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    Clinical Trial Results:
    A Double-blind, Placebo-Controlled, Randomized Withdrawal Following Open-label Therapy Study to Assess the Safety and Efficacy of Levoketoconazole (2S,4R-ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome

    Summary
    EudraCT number
    		 2017-001219-35
    Trial protocol
    		 ES   FR   BG   HU   PL   NL   DK   GR   IT   RO  
    Global end of trial date
    31 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Feb 2022
    First version publication date
    06 Feb 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    COR-2017-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03277690
    WHO universal trial number (UTN)
    		 -
    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, info@cortendo.com
    Scientific contact
    Clinical Trial Information, Cortendo AB, 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
    20 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 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
    To determine the effect of withdrawing to placebo versus continuing treatment with levoketoconazole on the cortisol therapeutic response previously established during open-label levoketoconazole therapy.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles set forth in the Declaration of Helsinki and the Guideline for ICH GCP (ICH E6). It also complies with the obligations and requirements of clinical investigators and all other requirements listed in 21 Code of Federal Regulations (CFR) 312. The investigators conducted all aspects of this study in accordance with all national, state, and local laws of the pertinent regulatory authorities as well as the study procedures provided by Cortendo AB (also referred to as Cortendo). The specific measures taken to protect subjects during the use of placebo was use of early rescue therapy. Early rescue was a key safety component of the study design that was intended to protect subjects from experiencing disease-related morbidity should they experience a documented loss of therapeutic effect at any time during the Randomized-withdrawal phase. Early rescue during the Randomized-withdrawal phase was to be considered after randomization when a subject demonstrated relapse of hypercortisolemia (i.e., loss of therapeutic response), defined as mUFC from 3 urine collections that is above 1.5× ULN mUFC from 3 urine collections that was above 1× ULN at baseline (RW0) and increases by more than 40% above the baseline value for SONICS-completer cohort subjects only. Other criteria for early rescue were specified in the protocol but were not needed, as all subjects requiring early rescue met this UFC criterion.
    Background therapy
    		 None. All treatments for Cushing's syndrome must have been washed out prior to or during the Screening period in order to qualify for dosing.
    Evidence for comparator
    		 A placebo comparator was used during the 8 week randomized-withdrawal phase of the study. Placebo administration was considered a priori as likely be ineffective to maintain cortisol normalization. Withdrawal to an active comparator was not considered as a practical matter, in that testing for superiority or non-inferiority to an active comparator would require a very large study size beyond the ability to recruit within a reasonable timeframe. Because of its efficiency, the randomized withdrawal design exposes a small number of subjects to placebo compared with most other designs. As an additional protection, subjects were to be provided early rescue therapy with open-label treatment at any time prior to the completion of the Randomized Withdrawal phase if the Investigator determined such rescue was needed based on pre-defined criteria (described in "Protection of trial subjects").
    Actual start date of recruitment
    15 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    84
    EEA total number of subjects
    59
    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)
    77
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screened: 172 Screen Failures 100 95 Failed Inclusion Criteria (80 INCL04, 3 INCL05, 1 INCL06, 12 INCL11) 5 Met Exclusion Criteria (1 EXCL09, 1 EXCL15, 1 EXCL22, 1 EXCL29, 1 EXCL32)

    Period 1
    Period 1 title
    Dose Titration and Maintenance
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Levoketoconazole
    Arm description
    		 Levoketoconazole tablets 150 mg strength, open-label to be titrated to therapeutic dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levoketoconazole
    Investigational medicinal product code
    COR-003
    Other name
    2S,4R-ketoconazole, normocort
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg tablets administered once or twice daily. Individualized dose. Dose range from 150 mg once daily to 1200 mg daily administered as 600 mg twice daily.

    Number of subjects in period 1
    		Levoketoconazole
    Started
    79
    Completed
    39
    Not completed
    40
         Consent withdrawn by subject
    8
         Physician decision
    1
         Adverse event, non-fatal
    15
         Sponsor decision - Randomization closed
    4
         Lack of efficacy
    9
         Protocol deviation
    3
    Period 2
    Period 2 title
    Randomized withdrawal
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Active and placebo tablets matching in appearance provided to to study investigators for dispensing. Randomization controlled using interactive response system.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Levoketoconazole
    Arm description
    		 Levoketoconazole, 150 mg tablets, blinded to identity of ingredients
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levoketoconazole
    Investigational medicinal product code
    COR-003
    Other name
    2S,4R-ketoconazole, normocort
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg tablets administered once or twice daily. Individualized dose. Dose range from 150 mg once daily to 1200 mg daily administered as 600 mg twice daily.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablets identical to levoketoconazole tablets. Ingredients blinded to identity.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to levoketoconazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Direct substitution for levoketoconazole regimen in RW phase without titration (ie withdrawal to placebo). Also added to existing blinded levoketoconazole regimen in Restoration using rapid titration to restore prior-established therapeutic dose (double dummy).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Three baseline periods were pre-defined but the registry provides for only 1 baseline period. The baseline period associated with the primary endpoint is Period 2 (Randomized-withdrawal.
    Number of subjects in period 2 [2]
    		Levoketoconazole Placebo
    Started
    21
    18
    Completed
    21
    22
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -
    Joined
    1
    4
         SONICS-completer randomized directly
    1
    4
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: As noted the total number of subjects enrolled is the number enrolled in Dose Titration and Maintenance plus the number directly randomized = 79+5 = 84.
    Period 3
    Period 3 title
    Restoration
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Blinding was limited to subjects who did not require open-label early rescue during RWW and was accomplished with a "double dummy," whereby the RW drug assignment determined the addition of placebo or active drug in Restoration, such that all subjects received active therapy at their prior-determined therapeutic dose in Restoration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects previously assigned to receive placebo during the RW phase received active therapy in Restoration. 21 of 22 received open-label levoketoconazole as early rescue and rapidly titrated to their therapeutic dose regimen; 1 of 22 received blinded placebo (continued from RW) + blinded levoketoconazole (newly added). The addition of blinded levoketoconazole used rapid titration to return the subject to their prior-established therapeutic dose of levoketoconazole.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levoketoconazole
    Investigational medicinal product code
    COR-003
    Other name
    2S,4R-ketoconazole, normocort
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg tablets administered once or twice daily. Individualized dose. Dose range from 150 mg once daily to 1200 mg daily administered as 600 mg twice daily.

    Arm title
    		 Levoketoconazole
    Arm description
    		 Subjects previously assigned to receive levoketoconazole during the RW phase continued to receive active therapy in Restoration. 4 of 21 received open-label levoketoconazole as early rescue and rapidly titrated to their therapeutic dose regimen; 17 of 22 received blinded levoketoconazole + blinded placebo (newly added). The addition of blinded placebo used the same rapid titration to emulate their prior-established therapeutic dose of levoketoconazole.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levoketoconazole
    Investigational medicinal product code
    COR-003
    Other name
    2S,4R-ketoconazole, normocort
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg tablets administered once or twice daily. Individualized dose. Dose range from 150 mg once daily to 1200 mg daily administered as 600 mg twice daily.

    Number of subjects in period 3
    		Placebo Levoketoconazole
    Started
    22
    21
    Completed
    22
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levoketoconazole
    Reporting group description
    		 Levoketoconazole, 150 mg tablets, blinded to identity of ingredients

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets identical to levoketoconazole tablets. Ingredients blinded to identity.

    Reporting group values
    		 Levoketoconazole Placebo Total
    Number of subjects
    		 22 22 44
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.0 ± 11.97 43.6 ± 10.96 -
    Gender categorical
    Units: Subjects
        Female
    		 15 19 34
        Male
    		 7 3 10
    Using antihypertensive medication
    Using at least 1 antihypertensive medication, a proxy for diagnosis of hypertension
    Units: Subjects
        Yes
    		 16 14 30
        No
    		 6 8 14
    Using antidiabetic medication
    Receiving 1 or more antidiabetic medication, a proxy for diagnosis of diabetes
    Units: Subjects
        Yes
    		 8 6 14
        No
    		 14 16 30
    Etiology of CS
    Anatomical etiology of endogenous Cushing's syndrome
    Units: Subjects
        Cushing's disease
    		 18 20 38
        Ectopic ACTH secretion
    		 0 0 0
        Adrenal-dependent
    		 3 1 4
        Unknown
    		 1 1 2
    Mean UFC (mUFC)
    Mean UFC represents the average of 24-hour UFC measured from nominally 3 adequate 24-hour urine collections. The assay ULN was 138 nmol/24 hours.
    Units: nmol/24 hours
        arithmetic mean (standard deviation)
    		 738.69 ± 1067.025 411.59 ± 436.176 -
    Subject analysis sets

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population is comprised of the 84 unique subjects who received at least 1 dose of levoketoconazole in any of the 3 study phases. Baseline for the safety population varies by cohort. For the levoketoconazole-naive cohort, baseline is the latest observation prior to the date of first receiving levoketoconazole in the Dose Titration-maintenance phase (N=79). For the SONICS-completer cohort (N=5), baseline is the latest observation prior to the date of receiving drug in the Randomized-withdrawal phase.

    Subject analysis sets values
    		 Safety population
    Number of subjects
    84
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44.7 ± 12.74
    Gender categorical
    Units: Subjects
        Female
    64
        Male
    20
    Using antihypertensive medication
    Using at least 1 antihypertensive medication, a proxy for diagnosis of hypertension
    Units: Subjects
        Yes
    59
        No
    25
    Using antidiabetic medication
    Receiving 1 or more antidiabetic medication, a proxy for diagnosis of diabetes
    Units: Subjects
        Yes
    33
        No
    51
    Etiology of CS
    Anatomical etiology of endogenous Cushing's syndrome
    Units: Subjects
        Cushing's disease
    70
        Ectopic ACTH secretion
    2
        Adrenal-dependent
    8
        Unknown
    4
    Mean UFC (mUFC)
    Mean UFC represents the average of 24-hour UFC measured from nominally 3 adequate 24-hour urine collections. The assay ULN was 138 nmol/24 hours.
    Units: nmol/24 hours
        arithmetic mean (standard deviation)
    746.73 ± 916.348

    End points

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    End points reporting groups
    Reporting group title
    Levoketoconazole
    Reporting group description
    		 Levoketoconazole tablets 150 mg strength, open-label to be titrated to therapeutic dose
    Reporting group title
    Levoketoconazole
    Reporting group description
    		 Levoketoconazole, 150 mg tablets, blinded to identity of ingredients

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets identical to levoketoconazole tablets. Ingredients blinded to identity.
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects previously assigned to receive placebo during the RW phase received active therapy in Restoration. 21 of 22 received open-label levoketoconazole as early rescue and rapidly titrated to their therapeutic dose regimen; 1 of 22 received blinded placebo (continued from RW) + blinded levoketoconazole (newly added). The addition of blinded levoketoconazole used rapid titration to return the subject to their prior-established therapeutic dose of levoketoconazole.

    Reporting group title
    Levoketoconazole
    Reporting group description
    		 Subjects previously assigned to receive levoketoconazole during the RW phase continued to receive active therapy in Restoration. 4 of 21 received open-label levoketoconazole as early rescue and rapidly titrated to their therapeutic dose regimen; 17 of 22 received blinded levoketoconazole + blinded placebo (newly added). The addition of blinded placebo used the same rapid titration to emulate their prior-established therapeutic dose of levoketoconazole.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population is comprised of the 84 unique subjects who received at least 1 dose of levoketoconazole in any of the 3 study phases. Baseline for the safety population varies by cohort. For the levoketoconazole-naive cohort, baseline is the latest observation prior to the date of first receiving levoketoconazole in the Dose Titration-maintenance phase (N=79). For the SONICS-completer cohort (N=5), baseline is the latest observation prior to the date of receiving drug in the Randomized-withdrawal phase.

    Primary: Loss of Therapeutic Response

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    End point title
    		 Loss of Therapeutic Response
    End point description
    Proportion of subjects with loss of therapeutic response to levoketoconazole upon withdrawing to placebo compared with the proportion of subjects with loss of therapeutic response upon continuing treatment with levoketoconazole. Loss of therapeutic response (i.e., relapse) is inferred based on mUFC from three 24-hour urinary free cortisol (UFC) measurements obtained at any visit from second through final Randomized-withdrawal phase visits (RW1 through RW5 inclusive) when: (1) mUFC is above 1.5× the ULN of the central laboratory’s reference range, OR (2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is above the ULN (i.e., >1.0× ULN) , OR (3) an early rescue criterion is met.
    End point type
    Primary
    End point timeframe
    Up to 8 weeks
    End point values
    		 Levoketoconazole Placebo
    Number of subjects analysed
    22
    22
    Units: proportion
        Proportion with loss of therapeutic response
    9
    21
    Statistical analysis title
    		 Primary Analysis Method of the Primary Endpoint
    Statistical analysis description
    Statistical significance testing was conducted using a logistic regression model containing fixed-effect terms for treatment group (levoketoconazole, placebo) and subject cohort. The results including the estimated proportion and standard error for each treatment group, the estimated difference and standard error (SE) between the 2 treatment groups, and associated 95% CI and p value were derived from the model.
    Comparison groups
    Levoketoconazole v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Mean difference (net)
    Point estimate
    -96.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -99.4
         upper limit
    		 -93.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.54
    Notes
    [1] - Although the logistic regression model was chosen a priori as the primary analysis method, the secondary analysis method is considered to provide the more definitive estimate of treatment efficacy. This is because of the imbalance of cohorts between treatment and placebo groups, resulting in 4 of the 5 subjects in the SONICS-completer cohort being randomized to placebo, all of whom had loss of therapeutic response.
    Statistical analysis title
    		 Secondary Analysis Method of Primary Endpoint
    Statistical analysis description
    Fisher's Exact Test
    Comparison groups
    Levoketoconazole v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0002
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    -54.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -75.7
         upper limit
    		 -27.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.38
    Notes
    [2] - A supportive analysis that did not require statistical modeling was conducted to confirm the results of the primary analysis. The proportions between the treatment groups were compared using a 2-sided Fisher’s Exact test and an exact unconditional two-sided 95% CI of the difference was calculated. Due to imbalance in the fixed effects for the logistic regression model, the Fischer's Exact Test results are considered the more definitive estimate of treatment effect.

    Secondary: Normalization of mUFC

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    End point title
    		 Normalization of mUFC
    End point description
    Proportion of subjects with normalization of mUFC at the end of Randomized-withdrawal phase
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks
    End point values
    		 Levoketoconazole Placebo
    Number of subjects analysed
    22
    22
    Units: Proportion
        Proportion with mUFC normalization
    11
    1
    Statistical analysis title
    		 Analysis of mUFC normalization
    Statistical analysis description
    Inferences derived from secondary efficacy analyses were gated on results from the primary efficacy analysis. Secondary efficacy analyses were hierarchically structured to ensure control of the familywise type I error rate at the 0.05 level. Hypothesis tests for secondary efficacy endpoints were based on null hypotheses that assumed no a priori differences between placebo and levoketoconazole treatments.
    Comparison groups
    Placebo v Levoketoconazole
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0015
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    45.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.2
         upper limit
    		 67.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.55
    Notes
    [3] - The proportions of subjects with normalization of mUFC at the end of Randomized-withdrawal phase were compared between treatment groups using Fisher’s Exact test.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During study conduct after receipt of at least 1 dose of study drug.
    Adverse event reporting additional description
    AEs were regarded as treatment-emergent (TEAE) if started on or after the time of first dose of study drug administration or, if present prior to first dose of study drug, increased in severity or relationship to study drug. Summaries of TEAEs are for the Randomized-withdrawal phase and for all 3 phases combined (the latter levoketoconazole only).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Levoketoconazole
    Reporting group description
    		 Levoketoconazole, 150 mg tablets, blinded to identity of ingredients

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets identical to levoketoconazole tablets. Ingredients blinded to identity.

    Reporting group title
    Safety Population
    Reporting group description
    		 The population of subjects that received at least 1 dose of levoketoconazole during the study, all phases combined.

    Serious adverse events
    		 Levoketoconazole Placebo Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    21 / 84 (25.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephropathy toxic
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
    Additional description: The safety population includes among the 3 subjects with SAEs of hypokalemia, the 1 subject with a related SAE of hypokalemia in the levoketoconazole group reported during Randomized-withdrawal phase.
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    3 / 84 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Levoketoconazole Placebo Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 22 (22.73%)
    5 / 22 (22.73%)
    66 / 84 (78.57%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    12 / 84 (14.29%)
         occurrences all number
    0
    0
    17
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 22 (4.55%)
    20 / 84 (23.81%)
         occurrences all number
    3
    1
    21
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 22 (9.09%)
    19 / 84 (22.62%)
         occurrences all number
    2
    2
    20
    Dizziness
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    11 / 84 (13.10%)
         occurrences all number
    0
    0
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 22 (4.55%)
    10 / 84 (11.90%)
         occurrences all number
    2
    1
    11
    Oedema peripheral
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    6 / 84 (7.14%)
         occurrences all number
    0
    0
    6
    Asthenia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    5 / 84 (5.95%)
         occurrences all number
    0
    0
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 22 (4.55%)
    24 / 84 (28.57%)
         occurrences all number
    2
    1
    34
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
    12 / 84 (14.29%)
         occurrences all number
    1
    3
    19
    Lip Dry
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    8 / 84 (9.52%)
         occurrences all number
    0
    0
    8
    Abdominal pain upper
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    6 / 84 (7.14%)
         occurrences all number
    0
    0
    6
    Abdominal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    5 / 84 (5.95%)
         occurrences all number
    0
    0
    6
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    5 / 84 (5.95%)
         occurrences all number
    0
    0
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    7 / 84 (8.33%)
         occurrences all number
    0
    0
    8
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    8 / 84 (9.52%)
         occurrences all number
    0
    0
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    5 / 84 (5.95%)
         occurrences all number
    0
    0
    5
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    8 / 84 (9.52%)
         occurrences all number
    0
    0
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    7 / 84 (8.33%)
         occurrences all number
    0
    0
    7
    Myalgia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    5 / 84 (5.95%)
         occurrences all number
    0
    0
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    7 / 84 (8.33%)
         occurrences all number
    0
    0
    7
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    21 / 84 (25.00%)
         occurrences all number
    0
    0
    28
    Decreased appetite
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    10 / 84 (11.90%)
         occurrences all number
    0
    0
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jun 2017
    Added instructions for SONICS-completers who require re-titration. Clarified that subjects who must re-establish their Therapeutic Dose via re-titration (at the outset of the study) may begin re-titration at their current or most recently received dose at the discretion of the Investigator, rather than start at DL1. Made corrections and clarifications to ensure consistency of wording and alignment of information throughout the Protocol Synopsis and Protocol.
    21 Jun 2018
    Added additional Information on Adverse Event of Special Interest (QTc Interval, Liver Function Test Abnormalities and Adrenal Insufficiency. Clarified which screening procedures apply to screening subjects. Updated to requirement to include additional safety visits for subjects currently on levoketoconazole requiring re-titrating after TM0 through TM2, dependent on dose escalations.
    14 Dec 2018
    Increased the target number of subjects for randomization to 54 with 27 in each treatment group. Clarified that subjects who completed SONICS but are being treated as part of the levoketoconazole-naïve cohort must re-establish their Therapeutic Dose according to the LOGICS definition.
    23 Sep 2019
    Clarification and updated wording on the number of potential randomized subjects and sample size determination. The updated text provides a range of target sample sizes from 46 to 54 that are dependent on the withdrawal rate prior to RW4 during the Randomized Withdrawal Phase.

    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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