Comparison of Oral Octreotide Capsules to Injectable Somatostatin Analogs in Acromegaly

Acromegaly Clinical Trial

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Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02685709
• Other study ID #: OOC-ACM-302
• Secondary ID: 2015-002854-11
• Status: Completed
• Phase: Phase 3
• Start date: February 2016
• Est. completion date: August 2021

Study information

• Verified date: March 2022
• Source: Chiasma, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 146
• Est. completion date: August 2021
• Est. primary completion date: October 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Acromegaly

Intervention

Drug:
• Octreotide capsules

Locations

Country	Name	City	State
Austria	Universitätsklinik für Innere Medizin Klinische Abteilung für Endokrinologie und Diabetologie	Graz
Austria	Medizinische Universität Wien	Wien
France	Hospices Civils de Lyon	Bron
France	Hôpital Bicêtre APHP	Le Kremlin-Bicêtre
Germany	Praxis für Endokrinologie und Diabetologie Dr M Droste	Oldenburg
Hungary	Magyar Honvedseg Egeszsegugyi Kozpont	Budapest
Hungary	University of Pecs	Pecs
Hungary	Szegedi Tudományegyetem, I. Belgyógyászati Klinika	Szeged
Italy	Policlinico di Monserrato U.O.C. Endocrinologia e Diabetologia	Monserrato
Italy	Università di Pisa Dipartimento di Medicina Clinica e Sperimentale	Pisa
Italy	Fondazione Policlinico Universitario A. Gemelli Università Cattolica del S.Cuore S.C. Endocrinologia e Malattie del Metabolismo	Rome
Lithuania	Hospital of LUHS Kauno Klinikos	Kaunas
Lithuania	Vaidotas Urbanavicius Individuali Imone	Vilnius
Poland	Katedra i Klinika Endokrynologii i Chorob Wewnetrznych Gdanski Uniwersytet Medyczny	Gdansk
Poland	Samodzielny Publiczny Szpital Kliniczny nr 1 we Wroclawiu, Klinika Endokrynologii, Diabetologii i Leczenia Izotopami	Wroclaw
Romania	"C.I. Parhon" National Institute of Endocrinology I Clinical Endocrinology Department - Endemic goitier and its complications	Bucharest
Russian Federation	Antrium Multidisciplinary Medical Clinic	Barnaul
Russian Federation	Interregional Clinical Diagnostic Center	Kazan
Russian Federation	Regional State Budgetary Healthcare Institution Regional State Hospital	Krasnoyarsk
Russian Federation	"Atlas" Medical Center	Moscow
Russian Federation	Sechenov Moscow First State Medical University	Moscow
Russian Federation	Vladimirsky Moscow Regional Research Clinical Institute	Moscow
Russian Federation	Novosibirsk State Regional Clinical Hospital	Novosibirsk
Russian Federation	Federal State Budgetary Institution "V. A. Almazov Federal North-West Medical Research Centre" of the Ministry of Health of the Russian Federation	Saint-Petersburg
Russian Federation	"Centre Diabetes" LLC	Samara
Serbia	Clinical Centre of Serbia, Clinic for Endocrinology Diabetes and Metabolic Diseases	Belgrade
Spain	Hospital Universitario de la Ribera	Alzira
Spain	Hospital Universitari Germans Trias i Pujol	Barcelona
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Complejo Hospitalario Universitario de Santiago de Compostela	Santiago de Compostela
Spain	Campus Del Hospital Universitario Virgen del Rocio	Sevilla
United Kingdom	University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital	Birmingham
United Kingdom	Central Manchester University Hospitals NHS Foundation Trust, Manchester Royal Infirmary	Manchester
United Kingdom	Royal Victoria Infirmary	Newcastle upon Tyne
United Kingdom	Royal Hallamshire Hospital	Sheffield
United States	Emory University	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	John H. Stroger, Jr. Hospital of Cook County	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Baylor College of Medicine	Houston	Texas
United States	Houston Methodist Research Institute	Houston	Texas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Keck Medical Center of University of Southern California	Los Angeles	California
United States	Rutgers - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Columbia University Medical Center	New York	New York
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Allegheny Endocrinology Associates	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Stanford University School of Medicine	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Chiasma, Inc.

Countries where clinical trial is conducted

United States,  Austria,  France,  Germany,  Hungary,  Italy,  Lithuania,  Poland,  Romania,  Russian Federation,  Serbia,  Spain,  United Kingdom, 

References & Publications (2)

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):. — View Citation

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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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