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    Clinical Trial Results:
    An Open-Label Extension Trial of IONIS GHR-LRX, an Antisense Inhibitor of the Growth Hormone Receptor Administered Monthly Subcutaneously to Patients with Acromegaly Being Treated with Long-Acting Somatostatin Receptor Ligands (SRL)

    Summary
    EudraCT number
    		 2019-000591-42
    Trial protocol
    		 HU   LT   PL   RO  
    Global end of trial date
    07 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2023
    First version publication date
    23 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS766720-CS3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03967249
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ionis Pharmaceuticals, Inc
    Sponsor organisation address
    2855 Gazelle Court, Carlsbad, CA 92010, United States,
    Public contact
    Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., +1 760603-3804, ClinicalTrials@ionisph.com
    Scientific contact
    Ionis Clinical Trial Information, Ionis Pharmaceuticals, Inc., +1 760603-3804, ClinicalTrials@ionisph.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
    07 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of extended dosing with ISIS 766720 in subjects with acromegaly.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Aug 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: 4
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Lithuania: 8
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Russian Federation: 16
    Worldwide total number of subjects
    39
    EEA total number of subjects
    14
    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)
    37
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 39 subjects were enrolled at 22 centres in the United States (US), Poland, Serbia, Hungary, Lithuania, and the Russian Federation from 27 August 2019 to 08 Apr 2021.

    Pre-assignment
    Screening details
    		 All 39 subjects rolled over from the index study ISIS 766720-CS2 (2017-004259-22) and were started at the same ISIS 766720 dose as the previous study of either 60, 80, 120, or 160 mg subcutaneous (SC) injection, every 28 days as an add-on to somatostatin receptor ligand (SRL) therapy for 53 weeks.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ISIS 766720 Maximum Low Dose
    Arm description
    		 Subjects who received 60 mg or 80 mg of ISIS 766720 in the index study, ISIS 766720-CS2, started at the same dose of ISIS 766720. Dose-escalated subjects are summarized by the maximum dose administered subcutaneously once every 28 days for 53 weeks with the option to continue treatment for another 52 weeks as add-on to SRL therapy in this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 766720
    Investigational medicinal product code
    Other name
    IONIS GHR-LRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ISIS 766720 60 mg, administered subcutaneously.

    Investigational medicinal product name
    Somatostatin Receptor Ligand (SRL)
    Investigational medicinal product code
    Other name
    Lanreotide, Octreotide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SRL therapy (lanreotide, octreotide) at the same dose and regimen as ISIS 766720-CS2 throughout this study.

    Investigational medicinal product name
    ISIS 766720
    Investigational medicinal product code
    Other name
    IONIS GHR-LRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ISIS 766720 80 mg, administered subcutaneously.

    Arm title
    		 ISIS 766720 Maximum High Dose
    Arm description
    		 Subjects who received 120 mg or 160 mg of ISIS 766720 in the index study, ISIS 766720-CS2, started at the same dose of ISIS 766720. Dose-escalated subjects are summarized by the maximum dose administered subcutaneously once every 28 days for 53 weeks with the option to continue treatment for another 52 weeks as add-on to SRL therapy in this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 766720
    Investigational medicinal product code
    Other name
    IONIS GHR-LRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ISIS 766720 120 mg, administered subcutaneously.

    Investigational medicinal product name
    Somatostatin Receptor Ligand (SRL)
    Investigational medicinal product code
    Other name
    Lanreotide, Octreotide
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SRL therapy (lanreotide, octreotide) at the same dose and regimen as ISIS 766720-CS2 throughout this study.

    Investigational medicinal product name
    ISIS 766720
    Investigational medicinal product code
    Other name
    IONIS GHR-LRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ISIS 766720 160 mg, administered subcutaneously.

    Number of subjects in period 1
    		ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose
    Started
    16
    23
    Completed
    15
    22
    Not completed
    1
    1
         Voluntary Withdrawal
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ISIS 766720 Maximum Low Dose
    Reporting group description
    		 Subjects who received 60 mg or 80 mg of ISIS 766720 in the index study, ISIS 766720-CS2, started at the same dose of ISIS 766720. Dose-escalated subjects are summarized by the maximum dose administered subcutaneously once every 28 days for 53 weeks with the option to continue treatment for another 52 weeks as add-on to SRL therapy in this study.

    Reporting group title
    ISIS 766720 Maximum High Dose
    Reporting group description
    		 Subjects who received 120 mg or 160 mg of ISIS 766720 in the index study, ISIS 766720-CS2, started at the same dose of ISIS 766720. Dose-escalated subjects are summarized by the maximum dose administered subcutaneously once every 28 days for 53 weeks with the option to continue treatment for another 52 weeks as add-on to SRL therapy in this study.

    Reporting group values
    		 ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose Total
    Number of subjects
    		 16 23 39
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.4 ( 11.4 ) 47.0 ( 12.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 13 11 24
        Male
    		 3 12 15
    Race
    Units: Subjects
        Black
    		 0 1 1
        White
    		 16 22 38
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 16 23 39

    End points

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    End points reporting groups
    Reporting group title
    ISIS 766720 Maximum Low Dose
    Reporting group description
    		 Subjects who received 60 mg or 80 mg of ISIS 766720 in the index study, ISIS 766720-CS2, started at the same dose of ISIS 766720. Dose-escalated subjects are summarized by the maximum dose administered subcutaneously once every 28 days for 53 weeks with the option to continue treatment for another 52 weeks as add-on to SRL therapy in this study.

    Reporting group title
    ISIS 766720 Maximum High Dose
    Reporting group description
    		 Subjects who received 120 mg or 160 mg of ISIS 766720 in the index study, ISIS 766720-CS2, started at the same dose of ISIS 766720. Dose-escalated subjects are summarized by the maximum dose administered subcutaneously once every 28 days for 53 weeks with the option to continue treatment for another 52 weeks as add-on to SRL therapy in this study.

    Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE) can be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not the AE is considered related to the medicinal (investigational) product. A TEAE is defined as an event that occurred after the initiation of the study drug dosing and before the end of the follow-up period. Safety Set included all subjects who were enrolled and received at least 1 dose of ISIS 766720 in the present study.
    End point type
    Primary
    End point timeframe
    From the first dose of the study drug up to end of study (up to approximately 3 years)
    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: As prespecified in the protocol only descriptive statistics were planned for this endpoint.
    End point values
    		 ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose
    Number of subjects analysed
    16
    23
    Units: subjects
    15
    21
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Insulin-like Growth Factor I (IGF-1) Levels

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    End point title
    		 Percent Change From Baseline in Insulin-like Growth Factor I (IGF-1) Levels
    End point description
    IGF-1 is a hormone that manages the effects of growth hormone (GH) in the body. Percent (%) change from baseline in IGF-1 levels was measured at Days 169 and 365. Pooled baseline was used for analysis, defined as 1) ISIS 766720-CS2 baseline for subjects with gap between last dose of ISIS 766720-CS2 and the first dose of ISIS 766720-CS3 <=45 days or 2) ISIS 766720-CS3 baseline for subjects with gap between last dose of ISIS 766720-CS2 and first dose of ISIS 766720-CS3 >45 days or subjects randomised to placebo in ISIS 766720-CS2 study. Negative % change from baseline indicates improvement. Per Protocol Set (PPS) included all Full Analysis Set (FAS) subjects who completed at least 9 of the 14 doses of ISIS 766720 and had no significant protocol deviations that would have been expected to affect efficacy. Number of subjects analysed indicates the number of subjects with data available for analyses. This analysis uses the Per-Protocol Set with IGF-1 >1.3 x ULN at ISIS 766720-CS3 Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 169 and 365
    End point values
    		 ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose
    Number of subjects analysed
    9
    17
    Units: percent change
    arithmetic mean (standard deviation)
        Day 169 (n=9, 17)
    14.4 ( 12.0 )
    -5.8 ( 21.1 )
        Day 365 (n=8, 15)
    -6.2 ( 12.3 )
    -11.7 ( 19.7 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Normalised IGF-1 Levels to Within 1.2 Times of Gender and Age-Adjusted Upper Limits

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    End point title
    		 Percentage of Subjects Achieving Normalised IGF-1 Levels to Within 1.2 Times of Gender and Age-Adjusted Upper Limits
    End point description
    Normalisation of circulating IGF-1 is a validated marker for the treatment of acromegaly. Normal IGF-1 levels for a subject differs based on age and gender. Number of subjects with a normal IGF-1 level which were 1.2 times within gender and age limits at Days 169 and 365 are presented where IGF-1 level is defined as the ratio of the serum IGF-1 level and the subject’s upper limit of normal (ULN). The ULN varied among subjects due to gender and age. Subjects whose calculated ratios were ≤1.2 or 1.0 were deemed as achieving normalised IGF. FAS included all enrolled subjects who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy or pharmacodynamic (PD) assessment. Number of subjects analysed indicates the number of subjects with data available for analyses. ‘n’ indicates the number of subjects analysed at the specified time point.
    End point type
    Secondary
    End point timeframe
    Days 169 and 365
    End point values
    		 ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose
    Number of subjects analysed
    14
    22
    Units: percentage of subjects
    number (not applicable)
        Day 169 (n=14, 22)
    21.4
    9.1
        Day 365 (n=11, 18)
    36.4
    22.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Normalised IGF-1 Levels to Within 1.0 Times of Gender and Age-Adjusted Upper Limits

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    End point title
    		 Percentage of Subjects Achieving Normalised IGF-1 Levels to Within 1.0 Times of Gender and Age-Adjusted Upper Limits
    End point description
    Normalisation of circulating IGF-1 is a validated marker for the treatment of acromegaly. Normal IGF-1 levels for a subject differs based on age and gender. Number of subjects with a normal IGF-1 level which were 1.0 times within gender and age limits at Days 169 and 365 are presented where IGF-1 level is defined as the ratio of the serum IGF-1 level and the subject’s ULN. The ULN varied among subjects due to gender and age. Subjects whose calculated ratios were ≤1.2 or 1.0 were deemed as achieving normalised IGF. FAS included all enrolled subjects who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy or PD assessment. Number of subjects analysed indicates the number of subjects with data available for analyses. ‘n’ indicates the number of subjects analysed at the specified time point.
    End point type
    Secondary
    End point timeframe
    Days 169 and 365
    End point values
    		 ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose
    Number of subjects analysed
    14
    22
    Units: percentage of subjects
    number (not applicable)
        Day 169 (n=14, 22)
    21.4
    0.0
        Day 365 (n=11, 18)
    27.3
    5.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Began Other Acromegaly Medication

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    End point title
    		 Percentage of Subjects who Began Other Acromegaly Medication
    End point description
    FAS included all enrolled subjects who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy or PD assessment.
    End point type
    Secondary
    End point timeframe
    From the first dose of the study drug up to approximately 3 years
    End point values
    		 ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose
    Number of subjects analysed
    16
    23
    Units: percentage of subjects
        number (not applicable)
    0.0
    13.0
    No statistical analyses for this end point

    Secondary: Time From First Dose of ISIS 766720 in This Open-label Extension (CS3) Study to Date of Initiation of Other Acromegaly Medications

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    End point title
    		 Time From First Dose of ISIS 766720 in This Open-label Extension (CS3) Study to Date of Initiation of Other Acromegaly Medications
    End point description
    FAS included all enrolled subjects who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy or PD assessment.
    End point type
    Secondary
    End point timeframe
    From the first dose of the study drug up to approximately 3 years
    End point values
    		 ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose
    Number of subjects analysed
    0 [2]
    3
    Units: days
        median (full range (min-max))
    ( to )
    376.0 (158.0 to 419.0)
    Notes
    [2] - Number of subjects analysed for the endpoint included subjects who began other acromegaly medication
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of the study drug up to end of study (up to approximately 2 years)
    Adverse event reporting additional description
    Safety Set included all subjects who were enrolled and received at least 1 dose of ISIS 766720 in the present study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    ISIS 766720 Maximum Low Dose
    Reporting group description
    		 Subjects who received 60 mg or 80 mg of ISIS 766720 in the index study, ISIS 766720-CS2, continued to receive the same dose of ISIS 766720 as the maximum dose administered subcutaneously once every 28 days for 105 weeks as add-on to SRL therapy in this study.

    Reporting group title
    ISIS 766720 Maximum High Dose
    Reporting group description
    		 Subjects who received 120 mg or 160 mg of ISIS 766720 in the index study, ISIS 766720-CS2, continued to receive the same dose of ISIS 766720 as the maximum dose administered subcutaneously once every 28 days for 105 weeks as add-on to SRL therapy in this study.

    Serious adverse events
    		 ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 16 (25.00%)
    9 / 23 (39.13%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure chronic
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    IIIrd nerve disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterovaginal prolapse
         subjects affected / exposed [1]
    0 / 13 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Drug dependence
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 23 (13.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Number of subjects exposed to this adverse event term is based on the female population in this study.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ISIS 766720 Maximum Low Dose ISIS 766720 Maximum High Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 16 (93.75%)
    20 / 23 (86.96%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon adenoma
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Uterine leiomyoma
         subjects affected / exposed [2]
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 23 (4.35%)
         occurrences all number
    7
    1
    Arteriosclerosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Hypotension
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Varicose vein
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Administration site haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Administration site pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Administration site pruritus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Administration site swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Asthenia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Chest discomfort
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    Chills
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Injection site erythema
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed [3]
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Cervical polyp
         subjects affected / exposed [4]
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Dysmenorrhoea
         subjects affected / exposed [5]
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Gynaecomastia
         subjects affected / exposed [6]
    0 / 13 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Pelvic prolapse
         subjects affected / exposed [7]
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal inflammation
         subjects affected / exposed [8]
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Emotional distress
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 23 (8.70%)
         occurrences all number
    5
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    Coronavirus test positive
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    3
    Red blood cell sedimentation rate increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Radius fracture
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Road traffic accident
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Type V hyperlipidaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Cardiac disorders
    Mitral valve incompetence
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 23 (17.39%)
         occurrences all number
    0
    4
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 23 (17.39%)
         occurrences all number
    0
    4
    Sinus bradycardia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Arrhythmia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Bundle branch block left
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Ventricular failure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 23 (4.35%)
         occurrences all number
    6
    1
    Dizziness
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Diabetic neuropathy
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    IIIrd nerve disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Intercostal neuralgia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Radiculopathy
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 23 (4.35%)
         occurrences all number
    3
    1
    Anaemia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Leukopenia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Thrombocytosis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Astigmatism
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 23 (8.70%)
         occurrences all number
    2
    2
    Diarrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    6
    Nausea
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    4
    Abdominal pain lower
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Chronic gastritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Malpositioned teeth
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Cholecystitis acute
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Nonalcoholic fatty liver disease
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Urticaria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    Hyperoxaluria
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Renal colic
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Goitre
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Pituitary cyst
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 23 (8.70%)
         occurrences all number
    1
    3
    Osteoarthritis
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    Arthralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Arthritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Spinal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Infections and infestations
    Coronavirus infection
         subjects affected / exposed
    1 / 16 (6.25%)
    6 / 23 (26.09%)
         occurrences all number
    1
    7
    Urinary tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    4 / 23 (17.39%)
         occurrences all number
    2
    6
    Viral infection
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 23 (0.00%)
         occurrences all number
    7
    0
    Gingivitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Periodontitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Pulpitis dental
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Urethritis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Vaginal infection
         subjects affected / exposed [9]
    1 / 13 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 23 (0.00%)
         occurrences all number
    4
    0
    Dyslipidaemia
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    1
    Hyperalbuminaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Notes
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Number of subjects exposed to this adverse event term is based on the female population in this study.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Number of subjects exposed to this adverse event term is based on the female population in this study.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Number of subjects exposed to this adverse event term is based on the female population in this study.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Number of subjects exposed to this adverse event term is based on the female population in this study.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Number of subjects exposed to this adverse event term is based on the female population in this study.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Number of subjects exposed to this adverse event term is based on the female population in this study.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Number of subjects exposed to this adverse event term is based on the female population in this study.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Number of subjects exposed to this adverse event term is based on the female population in this study.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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