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    Clinical Trial Results:
    An open label exploratory study to evaluate the safety, pharmacokinetics and efficacy of CRN00808 in patients with acromegaly treated with somatostatin analogue based treatment regimens (ACROBAT EDGE)

    Summary
    EudraCT number
    		 2018-002230-20
    Trial protocol
    		 HU   SK   DE   GR   PL   GB   IT   RO  
    Global end of trial date
    31 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Sep 2024
    First version publication date
    27 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRN00808-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03789656
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Crinetics Pharmaceuticals, Inc.
    Sponsor organisation address
    6055 Lusk Blvd, San Diego, United States, CA 92121
    Public contact
    Crinetics Clinical Trials, Crinetics Pharmaceuticals, Inc., , Crinetics Pharmaceuticals, clinicaltrials@crinetics.com
    Scientific contact
    Crinetics Clinical Trials, Crinetics Pharmaceuticals, Inc., , Crinetics Pharmaceuticals, clinicaltrials@crinetics.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1.To evaluate the efficacy of paltusotine (CRN00808) in acromegaly subjects treated with somatostatin receptor ligand (SRL) based treatment regimens; 2.To evaluate the safety and tolerability of paltusotine (CRN00808)in acromegaly subjects; 3.To evaluate the pharmacokinetics (PK) of paltusotine (CRN00808)in acromegaly subjects.
    Protection of trial subjects
    This study was conducted in accordance with the protocol and the Declaration of Helsinki, as well as current ICH GCP guidelines and applicable regulatory requirements
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    Brazil: 13
    Worldwide total number of subjects
    47
    EEA total number of subjects
    19
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    39
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 45 subjects were planned to be enrolled in the study. 47 subjects participated in the study.

    Pre-assignment
    Screening details
    		 A total of 88 subjects were screened for eligibility, of which 41 were screen failures, and 47 subjects were enrolled in the study. Of the 47 subjects who received paltusotine (CRN00808), 42 subjects completed the trial, 4 subjects withdrew from the treatment period, and 1 subject withdrew during follow-up.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study, the study drug was not blinded. However, after the initial dose, further dose increases/decreases were blinded to the Investigator and subject.

    Arms
    Arm title
    		 Treatment
    Arm description
    		 This was a Phase 2, open-label, dose blinded, exploratory study designed to evaluate the efficacy, safety, and PK of paltusotine in subjects with acromegaly treated with SRL based treatment regimens. All patients enrolled in the study were treated with paltusotine. The first dose was 10mg for all subjects and uptitrated in a blinded manner from week 4 onwards.
    Arm type
    		 Experimental

    Investigational medicinal product name
    paltusotine
    Investigational medicinal product code
    CRN00808
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The first dose was 10 mg for all subjects at V3, which occurred 4 weeks after V1b, when the last dose of standard acromegaly treatment was administered. Subjects self administered the study drug (4 capsules daily). During the V6/W4 and V9/W7, the dose was titrated up in a blinded fashion, if the preceding IGF-1 values collected in V4/W2, and in V7/W5, respectively, were >0.9× ULN and if the subject tolerated the current dose. At V12/W10, the dose was titrated up in a blinded fashion, if the preceding IGF-1 value collected in V10/W8 was >ULN and if the subject tolerated the current dose. Dose increases in 10 mg increments were allowed only at the V6/W4 (from 10 mg to 20 mg), V9/W7 (from 10 mg to 20 mg, or from 20 mg to 30 mg), and V12/W10 (from 10 mg to 20 mg, from 20 mg to 30 mg, or from 30 mg to 40 mg). No further up-titration was allowed. The daily dose did not exceed 40 mg. No further treatment with the study drug was allowed after completion of V14/W13.

    Number of subjects in period 1
    		Treatment
    Started
    47
    Completed
    42
    Not completed
    5
         Consent withdrawn by subject
    1
         Unable to travel
    1
         COVID-19
    1
         Prohibited Medication
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 All subjects who received at least 1 dose of study drug. Of the 47 subjects who received CRN00808-03, 42 subjects completed the trial, 4 subjects withdrew from treatment period, and 1 subject withdrew consent during follow up. No subjects withdrew due to adverse events.

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 47 47
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 39 39
        From 65-84 years
    		 8 8
        85 years and over
    		 0 0
    Age continuous
    The median age of all subjects participating in the study
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 51.0 (43.0 to 61.0) -
    Gender categorical
    Units: Subjects
        Male
    		 20 20
        Female
    		 27 27
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 13 13
        Not Hispanic or Latino
    		 34 34
    Race
    Units: Subjects
        White
    		 42 42
        Asian
    		 1 1
        Black or African American
    		 2 2
        Other
    		 2 2
    Geographic Region
    Units: Subjects
        North America
    		 8 8
        Europe
    		 24 24
        Rest of World
    		 15 15
    Height
    For overall trial, based on n=46, one participant did not report. For group 1, based on n=24.
    Units: centimetre
        median (inter-quartile range (Q1-Q3))
    		 170.25 (165.00 to 176.10) -
    Weight
    For overall trial, based on n=46, one participant did not report. For group 1, based on n=24.
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 87.15 (75.10 to 104.20) -
    BMI
    For overall trial, based on n=46, one participant did not report. For group 1, based on n=24.
    Units: kilogram(s)/square metre
        median (inter-quartile range (Q1-Q3))
    		 29.95 (26.50 to 34.80) -
    Ring Size
    For overall trial, based on n=46, one participant did not report. For group 1, based on n=24.
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    		 12.0 (9.0 to 13.0) -
    IGF-1 (x ULN) at Baseline
    Units: x ULN
        median (inter-quartile range (Q1-Q3))
    		 1.214 (0.965 to 1.466) -
    Serum Growth Hormone Levels
    Units: nanogram(s)/millilitre
        median (inter-quartile range (Q1-Q3))
    		 0.8733 (0.4688 to 1.6127) -
    Acromegaly Symptom Diary (ASD) Score
    For overall trial, based on n=20 For group 1, based on n=13 For group 2, based on n=4 For group 3, based on n=2
    Units: ASD Score
        median (inter-quartile range (Q1-Q3))
    		 12.00 (4.21 to 23.93) -
    IGFBP-3
    Units: x ULN
        median (inter-quartile range (Q1-Q3))
    		 0.786 (0.687 to 0.882) -
    Subject analysis sets

    Subject analysis set title
    Group 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy Analysis Set - Primary Analysis Population for all efficacy analyses. Only includes subjects from Group 1. Eligibility to enter this group was specified as: Partial responders on a stable treatment of octreotide long-acting release (LAR) or lanreotide depot (at least 1 Screening IGF-1 value was greater than upper limit of normal (ULN), and the V2 value was ≤2.5× ULN)

    Subject analysis set title
    Group 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligibility to enter this group was specified as: Partial responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (at least 1 Screening IGF-1 value was >ULN, and the V2 value was ≤2.5 × ULN)

    Subject analysis set title
    Group 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligibility to enter this group was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (mean of Screening IGF-1 values were ≤ULN)

    Subject analysis set title
    Group 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligibility to enter this group was specified as: Complete responders on a stable dose of pasireotide LAR (mean of Screening IGF-1 values were ≤ULN)

    Subject analysis set title
    Group 5
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Eligibility to enter this group was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and pegvisomant (mean of Screening IGF-1 values were ≤ULN).

    Subject analysis set title
    Group 1 - Octreotide LAR
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in Group 1 previously treated with Octreotide LAR

    Subject analysis set title
    Group 1 - Lanreotide depot
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in Group 1 previously treated with Lanreotide depot

    Subject analysis set title
    Group 3, 4, and 5
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligibility to enter group 3 was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (mean of Screening IGF-1 values were ≤ULN) Eligibility to enter group 4 was specified as: Complete responders on a stable dose of pasireotide LAR(mean of Screening IGF-1 values were ≤ULN) Eligibility to enter group 5 was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and pegvisomant (mean of Screening IGF-1 values were ≤ULN).

    Subject analysis sets values
    		 Group 1 Group 2 Group 3 Group 4 Group 5 Group 1 - Octreotide LAR Group 1 - Lanreotide depot Group 3, 4, and 5
    Number of subjects
    25
    10
    5
    4
    3
    13
    12
    7
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
        Adults (18-64 years)
    22
    8
    4
    3
    2
        From 65-84 years
    3
    2
    1
    1
    1
        85 years and over
    0
    0
    0
    0
    0
    Age continuous
    The median age of all subjects participating in the study
    Units: years
        median (inter-quartile range (Q1-Q3))
    52 (46.0 to 59.0)
    52.5 (39.0 to 61.0)
    51.0 (49.0 to 54.0)
    56.0 (48.0 to 64.5)
    38.0 (35.0 to 66.0)
    Gender categorical
    Units: Subjects
        Male
    14
    3
    2
    1
    0
        Female
    11
    7
    3
    3
    3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    4
    6
    2
    0
    1
        Not Hispanic or Latino
    21
    4
    3
    4
    2
    Race
    Units: Subjects
        White
    25
    5
    5
    4
    3
        Asian
    0
    1
    0
    0
    0
        Black or African American
    0
    2
    0
    0
    0
        Other
    0
    2
    0
    0
    0
    Geographic Region
    Units: Subjects
        North America
    3
    1
    0
    2
    2
        Europe
    18
    2
    1
    2
    1
        Rest of World
    4
    7
    4
    0
    0
    Height
    For overall trial, based on n=46, one participant did not report. For group 1, based on n=24.
    Units: centimetre
        median (inter-quartile range (Q1-Q3))
    173.95 (166.50 to 178.50)
    167.75 (160.00 to 173.00)
    173.00 (164.00 to 176.00)
    169.45 (168.45 to 179.65)
    157.50 (155.50 to 169.00)
    Weight
    For overall trial, based on n=46, one participant did not report. For group 1, based on n=24.
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    90.95 (76.05 to 103.60)
    84.95 (75.00 to 117.00)
    87.30 (79.70 to 88.20)
    107.00 (88.75 to 114.35)
    77.50 (59.00 to 82.40)
    BMI
    For overall trial, based on n=46, one participant did not report. For group 1, based on n=24.
    Units: kilogram(s)/square metre
        median (inter-quartile range (Q1-Q3))
    29.25 (26.30 to 34.15)
    30.30 (27.90 to 38.10)
    28.50 (28.20 to 30.40)
    34.85 (29.55 to 37.25)
    31.20 (20.70 to 34.10)
    Ring Size
    For overall trial, based on n=46, one participant did not report. For group 1, based on n=24.
    Units: millimetre(s)
        median (inter-quartile range (Q1-Q3))
    12.5 (9.5 to 14.5)
    12.0 (9.0 to 12.0)
    11.0 (10.0 to 12.0)
    12.5 (9.5 to 19.0)
    8.0 (8.0 to 9.0)
    IGF-1 (x ULN) at Baseline
    Units: x ULN
        median (inter-quartile range (Q1-Q3))
    1.335 (1.078 to 1.471)
    1.400 (1.214 to 1.650)
    0.922 (0.864 to 0.928)
    0.659 (0.600 to 0.842)
    0.909 (0.806 to 0.964)
    Serum Growth Hormone Levels
    Units: nanogram(s)/millilitre
        median (inter-quartile range (Q1-Q3))
    0.6907 (0.4910 to 1.5545)
    1.0490 (0.5118 to 1.6127)
    0.8733 (0.7088 to 1.5585)
    0.1976 (0.1518 to 0.6460)
    2.8763 (0.1403 to 10.2843)
    Acromegaly Symptom Diary (ASD) Score
    For overall trial, based on n=20 For group 1, based on n=13 For group 2, based on n=4 For group 3, based on n=2
    Units: ASD Score
        median (inter-quartile range (Q1-Q3))
    13.50 (5.29 to 24.00)
    8.79 (3.29 to 17.71)
    2.21 (1.00 to 3.43)
    43.14 (43.14 to 43.14)
    IGFBP-3
    Units: x ULN
        median (inter-quartile range (Q1-Q3))
    0.789 (0.736 to 0.899)
    0.803 (0.725 to 0.886)
    0.684 (0.668 to 0.693)
    0.585 (0.540 to 0.788)
    0.716 (0.662 to 0.754)

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 This was a Phase 2, open-label, dose blinded, exploratory study designed to evaluate the efficacy, safety, and PK of paltusotine in subjects with acromegaly treated with SRL based treatment regimens. All patients enrolled in the study were treated with paltusotine. The first dose was 10mg for all subjects and uptitrated in a blinded manner from week 4 onwards.

    Subject analysis set title
    Group 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy Analysis Set - Primary Analysis Population for all efficacy analyses. Only includes subjects from Group 1. Eligibility to enter this group was specified as: Partial responders on a stable treatment of octreotide long-acting release (LAR) or lanreotide depot (at least 1 Screening IGF-1 value was greater than upper limit of normal (ULN), and the V2 value was ≤2.5× ULN)

    Subject analysis set title
    Group 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligibility to enter this group was specified as: Partial responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (at least 1 Screening IGF-1 value was >ULN, and the V2 value was ≤2.5 × ULN)

    Subject analysis set title
    Group 3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligibility to enter this group was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (mean of Screening IGF-1 values were ≤ULN)

    Subject analysis set title
    Group 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligibility to enter this group was specified as: Complete responders on a stable dose of pasireotide LAR (mean of Screening IGF-1 values were ≤ULN)

    Subject analysis set title
    Group 5
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Eligibility to enter this group was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and pegvisomant (mean of Screening IGF-1 values were ≤ULN).

    Subject analysis set title
    Group 1 - Octreotide LAR
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in Group 1 previously treated with Octreotide LAR

    Subject analysis set title
    Group 1 - Lanreotide depot
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in Group 1 previously treated with Lanreotide depot

    Subject analysis set title
    Group 3, 4, and 5
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligibility to enter group 3 was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (mean of Screening IGF-1 values were ≤ULN) Eligibility to enter group 4 was specified as: Complete responders on a stable dose of pasireotide LAR(mean of Screening IGF-1 values were ≤ULN) Eligibility to enter group 5 was specified as: Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and pegvisomant (mean of Screening IGF-1 values were ≤ULN).

    Primary: Efficacy Analysis Set (EAS)

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    End point title
    		 Efficacy Analysis Set (EAS) [1]
    End point description
    Change from baseline in IGF-1 level at Week 13/End of Treatment (W13/EoT) in Group 1 subjects Efficacy Analysis Set (EAS). The primary efficacy analyses, using the EAS, evaluated change from Baseline to W13, at an alpha level of 0.05, using the Wilcoxon Signed-Rank test. Descriptive statistics of values and change from Baseline by group and total were presented including the arithmetic and geometric means with associated 95% CIs. Baseline value was defined as mean of IGF-1 prior to first dose. Last on treatment assessment was used for W13/EoT if subject discontinued before W13. p = 0.6285
    End point type
    Primary
    End point timeframe
    Change from baseline in IGF-1 level at W13/EoT in Group 1 subjects Efficacy Analysis Set (EAS).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Please review endpoint description for details of statistical analyses performed
    End point values
    		 Group 1
    Number of subjects analysed
    25
    Units: × ULN
    median (inter-quartile range (Q1-Q3))
        Change from Baseline
    -0.034 (-0.107 to 0.107)
    No statistical analyses for this end point

    Secondary: Proportion of subjects with IGF-1 ≤ULN in Groups 3, 4 and 5 subjects only at W13/EoT

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    End point title
    		 Proportion of subjects with IGF-1 ≤ULN in Groups 3, 4 and 5 subjects only at W13/EoT
    End point description
    The secondary endpoint was the proportion of subjects who maintained IGF-1 response, defined as the last assessment before the EoT with IGF-1 ≤1.0× ULN meet responder criteria, in Group 3, 4, and 5 subjects only at W13/EoT. Data were analysed using Clopper-Pearson method. The number/percentage, with associated two-sided exact (Clopper-Pearson) 95% CIs, of subjects in each category (response/non-response) were presented by group and total for the full analysis set (FAS), limited to Groups 3, 4, and 5, including a nominal p-value from an exact binomial test. p value =0.3877 for groups 3, 4, and 5.
    End point type
    Secondary
    End point timeframe
    Proportion of subjects with IGF-1 ≤ULN in Groups 3, 4, and 5 subjects at W13/EoT.
    End point values
    		 Group 3, 4, and 5
    Number of subjects analysed
    12
    Units: Subjects
        W13/EoT (Response)
    4
        W13/EoT (No Response)
    8
    No statistical analyses for this end point

    Secondary: Proportion of subjects with IGF-1 ≤1.5× ULN at W13/EoT

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    End point title
    		 Proportion of subjects with IGF-1 ≤1.5× ULN at W13/EoT
    End point description
    Proportion of subjects who maintained ICG-1 response, defined as last assessment before EoT with IGF-1 ≤1.5× ULN. Values, with associated two-sided exact (Clopper-Pearson) 95% CIs, of subjects in each category (number and percentage) were presented by group and total for FAS, including a nominal p-value from an exact binomial test. Endpoint was analyzed for lanreotide vs octreotide subgroup using EAS. p value = 0.0041
    End point type
    Secondary
    End point timeframe
    Proportion of subjects with IGF-1 ≤1.5× ULN at W13/EoT.
    End point values
    		 Group 1
    Number of subjects analysed
    25
    Units: Subjects
        W13/EoT (Response)
    20
        W13/EoT (No Response)
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Subjects were monitored until the end of the 4-week follow-up period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Partial responders on a stable treatment of octreotide long-acting release (LAR) or lanreotide depot (at least 1 Screening IGF-1 value was greater than upper limit of normal (ULN), and the V2 value was ≤2.5× ULN)

    Reporting group title
    Group 2
    Reporting group description
    		 Partial responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (at least 1 Screening IGF‑1 value was >ULN, and the V2 value was ≤2.5 × ULN)

    Reporting group title
    Group 3
    Reporting group description
    		 Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and a dopamine agonist (bromocriptine or cabergoline) (mean of Screening IGF-1 values were ≤ULN)

    Reporting group title
    Group 4
    Reporting group description
    		 Complete responders on a stable dose of pasireotide LAR (mean of Screening IGF‑1 values were ≤ULN)

    Reporting group title
    Group 5
    Reporting group description
    		 Complete responders on a stable combination treatment of SRL (ie, octreotide LAR or lanreotide depot) and pegvisomant (mean of Screening IGF-1 values were ≤ULN).

    Serious adverse events
    		 Group 1 Group 2 Group 3 Group 4 Group 5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Group 1 Group 2 Group 3 Group 4 Group 5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 25 (80.00%)
    8 / 10 (80.00%)
    3 / 5 (60.00%)
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 25 (32.00%)
    4 / 10 (40.00%)
    1 / 5 (20.00%)
    2 / 4 (50.00%)
    1 / 3 (33.33%)
         occurrences all number
    15
    13
    2
    4
    2
    Paresthesia
         subjects affected / exposed
    4 / 25 (16.00%)
    2 / 10 (20.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    10
    6
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 25 (20.00%)
    5 / 10 (50.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    9
    12
    0
    0
    0
    Peripheral swelling
         subjects affected / exposed
    3 / 25 (12.00%)
    3 / 10 (30.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    6
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    2
    0
    2
    1
    Abdominal discomfort
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    0
    1
    0
    Abdominal distension
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    3
    2
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Sleep apnea syndrome
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 10 (40.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    5
    6
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 25 (20.00%)
    4 / 10 (40.00%)
    0 / 5 (0.00%)
    2 / 4 (50.00%)
    2 / 3 (66.67%)
         occurrences all number
    9
    5
    0
    5
    2
    Back pain
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperglycemia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2019
    • Added patient-facing QoL and acromegaly symptom scales with corresponding adjustments to the study secondary/exploratory endpoints. The purpose of these scales was to collect patient-reported data to further the development of a scale to assess the symptom burden of acromegaly. • Added additional stopping criteria for cardiac, liver, and other clinical conditions. • Changed to the pre-dose collection of IGF-1 samples for endpoint-related visits. • Modification of certain inclusion/exclusion criteria and additional administrative updates.
    07 Jun 2019
    • The demotion of a Secondary Endpoint to an Exploratory Endpoint (Proportion of subjects who achieved serum GH <5.0 ng/mL at W13). • Certain visits where minimal study procedures were performed were changed to Phone Call visits instead of site visits to reduce visit burden on subjects. • Changes to IGF-1 sample collection and titration criteria were made due to the change in visit structure of certain visits from site to Phone Visits. • Included the option to allow for certain visits to be conducted by mobile home health professionals at the option of the PI and subject. These home health assessments were performed by qualified and trained staff and under the supervision of each site PI, with activities specifically delegated by the PI. • Reduction in collection time-points of the ASD. • Changes to ASD scale question, wording, and scoring of the total ASD. • Subjects with prior radiation therapy in some circumstances were allowed to enroll in the study if there was recent documented evidence of elevated IGF-1 values, which indicated that the radiation therapy was not contributing to efficacy at baseline.
    24 Mar 2020
    COVID-19 Emergency Amendment - Changes to Study visit schedule and assessments - Changes to Subject Withdrawal Criteria - Changes to Provision of Study Drug and Study Supplies - Changes to IGF-1 Measurements and Titration For Titration Visits, if prior IGF-1 data are not available at the time of potential dose up-titration visits, and tolerability has been evaluated by the Investigator and considered acceptable, the study drug dose will be up-titrated in 10 mg increments as per current protocol titration.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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