Acromegaly
Conditions
Keywords
Octreotide Capsules, Acromegaly, somatostatin receptor ligands (SRLs), Mpowered, OOC-ACM-302
Brief 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).
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.
Interventions
Sponsors
Chiasma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Are Biochemically Controlled Throughout the RCT Phase | 62 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Maintain or Reduce the Overall Number of Active Acromegaly Symptoms at the End of the RCT Phase | 62 weeks | 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 |
| Proportion of Patients Who Maintain or Improve Their Overall Acromegaly Index of Severity (AIS) Score at the End 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 (improvement defined as a reduction of at least one point in the AIS score), compared to week 26 (start of the RCT phase) |
| Proportion of Patients With Clinical and Biochemical Control at the End of the RCT Phase | Week 62/ End of treatment; EOT | 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) |
| Change in IGF-1 Levels in the RCT Phase | Change from Week 26 to week 62 | 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 in GH Levels in the RCT Phase | Change from Week 26 to week 62 | Change in GH levels from the start of the randomized phase through the end of RCT phase. |
| Proportion of Patients of Those Completing the RCT Phase Who Entered the Study Extension Phase | 62 weeks | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| EuroQol - 5 Dimensions - 5 Levels (EQ-5D-5L) Index Scores During the Run-in Phase | 26 weeks | 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. |
| Change From Baseline to End of RCT Phase in WPAI | 26 weeks | 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). |
| Proportion of Patients Reporting Injection Site Reactions in the Acro-TSQ During the RCT Phase | 62 weeks | 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. |
| Change in Acromegaly Treatment Satisfaction Questionnaire (ACRO-TSQ) Scores From Baseline to End of Run-in in Randomized Patients. | 26 weeks | 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. |
| Change From Baseline to End of Run-in Phase in WPAI | 62 weeks | 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). |
| Proportion of Patients Reporting Interference With Daily Activities in Acro-TSQ During the RCT Phase | 62 weeks | 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. |
| Proportion of Patients on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark Analysis | Average of weeks 58 and 62 | 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 |
| Proportion of Week 26 Responders on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark Sensitivity Analysis | 62 weeks | Proportion of patients on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark sensitivity analysis- Week 26 responders |
| Proportion of Patients Biochemically Controlled at the End of Run-in | 26 weeks | 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 |
| Proportion of Patients With a Reduction in the Overall Number of Active Acromegaly Symptoms at the End of the Run-in Phase | 26 weeks | 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 |
| Proportion of Patients With Improved Acromegaly Index of Severity (AIS) Score at the End of the Run-in Phase | 26 weeks | 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). |
Countries
Austria, France, Germany, Hungary, Italy, Lithuania, Poland, Romania, Russia, Serbia, Spain, United Kingdom, United States
Participant flow
Recruitment details
146 patients were enrolled into the Run-in phase. A total of 116 patients completed the Run-in phase and 30 patients discontinued the Run in phase. Of the 116 patients who completed the Run-in phase, 92 patients with IGF-1\<1.3 ULN entered the RCT phase, 11 patients with IGF-1≥1.3 and \<2 ULN on the highest octreotide dose entered the Combination phase, and 13 patients did not continue treatment.
Pre-assignment details
Prior to Run-in - all patients treated with SRLs (59.6% octreotide and 39.4% on lanreotide). 78.8% of patients were treated with medium to high doses of SRLs. Prior to RCT - all patients were on oral octreotide capsules.
Participants by arm
| Arm | Count |
|---|---|
| Run-in Phase Oral octreotide capsules
Octreotide capsules: Octreotide capsules 40mg/day, 60mg/day, 80mg/day | 146 |
| RCT Phase - Oral Oral octreotide capsules
Octreotide capsules: Octreotide capsules 40mg/day, 60mg/day, 80mg/day | 55 |
| RCT Phase - Injectables Injectable somatostatin analogs (octreotide or lanreotide)
Injectable Somatostatin Analogs (octreotide or lanreotide): Octreotide - 10, 20, 30mg. Lanreotide 60,90, 120mg. | 37 |
| Combination Phase (Sub-study) Octreotide capsules plus cabergoline
Octreotide capsules: Octreotide capsules 40mg/day, 60mg/day, 80mg/day
Cabergoline: Cabergoline - 3.5mg/week | 14 |
| Total | 252 |
Baseline characteristics
| Characteristic | Combination Phase (Sub-study) | Total | RCT Phase - Injectables | RCT Phase - Oral | Run-in Phase |
|---|---|---|---|---|---|
| Acromegaly Index of Severity (AIS) symptom score Combination phase | 6.8 units on a scale STANDARD_DEVIATION 3.95 | 6.8 units on a scale STANDARD_DEVIATION 3.95 | — | — | — |
| Acromegaly Index of Severity (AIS) symptom score RCT phase | — | 4.5 units on a scale STANDARD_DEVIATION 2.96 | 5 units on a scale STANDARD_DEVIATION 2.98 | 4.2 units on a scale STANDARD_DEVIATION 2.92 | — |
| Acromegaly Index of Severity (AIS) symptom score Run-in phase | — | 4.8 units on a scale STANDARD_DEVIATION 3.1 | — | — | 4.8 units on a scale STANDARD_DEVIATION 3.1 |
| Age, Categorical Combination Phase <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Combination Phase >=65 years | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Combination Phase Between 18 and 65 years | 11 Participants | 11 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical RCT phase <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical RCT phase >=65 years | 0 Participants | 14 Participants | 5 Participants | 9 Participants | 0 Participants |
| Age, Categorical RCT phase Between 18 and 65 years | 0 Participants | 78 Participants | 32 Participants | 46 Participants | 0 Participants |
| Age, Categorical Run-in phase <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Run-in phase >=65 years | 0 Participants | 22 Participants | 0 Participants | 0 Participants | 22 Participants |
| Age, Categorical Run-in phase Between 18 and 65 years | 0 Participants | 124 Participants | 0 Participants | 0 Participants | 124 Participants |
| Age, Continuous Combination phase | 59.8 years STANDARD_DEVIATION 5.82 | 59.8 years STANDARD_DEVIATION 5.82 | — | — | — |
| Age, Continuous RCT phase | — | 54.5 years STANDARD_DEVIATION 10.05 | 55.2 years STANDARD_DEVIATION 8.78 | 54.1 years STANDARD_DEVIATION 10.88 | — |
| Age, Continuous Run-in phase | — | 54.1 years STANDARD_DEVIATION 10.5 | — | — | 54.1 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Combination phase Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Combination phase Not Hispanic or Latino | 14 Participants | 14 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Combination phase Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) RCT phase Hispanic or Latino | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) RCT phase Not Hispanic or Latino | 0 Participants | 83 Participants | 33 Participants | 50 Participants | 0 Participants |
| Ethnicity (NIH/OMB) RCT phase Unknown or Not Reported | 0 Participants | 6 Participants | 2 Participants | 4 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Run-in phase Hispanic or Latino | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Run-in phase Not Hispanic or Latino | 0 Participants | 130 Participants | 0 Participants | 0 Participants | 130 Participants |
| Ethnicity (NIH/OMB) Run-in phase Unknown or Not Reported | 0 Participants | 11 Participants | 0 Participants | 0 Participants | 11 Participants |
| GH Combination phase | 0.94 ng/ mL STANDARD_DEVIATION 0.544 | 0.94 ng/ mL STANDARD_DEVIATION 0.544 | — | — | — |
| GH RCT phase | — | 0.58 ng/ mL STANDARD_DEVIATION 0.579 | 0.62 ng/ mL STANDARD_DEVIATION 0.634 | 0.55 ng/ mL STANDARD_DEVIATION 0.544 | — |
| GH Run-in phase | — | 0.88 ng/ mL STANDARD_DEVIATION 0.818 | — | — | 0.88 ng/ mL STANDARD_DEVIATION 0.818 |
| IGF-1 levels Combination phase | 1.5 X Upper limit of normal (ULN) STANDARD_DEVIATION 0.35 | 1.5 X Upper limit of normal (ULN) STANDARD_DEVIATION 0.35 | — | — | — |
| IGF-1 levels RCT phase | — | 0.9 X Upper limit of normal (ULN) STANDARD_DEVIATION 0.3 | 0.8 X Upper limit of normal (ULN) STANDARD_DEVIATION 0.21 | 0.9 X Upper limit of normal (ULN) STANDARD_DEVIATION 0.35 | — |
| IGF-1 levels Run-in phase | — | 0.9 X Upper limit of normal (ULN) STANDARD_DEVIATION 0.27 | — | — | 0.9 X Upper limit of normal (ULN) STANDARD_DEVIATION 0.27 |
| IGF-I categorical Combination phase- ≥ 1.3 ULN | 9 Participants | 9 Participants | 0 Participants | 0 Participants | 0 Participants |
| IGF-I categorical Combination phase- > 1 to < 1.3 ULN | 4 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| IGF-I categorical Combination phase- ≤ 1 ULN | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| IGF-I categorical RCT phase- ≥ 1.3 ULN | 0 Participants | 6 Participants | 0 Participants | 6 Participants | 0 Participants |
| IGF-I categorical RCT phase- > 1 to < 1.3 ULN | 0 Participants | 20 Participants | 8 Participants | 12 Participants | 0 Participants |
| IGF-I categorical RCT phase- ≤ 1 ULN | 0 Participants | 66 Participants | 29 Participants | 37 Participants | 0 Participants |
| IGF-I categorical Run-in phase- ≥ 1.3 ULN | 0 Participants | 10 Participants | 0 Participants | 0 Participants | 10 Participants |
| IGF-I categorical Run-in phase- > 1 to < 1.3 ULN | 0 Participants | 38 Participants | 0 Participants | 0 Participants | 38 Participants |
| IGF-I categorical Run-in phase- ≤ 1 ULN | 0 Participants | 98 Participants | 0 Participants | 0 Participants | 98 Participants |
| Race (NIH/OMB) Combination phase American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Combination phase Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Combination phase Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Combination phase More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Combination phase Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Combination phase Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Combination phase White | 14 Participants | 14 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) RCT phase American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) RCT phase Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) RCT phase Black or African American | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) RCT phase More than one race | 0 Participants | 6 Participants | 2 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) RCT phase Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) RCT phase Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) RCT phase White | 0 Participants | 84 Participants | 35 Participants | 49 Participants | 0 Participants |
| Race (NIH/OMB) Run-in phase American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Run-in phase Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Run-in phase Black or African American | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Run-in phase More than one race | 0 Participants | 9 Participants | 0 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) Run-in phase Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Run-in phase Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Run-in phase White | 0 Participants | 133 Participants | 0 Participants | 0 Participants | 133 Participants |
| Region of Enrollment Austria | — | 5 Participants | 0 Participants | 5 Participants | 6 Participants |
| Region of Enrollment France | — | 6 Participants | 2 Participants | 4 Participants | 10 Participants |
| Region of Enrollment Germany | — | 1 Participants | — | — | 1 Participants |
| Region of Enrollment Hungary | — | 2 Participants | 1 Participants | 1 Participants | 3 Participants |
| Region of Enrollment Italy | — | 2 Participants | 0 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Lithuania | — | 2 Participants | 1 Participants | 1 Participants | 8 Participants |
| Region of Enrollment Russia | 10 Participants | 42 Participants | 18 Participants | 24 Participants | 65 Participants |
| Region of Enrollment Serbia | 1 Participants | 6 Participants | 2 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Spain | — | 6 Participants | 3 Participants | 1 Participants | 6 Participants |
| Region of Enrollment United States | 3 Participants | 37 Participants | 10 Participants | 14 Participants | 37 Participants |
| Sex: Female, Male Combination phase Female | 10 Participants | 10 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Combination phase Male | 4 Participants | 4 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male RCT phase Female | 0 Participants | 61 Participants | 26 Participants | 35 Participants | 0 Participants |
| Sex: Female, Male RCT phase Male | 0 Participants | 31 Participants | 11 Participants | 20 Participants | 0 Participants |
| Sex: Female, Male Run-in phase Female | 0 Participants | 94 Participants | 0 Participants | 0 Participants | 94 Participants |
| Sex: Female, Male Run-in phase Male | 0 Participants | 52 Participants | 0 Participants | 0 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 146 | 1 / 55 | 0 / 37 | 0 / 14 |
| other Total, other adverse events | 106 / 146 | 39 / 55 | 26 / 37 | 11 / 14 |
| serious Total, serious adverse events | 6 / 146 | 3 / 55 | 3 / 37 | 0 / 14 |
Outcome results
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
Time frame: 62 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients Who Are Biochemically Controlled Throughout the RCT Phase | 50 Participants |
| RCT Phase - Injectables | Proportion of Patients Who Are Biochemically Controlled Throughout the RCT Phase | 37 Participants |
95% CI: [-19.9, 0.5]Stratified Miettinen & Nurminen (M&N)
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.
Time frame: Change from Week 26 to week 62
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RCT Phase - Oral | Change in GH Levels in the RCT Phase | -0.02 ng/mL | Standard Deviation 0.506 |
| RCT Phase - Injectables | Change in GH Levels in the RCT Phase | 0.27 ng/mL | Standard Deviation 1.219 |
Comparison: Secondary endpoints were analyzed without adjustment for multiplicity or predefined noninferiority margins and therefore were interpreted as exploratory.~This endpoint is descriptive with no formal statistical hypothesis testing.
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
Time frame: Change from Week 26 to week 62
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RCT Phase - Oral | Change in IGF-1 Levels in the RCT Phase | -0.01 x Upper limit of normal (ULN) | Standard Deviation 0.199 |
| RCT Phase - Injectables | Change in IGF-1 Levels in the RCT Phase | -0.04 x Upper limit of normal (ULN) | Standard Deviation 0.133 |
Comparison: Secondary endpoints were analyzed without adjustment for multiplicity or predefined noninferiority margins and therefore were interpreted as exploratory.~This endpoint is descriptive with no formal statistical hypothesis testing.
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
Time frame: 62 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients of Those Completing the RCT Phase Who Entered the Study Extension Phase | 34 Participants |
| RCT Phase - Injectables | Proportion of Patients of Those Completing the RCT Phase Who Entered the Study Extension Phase | 18 Participants |
Comparison: Secondary endpoints were analyzed without adjustment for multiplicity or predefined noninferiority margins and therefore were interpreted as exploratory.Clopper-Pearson method
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)
Time frame: 62 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients Who Maintain or Improve Their Overall Acromegaly Index of Severity (AIS) Score at the End of the RCT Phase | 40 Participants |
| RCT Phase - Injectables | Proportion of Patients Who Maintain or Improve Their Overall Acromegaly Index of Severity (AIS) Score at the End of the RCT Phase | 25 Participants |
Comparison: Secondary endpoints were analyzed without adjustment for multiplicity or predefined noninferiority margins and therefore were interpreted as exploratory.~This endpoint is descriptive with no formal statistical hypothesis testing.
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
Time frame: 62 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients Who Maintain or Reduce the Overall Number of Active Acromegaly Symptoms at the End of the RCT Phase | 41 Participants |
| RCT Phase - Injectables | Proportion of Patients Who Maintain or Reduce the Overall Number of Active Acromegaly Symptoms at the End of the RCT Phase | 26 Participants |
Comparison: Secondary endpoints were analyzed without adjustment for multiplicity or predefined noninferiority margins and therefore were interpreted as exploratory.~This endpoint is descriptive with no formal statistical hypothesis testing.Clopper-Pearson method
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)
Time frame: Week 62/ End of treatment; EOT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients With Clinical and Biochemical Control at the End of the RCT Phase | 36 Participants |
| RCT Phase - Injectables | Proportion of Patients With Clinical and Biochemical Control at the End of the RCT Phase | 27 Participants |
Comparison: Secondary endpoints were analyzed without adjustment for multiplicity or predefined noninferiority margins and therefore were interpreted as exploratory.~This endpoint is descriptive with no formal statistical hypothesis testing.
Other Pre-specified
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).
Time frame: 26 weeks
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RCT Phase - Oral | Change From Baseline to End of RCT Phase in WPAI | Absenteeism (%) | -0.34 Percentage change from Baseline RCT |
| RCT Phase - Oral | Change From Baseline to End of RCT Phase in WPAI | Presenteeism (%) | 1.85 Percentage change from Baseline RCT |
| RCT Phase - Oral | Change From Baseline to End of RCT Phase in WPAI | Work productivity loss (%) | 1.49 Percentage change from Baseline RCT |
| RCT Phase - Oral | Change From Baseline to End of RCT Phase in WPAI | Activity impairment (%) | 0.84 Percentage change from Baseline RCT |
| RCT Phase - Injectables | Change From Baseline to End of RCT Phase in WPAI | Activity impairment (%) | 4.34 Percentage change from Baseline RCT |
| RCT Phase - Injectables | Change From Baseline to End of RCT Phase in WPAI | Absenteeism (%) | 0.79 Percentage change from Baseline RCT |
| RCT Phase - Injectables | Change From Baseline to End of RCT Phase in WPAI | Work productivity loss (%) | 6.93 Percentage change from Baseline RCT |
| RCT Phase - Injectables | Change From Baseline to End of RCT Phase in WPAI | Presenteeism (%) | 5.98 Percentage change from Baseline RCT |
Other Pre-specified
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).
Time frame: 62 weeks
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| RCT Phase - Oral | Change From Baseline to End of Run-in Phase in WPAI | Absenteeism (%) | -0.81 Percentage change from Run-in baseline |
| RCT Phase - Oral | Change From Baseline to End of Run-in Phase in WPAI | Presenteeism (%) | -6.65 Percentage change from Run-in baseline |
| RCT Phase - Oral | Change From Baseline to End of Run-in Phase in WPAI | Work Productivity Loss (%) | -6.92 Percentage change from Run-in baseline |
| RCT Phase - Oral | Change From Baseline to End of Run-in Phase in WPAI | Activity Impairment (%) | -4.94 Percentage change from Run-in baseline |
Other Pre-specified
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.
Time frame: 26 weeks
Population: Change in Acro-TSQ domains in randomized patients
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| RCT Phase - Oral | Change in Acromegaly Treatment Satisfaction Questionnaire (ACRO-TSQ) Scores From Baseline to End of Run-in in Randomized Patients. | Emotional reaction - Change from baseline | 9.65 score on a scale |
| RCT Phase - Oral | Change in Acromegaly Treatment Satisfaction Questionnaire (ACRO-TSQ) Scores From Baseline to End of Run-in in Randomized Patients. | GI interference - Change from baseline | 4.24 score on a scale |
| RCT Phase - Oral | Change in Acromegaly Treatment Satisfaction Questionnaire (ACRO-TSQ) Scores From Baseline to End of Run-in in Randomized Patients. | Symptom interference- Change from baseline | 2.45 score on a scale |
| RCT Phase - Oral | Change in Acromegaly Treatment Satisfaction Questionnaire (ACRO-TSQ) Scores From Baseline to End of Run-in in Randomized Patients. | Treatment convenience - Change from baseline | 6.37 score on a scale |
| RCT Phase - Oral | Change in Acromegaly Treatment Satisfaction Questionnaire (ACRO-TSQ) Scores From Baseline to End of Run-in in Randomized Patients. | Treatment satisfaction - Change from baseline | 6.73 score on a scale |
Other Pre-specified
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.
Time frame: 26 weeks
Population: All patients who were randomized to the RCT phase
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RCT Phase - Oral | EuroQol - 5 Dimensions - 5 Levels (EQ-5D-5L) Index Scores During the Run-in Phase | 0.0433 units on a scale |
Other Pre-specified
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
Time frame: 26 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients Biochemically Controlled at the End of Run-in | 94 Participants |
95% CI: [56, 72.1]
Other Pre-specified
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
Time frame: Average of weeks 58 and 62
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark Analysis | 49 Participants |
| RCT Phase - Injectables | Proportion of Patients on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark Analysis | 35 Participants |
Comparison: This endpoints is descriptive with no formal statistical hypothesis testing.
Other Pre-specified
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.
Time frame: 62 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients Reporting Injection Site Reactions in the Acro-TSQ During the RCT Phase | 0 Participants |
| RCT Phase - Injectables | Proportion of Patients Reporting Injection Site Reactions in the Acro-TSQ During the RCT Phase | 17 Participants |
Comparison: This endpoint is descriptive with no formal statistical hypothesis testing
Other Pre-specified
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.
Time frame: 62 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients Reporting Interference With Daily Activities in Acro-TSQ During the RCT Phase | 0 Participants |
| RCT Phase - Injectables | Proportion of Patients Reporting Interference With Daily Activities in Acro-TSQ During the RCT Phase | 13 Participants |
Comparison: This endpoint is descriptive with no formal statistical hypothesis testing.
Other Pre-specified
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
Time frame: 26 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients With a Reduction in the Overall Number of Active Acromegaly Symptoms at the End of the Run-in Phase | 97 Participants |
95% CI: [58.5, 74.1]
Other Pre-specified
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).
Time frame: 26 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Patients With Improved Acromegaly Index of Severity (AIS) Score at the End of the Run-in Phase | 45 Participants |
95% CI: [38.7, 59.1]
Other Pre-specified
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
Time frame: 62 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RCT Phase - Oral | Proportion of Week 26 Responders on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark Sensitivity Analysis | 45 Participants |
| RCT Phase - Injectables | Proportion of Week 26 Responders on Octreotide Capsules Who Are Biochemically Controlled at the End of the RCT Phase- Landmark Sensitivity Analysis | 34 Participants |
Comparison: This endpoints is descriptive with no formal statistical hypothesis testing