Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    An Open Label Study to Assess the Safety and Efficacy of COR-003 (2S,4R-Ketoconazole) in the Treatment of Endogenous Cushing's Syndrome (CS)

    Summary
    EudraCT number
    		 2013-002133-37
    Trial protocol
    		 GB   ES   BE   NL   SE   DK   DE   IT   BG   CZ   HU  
    Global end of trial date
    20 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2021
    First version publication date
    13 May 2021
    Other versions
    Summary report(s)
    		 Efficacy and Safety of levoketoconazole
    Efficacy and Safety of Levoketoconazole Suppl data
    Levoketoconazole improves clinical signs and symptoms
    Levoketoconazole in the Treatment of CS with Diabetes
    Levoketoconazole in the Treatment of Diabetes suppl table

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    COR-2012-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01838551
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 COR202101: SONICS
    Sponsors
    Sponsor organisation name
    Cortendo AB
    Sponsor organisation address
    900 Northbrook Drive, Suite 200, Trevose, United States, 19053
    Public contact
    Clinical Trial Information, Cortendo AB, +1 609878179, info@cortendo.com
    Scientific contact
    Clinical Trial Information, Cortendo AB, +1 609878179, info@cortendo.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
    21 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical responder rate, defined as the proportion of subjects with normal UFC after 6 months of treatment with COR-003 in the Maintenance Phase without dose increase, and to evaluate the range of effective doses in subjects with various levels of hypercortisolism.
    Protection of trial subjects
    Withdrawal criteria defined for events relating to QT interval prolongation and laboratory abnormalities related to liver tests.
    Background therapy
    		 None defined
    Evidence for comparator
    		 No comparators used.
    Actual start date of recruitment
    30 Jul 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Regulatory reason, Scientific research
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    United States: 28
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Turkey: 3
    Worldwide total number of subjects
    94
    EEA total number of subjects
    52
    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)
    89
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 201 patients were screened between 30 July 2014 and 30 June 2017. Of these, 107 patients were screening failures, predominantly because they did not meet eligibility criteria.

    Period 1
    Period 1 title
    Titration Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Levoketoconazole Titration Phase
    Arm description
    		 The initial dose was levoketoconazole 150 mg BID (300 mg/day), taken as 1 tablet in the morning and 1 tablet in the evening. During the first 2 to 21 weeks, dose was titrated in protocol-defined increments up to each subject's therapeutic dose, based on the subject's urinary free cortisol (UFC) levels and safety/tolerability. The interval between upward dose adjustments was to be approximately 18 days. The lowest allowed dose was 150 mg/day for subjects who could not tolerate 150 mg BID; the highest allowed dose was 600 mg BID (1200 mg/day). The therapeutic dose had been reached when mean UFC levels (determined from a total of 4 24-h urine collections) were ≤ULN of the assay, or the maximum allowed dose (600 mg BID) had been reached, or a clinically meaningful partial response and the maximal tolerated dose had been reached.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levoketoconazole
    Investigational medicinal product code
    COR-003
    Other name
    2S,4R-ketoconazole
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The initial dose was levoketoconazole 150 mg BID (300 mg/day), taken as 1 tablet in the morning and 1 tablet in the evening. During the first 2 to 21 weeks, dose was titrated in protocol-defined increments up to each subject's therapeutic dose, based on the subject's UFC levels and safety/tolerability. The interval between upward dose adjustments was to be approximately 18 days. The lowest allowed dose was 150 mg/day for subjects who could not tolerate 150 mg BID; the highest allowed dose was 600 mg BID (1200 mg/day). The therapeutic dose had been reached when mean UFC levels (determined from a total of 4 24-h urine collections) were ≤ULN of the assay, or the maximum allowed dose (600 mg BID) had been reached, or a clinically meaningful partial response and the maximal tolerated dose had been reached.

    Number of subjects in period 1
    		Levoketoconazole Titration Phase
    Started
    94
    Completed
    77
    Not completed
    17
         Physician decision
    1
         Consent withdrawn by subject
    4
         Adverse event, non-fatal
    6
         Not further specified
    3
         Lack of efficacy
    3
    Period 2
    Period 2 title
    Maintenance Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Levoketoconazole Maintenance Phase
    Arm description
    		 Dosing was to be continued for 6 months at the therapeutic dose established by dose titration in the Titration Phase. During the Maintenance Phase, levoketoconazole dose was not to be changed unless medically necessary.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levoketoconazole
    Investigational medicinal product code
    COR-003
    Other name
    2S,4R-ketoconazole
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing was to be continued for 6 months at the therapeutic dose established by dose titration in the Titration Phase. The required number of tablets was to be taken in the morning and evening following a protocol defined dosing scheme.

    Number of subjects in period 2
    		Levoketoconazole Maintenance Phase
    Started
    77
    Completed
    61
    Not completed
    16
         Physician decision
    1
         Consent withdrawn by subject
    4
         Adverse event, non-fatal
    6
         Not otherwise specified
    1
         Lack of efficacy
    4
    Period 3
    Period 3 title
    Extended Evaluation Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Levoketoconazole Extended Evaluation Phase
    Arm description
    		 During the Extended Evaluation Phase, levoketoconazole dosing was to continue as in the Maintenance Phase. Dosing was to be continued for 6 months. The levoketoconazole dose was not to be changed unless medically necessary.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levoketoconazole
    Investigational medicinal product code
    COR-003
    Other name
    2S,4R-ketoconazole
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing was to be continued as in the Maintenance Phase. The required number of tablets was to be taken in the morning and evening following a protocol defined dosing scheme.

    Number of subjects in period 3 [1]
    		Levoketoconazole Extended Evaluation Phase
    Started
    60
    Completed
    46
    Not completed
    14
         Adverse event, serious fatal
    1
         Physician decision
    2
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    4
         Not otherwise specified
    2
         Lack of efficacy
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: All patients but one continued into the Extended Evaluation Phase while one patient chose not to continue.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Titration Phase
    Reporting group description
    		 -

    Reporting group values
    		 Titration Phase Total
    Number of subjects
    		 94 94
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 89 89
        From 65-84 years
    		 5 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.7 ± 13.4 -
    Gender categorical
    Units: Subjects
        Female
    		 77 77
        Male
    		 17 17
    Biological cause
    Units: Subjects
        Cushing's disease
    		 80 80
        Ectopic ACTH secretion
    		 1 1
        Adrenal dependent
    		 8 8
        Unknown
    		 5 5
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 84.0 ± 23.4 -
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 30.8 ± 8.2 -
    Time since diagnosis
    Units: months
        arithmetic mean (standard deviation)
    		 68.0 ± 80.4 -
    Baseline mUFC molar concentration
    Units: nmol/24 h
        arithmetic mean (standard deviation)
    		 671.4 ± 743.1 -
    Baseline mUFC mass concentration
    Units: ug/24 h
        arithmetic mean (standard deviation)
    		 243.3 ± 269.3 -
    Baseline mUFC x ULN
    Units: Multiples of ULN
        arithmetic mean (standard deviation)
    		 4.9 ± 5.4 -
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who received at least 1 dose of levoketoconazole. This population is used for the evaluation of efficacy and all safety analyses.

    Subject analysis set title
    ITT2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Identical to ITT

    Subject analysis sets values
    		 ITT ITT2
    Number of subjects
    94
    94
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    89
        From 65-84 years
    5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.7 ± 13.5
    ±
    Gender categorical
    Units: Subjects
        Female
    77
        Male
    17
    Biological cause
    Units: Subjects
        Cushing's disease
    80
        Ectopic ACTH secretion
    1
        Adrenal dependent
    8
        Unknown
    5
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    ±
    ±
    Body mass index
    Units: kg/m2
        arithmetic mean (standard deviation)
    ±
    ±
    Time since diagnosis
    Units: months
        arithmetic mean (standard deviation)
    ±
    ±
    Baseline mUFC molar concentration
    Units: nmol/24 h
        arithmetic mean (standard deviation)
    ±
    ±
    Baseline mUFC mass concentration
    Units: ug/24 h
        arithmetic mean (standard deviation)
    ±
    ±
    Baseline mUFC x ULN
    Units: Multiples of ULN
        arithmetic mean (standard deviation)
    ±
    ±

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Levoketoconazole Titration Phase
    Reporting group description
    		 The initial dose was levoketoconazole 150 mg BID (300 mg/day), taken as 1 tablet in the morning and 1 tablet in the evening. During the first 2 to 21 weeks, dose was titrated in protocol-defined increments up to each subject's therapeutic dose, based on the subject's urinary free cortisol (UFC) levels and safety/tolerability. The interval between upward dose adjustments was to be approximately 18 days. The lowest allowed dose was 150 mg/day for subjects who could not tolerate 150 mg BID; the highest allowed dose was 600 mg BID (1200 mg/day). The therapeutic dose had been reached when mean UFC levels (determined from a total of 4 24-h urine collections) were ≤ULN of the assay, or the maximum allowed dose (600 mg BID) had been reached, or a clinically meaningful partial response and the maximal tolerated dose had been reached.
    Reporting group title
    Levoketoconazole Maintenance Phase
    Reporting group description
    		 Dosing was to be continued for 6 months at the therapeutic dose established by dose titration in the Titration Phase. During the Maintenance Phase, levoketoconazole dose was not to be changed unless medically necessary.
    Reporting group title
    Levoketoconazole Extended Evaluation Phase
    Reporting group description
    		 During the Extended Evaluation Phase, levoketoconazole dosing was to continue as in the Maintenance Phase. Dosing was to be continued for 6 months. The levoketoconazole dose was not to be changed unless medically necessary.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who received at least 1 dose of levoketoconazole. This population is used for the evaluation of efficacy and all safety analyses.

    Subject analysis set title
    ITT2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Identical to ITT

    Primary: mUFC Complete Response Rate

    		 Close Top of page
    End point title
    		 mUFC Complete Response Rate
    End point description
    Clinical response to levoketoconazole was defined as mean 24-h urinary free cortisol concentration (mUFC) less than or equal to the ULN (upper limit of normal) of the reference range following 6 months of therapy in the Maintenance Phase without a dose increase during that phase. The proportion of responders at the end of maintenance phase visit for all dose groups combined was estimated using a generalised linear model with repeated measurements and with region (US vs non-US), concurrent CS median conditions (diabetes [Yes/NO], hypertension [Yes/No]), age (rounded median split based on the ITT population), sex, disease duration (years), prior CS medication (Yes/No), prior radiation therapy (Yes/No) as baseline covariates and visit as an independent factor. The LS mean estimate of the UFC response after 6 months of treatment in maintenance phase with 95% confidence interval was used to infer efficacy.
    End point type
    Primary
    End point timeframe
    6-month Maintenance Phase
    End point values
    		 ITT ITT2
    Number of subjects analysed
    94
    94 [1]
    Units: Proportion of responders
        least squares mean (standard error)
    0.30 ± .05
    .30 ± .05
    Notes
    [1] - Identical to ITT
    Statistical analysis title
    		 Primary Efficacy Endpoint Analysis
    Statistical analysis description
    The GLM described above was used as the primary analysis method. Under the null hypothesis of at most 20% responders, 90 subjects in the ITT population provided 90% power with 2-sided type 1 error of 0.05 assuming an observed response of 35%. The Wald 95% confidence interval around the UFC response estimate provided by the GLM served as the primary basis of statistical inference.
    Comparison groups
    ITT v ITT2
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0154 [3]
    Method
    		 Generalized Linear Model
    Parameter type
    		 Proportion
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 0.4
    Notes
    [2] - A superiority analysis comparing the observed ITT response to thg null hypothesized rate. Subjects were imputed as non-responders for the primary endpoint if they: withdrew prior to Month 6 of maintenance phase; had a dose increase relative to the therapeutic dose during maintenance phase; Month 6 mUFC data were missing or inadequate; had received radiation therapy and exhibited no rebound increase in mUFC following withdrawal of levoketoconazole immediately after the end of maintenance phase
    [3] - The one-sided p-value calculated was based on a null hypothesis that true response is less than or equal 0.20.

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Reported TEAEs are summarized from the first day of study drug administration through the last day plus 30 days. For the ITT pop, median was ~14 (mean ~12, max ~23) months.
    Adverse event reporting additional description
    Only treatment-emergent AEs are reported
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Levoketoconazole, all phases combined
    Reporting group description
    		 All patients enroled and treated i.e. who receive at least one dose of study drug

    Serious adverse events
    		 Levoketoconazole, all phases combined
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 94 (17.02%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of the colon
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Benign ovarian tumour
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gamma-glutamyltransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Hyphaema
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pyelonephritis chronic
         subjects affected / exposed
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Levoketoconazole, all phases combined
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    92 / 94 (97.87%)
    Vascular disorders
    Hypertension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    18 / 94 (19.15%)
         occurrences all number
    24
    General disorders and administration site conditions
    Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    18 / 94 (19.15%)
         occurrences all number
    24
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    16 / 94 (17.02%)
         occurrences all number
    20
    Asthenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    8
    Reproductive system and breast disorders
    Menstruation irregular
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    7
    Psychiatric disorders
    Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    9
    Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    7
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 94 (15.96%)
         occurrences all number
    20
    Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 94 (12.77%)
         occurrences all number
    13
    Gamma-glutamyltransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 94 (11.70%)
         occurrences all number
    16
    Electrocardiogram QT prolonged
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    13
    Blood alkaline phosphatase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    6
    Cardiac disorders
    Palpitations
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    8
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    27 / 94 (28.72%)
         occurrences all number
    52
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 94 (12.77%)
         occurrences all number
    12
    Dysgeusia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    7
    Gastrointestinal disorders
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    31 / 94 (32.98%)
         occurrences all number
    44
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 94 (14.89%)
         occurrences all number
    17
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 94 (10.64%)
         occurrences all number
    16
    Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    9
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    9
    Gastrooesophageal reflux disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    6
    Dyspepsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Dry skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 94 (11.70%)
         occurrences all number
    11
    Alopecia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    9
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 94 (8.51%)
         occurrences all number
    11
    Hyperhidrosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    7
    Pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 94 (14.89%)
         occurrences all number
    14
    Myalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 94 (9.57%)
         occurrences all number
    12
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 94 (7.45%)
         occurrences all number
    7
    Musculoskeletal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    6
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 94 (6.38%)
         occurrences all number
    6
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 94 (12.77%)
         occurrences all number
    18
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 94 (11.70%)
         occurrences all number
    11
    Metabolism and nutrition disorders
    Hypokalaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 94 (13.83%)
         occurrences all number
    14
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 94 (5.32%)
         occurrences all number
    5

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2014
    - Increase in window for time between dose adjustments from ±2 to ±7 days - Increase in duration of screening phase from 8 to about 12 weeks - Allowance of screening assessments to occur following ICF signature and discontinuation of prohibited medications
    16 Apr 2015
    - Removal of ambulatory blood pressure assessments; physician and subject VAS questionnaires; option for TID dosing - Addition of the CushingQOL and BDI-II - Modification of LNSC to be measured over 2 instead of 3 nights - Decrease in number of PK samples to be collected
    25 Oct 2016
    - Removal of: FU visit for patients participating in Expanded Access Program; extra 24-h urine collection at start of Maintenance Phase; magnetic resonance imaging at FU visit for patients completing Month 12 of the Extended Evaluation phase - Addition of: guidance for rescreening; PK sampling with persistent and confirmed QTc prolongation; visit windows (±7 and ±14 days) during Maintenance and Extended Evaluation phases, respectively; hypothesis testing for clinical laboratory values, vital signs and ECG - Increase in washout period for pasireotide LAR from 8 to 12 weeks - Clarification added regarding expected values for normal 24-h creatinine excretion rates - Clarifications added on prohibited and precautionary medications use - Clarification added regarding data restriction plan (for availability of efficacy data during conduct of the study) - Realigned secondary and exploratory objectives and endpoints - Clarified analytical methods for some secondary and exploratory endpoints

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33216275
    http://www.ncbi.nlm.nih.gov/pubmed/31542384
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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.

    European Medicines Agency © 1995-Mon Apr 29 05:20:35 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA