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
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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
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Results information
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Results version number |
v1(current) |
This version publication date |
06 Feb 2022
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First version publication date |
06 Feb 2022
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
COR-2017-01
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03277690 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Cortendo AB
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Sponsor organisation address |
900 Northbrook Drive, Suite 200, Trevose, United States, 19053
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Public contact |
Clinical Trial Information, Cortendo AB, info@cortendo.com
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Scientific contact |
Clinical Trial Information, Cortendo AB, info@cortendo.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
20 Oct 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Aug 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Aug 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 2
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Country: Number of subjects enrolled |
Poland: 2
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
Bulgaria: 13
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
Greece: 6
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Country: Number of subjects enrolled |
Hungary: 5
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Country: Number of subjects enrolled |
Italy: 16
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Country: Number of subjects enrolled |
Israel: 7
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Country: Number of subjects enrolled |
Romania: 9
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Country: Number of subjects enrolled |
United States: 18
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Worldwide total number of subjects |
84
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EEA total number of subjects |
59
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
77
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From 65 to 84 years |
7
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||
Pre-assignment
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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
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Period 1 title |
Dose Titration and Maintenance
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||
Arms
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Arm title
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Levoketoconazole | |||||||||||||||||||||
Arm description |
Levoketoconazole tablets 150 mg strength, open-label to be titrated to therapeutic dose | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Levoketoconazole
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Investigational medicinal product code |
COR-003
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Other name |
2S,4R-ketoconazole, normocort
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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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.
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Period 2
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Period 2 title |
Randomized withdrawal
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Is this the baseline period? |
Yes [1] | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Investigator, Monitor, Data analyst, Carer, Assessor, Subject | |||||||||||||||||||||
Blinding implementation details |
Active and placebo tablets matching in appearance provided to to study investigators for dispensing. Randomization controlled using interactive response system.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Levoketoconazole | |||||||||||||||||||||
Arm description |
Levoketoconazole, 150 mg tablets, blinded to identity of ingredients | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Levoketoconazole
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Investigational medicinal product code |
COR-003
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Other name |
2S,4R-ketoconazole, normocort
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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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.
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
Placebo tablets identical to levoketoconazole tablets. Ingredients blinded to identity. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo to levoketoconazole
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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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).
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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. |
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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. |
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Period 3
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Period 3 title |
Restoration
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Is this the baseline period? |
No | |||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Investigator, Monitor, Subject, 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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
COR-003
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Other name |
2S,4R-ketoconazole, normocort
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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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.
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Arm title
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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
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Investigational medicinal product code |
COR-003
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Other name |
2S,4R-ketoconazole, normocort
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Levoketoconazole
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Reporting group description |
Levoketoconazole, 150 mg tablets, blinded to identity of ingredients | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo tablets identical to levoketoconazole tablets. Ingredients blinded to identity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety population
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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.
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End points reporting groups
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Reporting group title |
Levoketoconazole
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Reporting group description |
Levoketoconazole tablets 150 mg strength, open-label to be titrated to therapeutic dose | ||
Reporting group title |
Levoketoconazole
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Reporting group description |
Levoketoconazole, 150 mg tablets, blinded to identity of ingredients | ||
Reporting group title |
Placebo
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Reporting group description |
Placebo tablets identical to levoketoconazole tablets. Ingredients blinded to identity. | ||
Reporting group title |
Placebo
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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
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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
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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.
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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.
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End point type |
Primary
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End point timeframe |
Up to 8 weeks
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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.
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Comparison groups |
Levoketoconazole v Placebo
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Regression, Logistic | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-96.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-99.4 | ||||||||||||
upper limit |
-93.3 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1.54
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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. |
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Statistical analysis title |
Secondary Analysis Method of Primary Endpoint | ||||||||||||
Statistical analysis description |
Fisher's Exact Test
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Comparison groups |
Levoketoconazole v Placebo
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
= 0.0002 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-54.5
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-75.7 | ||||||||||||
upper limit |
-27.4 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
11.38
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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. |
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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
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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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.
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Comparison groups |
Placebo v Levoketoconazole
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Number of subjects included in analysis |
44
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.0015 | ||||||||||||
Method |
Fisher exact | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
45.5
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
19.2 | ||||||||||||
upper limit |
67.9 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
11.55
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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. |
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Adverse events information
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Timeframe for reporting adverse events |
During study conduct after receipt of at least 1 dose of study drug.
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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).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Levoketoconazole
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Reporting group description |
Levoketoconazole, 150 mg tablets, blinded to identity of ingredients | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Placebo tablets identical to levoketoconazole tablets. Ingredients blinded to identity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Safety Population
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Reporting group description |
The population of subjects that received at least 1 dose of levoketoconazole during the study, all phases combined. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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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. |
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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. |
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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. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |