1.3 times ULN; Their AIS score at week 62/EOT was maintained or reduced compared to week 26 (start of RCT phase)	Week 62/ End of treatment; EOT
Proportion of Patients Who Maintain or Reduce the Overall Number of Active Acromegaly Symptoms at the End of the RCT Phase	Proportion of patients who maintain or reduce the overall number of active acromegaly symptoms at the end of the RCT phase (week 62/ EOT) , compared to week 26 (start of the RCT phase	62 weeks
Proportion of Patients Who Maintain or Improve Their Overall Acromegaly Index of Severity (AIS) Score at the End of the RCT Phase	Proportion of patients who maintain or improve their overall Acromegaly index of severity (AIS) score at the end of the RCT phase (improvement defined as a reduction of at least one point in the AIS score), compared to week 26 (start of the RCT phase)	62 weeks
Proportion of Patients of Those Completing the RCT Phase Who Entered the Study Extension Phase	Proportion of patients of those completing the RCT phase (at a time octreotide capsules were not commercially available at the specific country), who entered the Study Extension phase, overall and by treatment group	62 weeks
Change in IGF-1 Levels in the RCT Phase	Change in IGF-1 levels from the start of the randomized phase to the end of RCT phase. Complete Responder (CR) is defined as IGF-1 ≤ 1 x ULN; Partial Responder (PR) is defined as 1 x ULN < IGF-1 < 1.3 x ULN, and Non-Responder (NR): IGF-1 ≥ 1.3 x ULN	Change from Week 26 to week 62
Change in GH Levels in the RCT Phase	Change in GH levels from the start of the randomized phase through the end of RCT phase.	Change from Week 26 to week 62

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients Reporting Injection Site Reactions in the Acro-TSQ During the RCT Phase	Proportion of patients reporting injection site reactions (ISRs). Acromegaly treatment satisfaction questionnaire (ACRO-TSQ) is a validated PRO tool assessing overall convenience and satisfaction with treatment and patient perception of symptomatic control and adverse drug. It includes 6 scales: Symptom Interference, (4 items); Treatment Convenience, (6 items); Injection Site Interference (2 items); GI Interference (3 items); Treatment Satisfaction, (3 items); and Emotional Reaction (3 items). Each scale score can range from 0 to 100, with 0 representing the lowest (highest burden/lower satisfaction) and 100 representing the best possible score (lowest burden/highest satisfaction) for each of the 6 scales. Positive ACRO-TSQ change scores indicate improvement while negative change scores indicate worsening.	62 weeks
Proportion of Patients Reporting Interference With Daily Activities in Acro-TSQ During the RCT Phase	Proportion of patients reporting interference with daily activities in the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ) during the RCT phase. Acro-TSQ is a validated PRO tool assessing overall convenience and satisfaction with treatment and patient perception of symptomatic control and adverse drug. It includes 6 scales: Symptom Interference, (4 items); Treatment Convenience, (6 items); Injection Site Interference (2 items); GI Interference (3 items); Treatment Satisfaction, (3 items); and Emotional Reaction (3 items). Each scale score can range from 0 to 100, with 0 representing the lowest (highest burden/lower satisfaction) and 100 representing the best possible score (lowest burden/highest satisfaction) for each of the 6 scales. Positive Acro-TSQ change scores indicate improvement while negative change scores indicate worsening.	62 weeks
Proportion of Patients on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark Analysis	Proportion of patients on octreotide capsules who are biochemically controlled at the end of the RCT phase defined as IGF-1< 1.3 x ULN based on average of weeks 58 and 62	Average of weeks 58 and 62
Proportion of Week 26 Responders on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark Sensitivity Analysis	Proportion of patients on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark sensitivity analysis- Week 26 responders	62 weeks
Proportion of Patients Biochemically Controlled at the End of Run-in	Proportion of patients biochemically controlled at the end of the Run-in phase, defined as average IGF-1 levels during weeks 24 and 26 < 1.3xULN	26 weeks
Proportion of Patients With a Reduction in the Overall Number of Active Acromegaly Symptoms at the End of the Run-in Phase	Proportion of patients with a reduction in the overall number of active acromegaly symptoms at the end of the Run-in phase compared to Baseline	26 weeks
Proportion of Patients With Improved Acromegaly Index of Severity (AIS) Score at the End of the Run-in Phase	Proportion of patients with improved AIS score at the end of the Run-in phase compared to Baseline Acromegaly index of severity (AIS) at the end of Run-in phase compared to Baseline. The Acromegaly Index of Severity (AIS) symptom score is calculated based on the presence and severity of 5 acromegaly signs/symptoms: headache, swelling of extremities, joint pain, sweating, and fatigue. Each symptom was graded from no symptoms (score 0), to mild symptoms (1), moderate (2), or severe symptoms (3).	26 weeks
EuroQol - 5 Dimensions - 5 Levels (EQ-5D-5L) Index Scores During the Run-in Phase	Change from baselines in EQ-5D-5L Index scores in randomized participants during the Run-in phase. EQ-5D-5L (five severity levels EQ-5D) is a standardized instrument completed by the patient for use as a measure of health outcome applicable to a wide range of health conditions. It comprises 5 dimensions of health: mobility, ability to self care, ability to undertake usual activities, pain and discomfort, and anxiety and depression. Based on qualitative and quantitative studies conducted by the EuroQol Group, there are 5 levels under each domain: 'no problems' (assigned a value of 1), 'slight problems' (assigned a value of 2), 'moderate problems' (assigned a value of 3), 'severe problems' (assigned a value of 4), and 'unable to/extreme problems' (assigned a value of 5). An EQ-5D Index score is calculated based on the responses to these 5 dimensions of health. Weights for use in the index calculation are not universally available. Higher values represent better health states.	26 weeks
Change From Baseline to End of RCT Phase in WPAI	Work Productivity and Activity Impairment Questionnaire- RCT phase. WPAI:SHP is a standardized and validated PRO questionnaire to measure health outcomes in clinical trial settings. It measures time missed from work, impairment of work and regular activities due to overall health and symptoms, relative to measures of general health perceptions, role (physical), role (emotional), pain, symptom severity, and global measures of work and interference with regular activity. The WPAI yields 4 types of scores: (1) absenteeism (work time missed); (2) presenteeism (impairment at work/reduced on-the-job effectiveness); (3) work productivity loss (overall work impairment/absenteeism plus presenteeism); and (4) activity impairment. Each of the 4 WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity (i.e., worse outcomes).	26 weeks
Change From Baseline to End of Run-in Phase in WPAI	Work Productivity and Activity Impairment Questionnaire- Run-in phase. WPAI:SHP is a standardized and validated PRO questionnaire to measure health outcomes in clinical trial settings. It measures time missed from work, impairment of work and regular activities due to overall health and symptoms, relative to measures of general health perceptions, role (physical), role (emotional), pain, symptom severity, and global measures of work and interference with regular activity. The WPAI yields 4 types of scores: (1) absenteeism (work time missed); (2) presenteeism (impairment at work/reduced on-the-job effectiveness); (3) work productivity loss (overall work impairment/absenteeism plus presenteeism); and (4) activity impairment. Each of the 4 WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity (i.e., worse outcomes).	62 weeks
Change in Acromegaly Treatment Satisfaction Questionnaire (ACRO-TSQ) Scores From Baseline to End of Run-in in Randomized Patients.	Change in Acromegaly treatment satisfaction questionnaire (ACRO-TSQ) PRO questionnaire from baseline to end of Run-in phase in randomized patients. Acro-TSQ is a validated PRO tool assessing overall convenience and satisfaction with treatment and patient perception of symptomatic control and adverse drug. It includes 6 scales: Symptom Interference, (4 items); Treatment Convenience, (6 items); Injection Site Interference (2 items); GI Interference (3 items); Treatment Satisfaction, (3 items); and Emotional Reaction (3 items). Each scale score can range from 0 to 100, with 0 representing the lowest (highest burden/lower satisfaction) and 100 representing the best possible score (lowest burden/highest satisfaction) for each of the 6 scales. Positive Acro-TSQ change scores indicate improvement while negative change scores indicate worsening.	26 weeks

Collaborators and Investigators

• Sponsor: Chiasma, Inc.
• Investigators: Study Chair: Maria Fleseriu, M.D., FACE, Northwest Pituitary Center, Oregon Health & Science University , Portland, OR, USA

Publications and helpful links

General Publications

• Melmed S, Popovic V, Bidlingmaier M, Mercado M, van der Lely AJ, Biermasz N, Bolanowski M, Coculescu M, Schopohl J, Racz K, Glaser B, Goth M, Greenman Y, Trainer P, Mezosi E, Shimon I, Giustina A, Korbonits M, Bronstein MD, Kleinberg D, Teichman S, Gliko-Kabir I, Mamluk R, Haviv A, Strasburger C. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter phase III trial. J Clin Endocrinol Metab. 2015 Apr;100(4):1699-708. doi: 10.1210/jc.2014-4113. Epub 2015 Feb 9. Erratum In: J Clin Endocrinol Metab. 2016 Oct;101(10 ):3863. J Clin Endocrinol Metab. 2020 Dec 1;105(12):
• Melmed S. New therapeutic agents for acromegaly. Nat Rev Endocrinol. 2016 Feb;12(2):90-8. doi: 10.1038/nrendo.2015.196. Epub 2015 Nov 27.
• Fleseriu M, Dreval A, Bondar I, Vagapova G, Macut D, Pokramovich YG, Molitch ME, Leonova N, Raverot G, Grineva E, Poteshkin YE, Gilgun-Sherki Y, Ludlam WH, Patou G, Haviv A, Gordon MB, Biermasz NR, Melmed S, Strasburger CJ. Maintenance of response to oral octreotide compared with injectable somatostatin receptor ligands in patients with acromegaly: a phase 3, multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2022 Feb;10(2):102-111. doi: 10.1016/S2213-8587(21)00296-5. Epub 2021 Dec 22. Erratum in: Lancet Diabetes Endocrinol. 2022 Mar;10(3):e3.

Helpful Links

• Click here for more information about Chiasma

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2016
• Primary Completion (Actual): October 1, 2020
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: January 28, 2016
• First Submitted That Met QC Criteria: February 14, 2016
• First Posted (Estimate): February 19, 2016

Study Record Updates

• Last Update Posted (Actual): April 22, 2022
• Last Update Submitted That Met QC Criteria: March 24, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Acromegaly; Octreotide Capsules; somatostatin receptor ligands (SRLs); Mpowered; OOC-ACM-302
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Musculoskeletal Diseases; Hypothalamic Diseases; Bone Diseases; Bone Diseases, Endocrine; Hyperpituitarism; Pituitary Diseases; Acromegaly; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Octreotide
• Other Study ID Numbers: OOC-ACM-302; 2015-002854-11 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No