Conditions: Endogenous Cushing's Syndrome
Keywords: Cushing Syndrome, Adrenocortical Hyperfunction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 84
Healthy volunteers: no

Brief summary:
This is a double-blind, randomized, placebo-controlled withdrawal and rescue/restoration study in subjects with endogenous Cushing's Syndrome (CS) previously treated with single-arm, open-label levoketoconazole that will assess efficacy, safety, tolerability, and pharmacokinetics of levoketoconazole.

Detailed description:
This is a double-blind, randomized, placebo-controlled withdrawal and rescue/restoration study in subjects with endogenous CS that will assess efficacy, safety, tolerability, and Pharmacokinetics (PK) of levoketoconazole. There are two populations (cohorts) of subjects: (1) subjects which were previous levoketoconazole study completers and (2) subjects that are levoketoconazole treatment naïve subjects.

Study methodology varies by cohort prior to randomization only. Following initial screening (washout as needed) and Dose Titration and Maintenance Periods, as applicable, this study will be conducted in two double-blind phases (a Withdrawal Phase and a Restoration Phase). The levoketoconazole-naïve cohort will need to go through the Dose Titration and Maintenance Phase. The longest anticipated total study participation duration is approximately 51 weeks.

Arms:
arm 1: Double blind withdrawal phase: Levoketoconazole (up to a dose of 1200 mg); Double blind restoration phase: Levoketoconazole plus Placebo arm 2: Double blind withdrawal phase: Placebo; Double blind restoration phase: Placebo plus Levoketoconazole

Interventions: intervention 1: Levoketoconazole intervention 2: Placebo
Intervention descriptions: intervention 1: During the double-blind Withdrawal Phase, patients will receive up to 1200 mg levoketoconazole daily.

During the double-blind Restoration Phase, patients will receive levoketoconazole plus placebo. intervention 2: During the double-blind Withdrawal Phase, patients will receive placebo tablets.

During the double-blind Restoration Phase, patients will receive placebo plus levoketoconazole.

Protocol document:
Prot_000.pdf: 
 
Amendment 4 
23 September 2019 
Page 1 of 162 
CONFIDENTIAL
 
 
 
CLINICAL STUDY PROTOCOL 
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 
Protocol Number 
COR-2017-01 
Compound 
Levoketoconazole  
IND No. 
115968 
EudraCT No. 
2017-001219-35  
 
Phase 
3 
Dates: 
 
Amendment 4 
Amendment 3 
Amendment 2 
Amendment 1 
23 September 2019 
14 December 2018 
21 June 2018 
06 July 2017 
Original 
17 April 2017 
 
 
Sponsor 
Cortendo AB 
900 Northbrook Drive, Suite 200 
Trevose, Pennsylvania, 19053 
USA 
 
 
 
Cortendo AB 
c/o TMF Sweden AB 
Sergels Torg 12 
111 57 Stockholm 
Sweden 
 
 


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Revision Chronology 
Version 
Date  
Final  
17 April 2017 
Amendment 1: 
• Throughout, clarified and corrected references to the visits in Randomized 
Withdrawal Phase:  RW1 is the second visit of the Randomized Withdrawal 
Phase and is the first time when loss of prior-established UFC response is 
assessed. Removed exploratory endpoint ‘Changes from Baseline (RW0) in late 
night salivary cortisol (LNSC) at all post-Baseline visits with these assessments 
through the final study visit (RES2)’, as this endpoint is included as the 
secondary endpoint ‘Changes from Baseline (RW0) in mean urinary free cortisol 
(mUFC) and LNSC at all post-Baseline visits with these assessments through the 
final study visit (RES2)’. 
• Clarified method of planned statistical analysis for primary endpoint and added 
additional details of planned statistical analyses for primary and secondary 
endpoints in synopsis.  
• Standardized definition of relapse throughout to match definition in Section 3.1.  
• Revised planned target population to comprise approximately one-half SONICS 
completers and one-half levoketoconazole-naïve (rather than two-thirds and one-
third as previously planned) and increased the maximum proportion of 
levoketoconazole-naïve subjects to 70%, if needed. 
• Clarified subject categorization of prior levoketoconazole use. Clarified screening 
and RW0 procedures for subjects who have exited SONICS more than six months 
prior to the Screening Phase and have been on a stable Therapeutic Dose 
throughout the previous 12-week period. 
• Inclusion criteria for all others: Corrected the dexamethasone value required. 
• Exclusion criteria: Added a criterion for subjects enrolled in SONICS who did 
not complete SONICS through Visit M12; removed the need for central reading 
of electrocardiogram (ECG) for Screening determination of eligibility; added 
alkaline phosphatase (AP) above 2X upper limit of normal (ULN) as grounds for 
exclusion; removed specification of uncontrolled hypertension (180/120 mmHg). 
• Clarified throughout that members of SONICS-Completer cohort must have 
maintained treatment with a Therapeutic Dose of levoketoconazole for a 
minimum of 12 weeks prior to screening.  
• Clarified that an Open Label Extension (OLE) study is being planned for 
qualifying participants in the current study. 
• Clarified that the Signs and Symptoms of Cushing’s Syndrome can also be 
performed by a qualified home healthcare professional with training. Specified 
that the person completing the Signs and Symptoms of Cushing’s assessments 
should, when possible, remain consistent for individual subjects. Specified that, 
in cases of clinically significant deterioration of clinical signs and symptoms of 
CS, home healthcare professionals should refer the subject back to the physician 
for corroboration prior to initiation of early rescue therapy. 
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• Removed descriptor of pharmacokinetic (PK) Sample Collection as applying only 
to Levoketoconazole-naïve and re-titrations only.  Removed PK sampling from 
visits TM1, RW0 and RES2.  Corrected inconsistency of PK requirement at TM7.  
Clarified that PK samples collected at hours 6 to 8 post-dose will be collected at a 
different visit (TM2-TM6) than the other PK samples. 
• Added instructions for SONICS-completers who require re-titration to Dosage 
and Administration section. 
• Clarified that additional safety visits were to occur for subjects receiving a total 
daily dose of 750 mg and above. 
• Removed requirement ‘and without evidence of cholestasis’ from grounds for 
discontinuation of investigational therapy in the case of: alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) above 3X ULN and total bilirubin 
(TBN) above 2X ULN or International Normalized Ratio (INR) above 1.5 not 
explained by any other cause such as viral hepatitis.  
• Added section describing withdrawal due to adrenal insufficiency. 
• Clarified that approximately 3 minutes was to elapse between triplicate heart rate 
measurements. 
• Added gamma-glutamyl transpeptidase (GGT) to panel of liver safety monitoring 
tests. 
• Corrected spelling of levonorgestrel. 
• Revised and clarified section on pituitary magnetic resonance imaging (MRI). 
• Corrected visit corresponding to dose escalation for the 750-mg dose level to 
TM3 (not TM4) and revised subsequent visits cited accordingly. 
• Clarified that when adrenal insufficiency is observed at Dose Level 1 (DL1), 
subjects may be provided a lower dose of 150 mg QD (Dose Level [DL] 0) 
following agreement with the Sponsor.  Subjects may resume the Dose Titration 
scheme after a dose reduction at the discretion of the Investigator and agreement 
of the Sponsor.   
• Added prohibition of donation of blood or blood products during the study. 
• Added that the total final tablet count (active + placebo) during Restoration Phase 
will equal twice the total tablet count of the Therapeutic Dose, not to exceed 8 
tablets twice daily (BID).  
• Added further details to dosage administration section ‘For levoketoconazole-
naïve subjects, the total daily dose will be titrated in 150 mg increments from a 
starting dose of 300 mg (dosed as 150 mg BID) up to a maximal daily dose of 
1200 mg (dosed as 600 mg BID) until a Therapeutic Dose is established.  The 
minimum daily dose is 150 mg once daily (QD) for subjects who cannot tolerate 
150 mg BID.  For subjects in the SONICS-completers cohort, the Therapeutic 
Dose will have been established prior to enrollment in this study.  For 
levoketoconazole-naïve subjects, the Therapeutic Dose will be established by the 
end of the Dose Titration / Maintenance Phase.  The Therapeutic Dose will be 
used as the target dose and dose-regimen during the Restoration Phase.’ 
• 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 


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recently received dose at the discretion of the Investigator, rather than start at 
DL1.   
• Clarified that potassium supplements are encouraged to maintain serum 
potassium levels within the normal range and above 4.0 mmol/L, which may 
reduce the risk of drug-induced QT interval (QTc) prolongation. 
• Clarified that timing of the first bi-annual Data Safety Monitoring Board (DSMB) 
meeting may be adjusted based on subject accrual.  Removed the requirement for 
the DSMB charter to be executed prior to study initiation. 
• Added criterion to oral glucose tolerance test (OGTT) and Impaired fasting 
glucose (IFG) (≥ 100 mg/dL (5.6 mmol/L) and < 126 mg/dL (7.0 mmol/L), 
respectively. 
• Clarified that changes of pituitary tumor will be summarized from Screening to 
Visits RW0 and RW5 (for the levoketoconazole-naïve cohort) and from Visit 
RW0 to RW5 (for the SONICS-completers cohort). 
• Clarified the statistical analyses of clinical signs and symptoms. 
• Corrected definition of prediabetic subjects from ‘above 100 mg/dL’ to ‘greater 
than or equal to 100 mg/dL’. 
• Clarified the definition of AESI of persistent QTc prolongation. 
• Clarified the definitions for adverse events (AEs) considered unrelated and 
unlikely related to study drug. 
• Time and events schedule: Table 8 added row for OGTT, removed MRI row, 
removed optional PK sampling at TM1, and made sampling at TM7 non-optional, 
added clarification footnotes regarding 24-h UFC/free cortisol/creatinine/ urinary 
volume (three collections) and that in case of AESI, a PK sample should be 
obtained as close to the time of the event as possible.  
• Time and events schedule: Table 9 removed PK sampling from RW0 and RES2 
but added footnote that that in case of AESI, a PK sample should be obtained as 
close to the time of the event as possible. Footnotes edited for clarity. 
• Appendix B added salivary cortisol and dexamethasone for completeness.  
Amendment 2:  
• Updated typographical errors. 
• Corrected the date of Amendment 1 in the Summary of Changes from 22 June 17 
to 06 July 2017.  
• Updates made to ensure consistency of wording and alignment of information 
between Protocol Synopsis and Protocol.  
• Corrected the changes in biomarkers of CS comorbidities list in the secondary 
objectives (Synopsis and Section 2.2), and Secondary Efficacy Analysis 
(Synopsis and Section 12.5.3.2) to be a consistent listing of biomarkers.  
• Changed condition 2 of the Primary Endpoint in the Synopsis and Sections 3.1, 
3.4, as well as related footnotes, from “at or above the ULN (i.e. ≥ 1.0X ULN)” 
to “above the ULN (i.e. >1.0X ULN).” 
• Changed condition 2 of the Primary Efficacy Analysis in the Synopsis and 
Sections 12.5.3.1 and 12.5.3.3 from “was at least 1.0X ULN” to “is above ULN 
(i.e. >1.0X ULN).” 
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• Changed condition 2 Partial loss of cortisol response from “below 1.5X ULN” to 
“no more than 1.5X ULN” in Early Rescue Criteria in the Synopsis and Section 
4.3.1. 
• Removed the phrase “necessitating open-label therapy” or “necessitating open-
label therapy to treat hypercortisolism” from condition 3 of the Primary Endpoint 
for early rescue in Synopsis and Sections 3.1, 3.4, 12.2, 12.5.3.1 and 12.5.3.3.  
• Added clarifying text in Synopsis and Section 4.2.2.1 for selected group of 
subjects who completed Visit M12 in SONICS either within 6 months or more 
than 6 months prior to the Screening Phase and not on a stable Therapeutic dose 
throughout the previous 12-week period.  Procedures for these subjects should 
mimic those of the levoketoconazole-naïve subjects.  
• Added clarifying text to Appendix A Table 7 for subjects who completed 
SONICS more than 6 months prior to the Screening Phase and have been on 
stable Therapeutic Dose to mimic Screening Procedures of the levoketoconazole-
naïve subjects.   
• Corrected the time to first normalization in Exploratory Endpoints beginning 
from “RES1” to “RW5” in the Synopsis and Section 3.4. Removed from Section 
12.5.3.2. 
• Corrected the statement in the Primary Endpoint in the Synopsis and in Section 
3.1 from “…from of three 24-hour UFC measurements…”. to read “…from three 
24-hour UFC measurements…”. 
• Revised text and definitions throughout protocol in regard to screening 
procedures to ensure alignment with Appendix A Table 7. 
• Added clarification that the DST is not needed at screening for subjects on 
levoketoconazole in Section 6.4.5.3 and Appendix A Table 7.  
• Added clarification of OGTT test timing and definition of whom should have the 
test performed in Appendix A Tables 8 and 9 footnotes. 
• Changed the population definition for the OGTT test from “non-diabetic” to “pre-
diabetic” in Appendix A Tables 8 and 9, and in the Other analytes/measures 
section of Appendix B Laboratory Analytes. 
• Updated wording throughout associated with the Dose Titration at Total Daily 
Doses of 750 mg or above and the need for additional safety visits in the Dose 
Titration and Maintenance Phase from “750 mg or higher” or “750 mg and 
above” or “beyond 600mg/day” or “exceeds 600 mg” or “beginning with 750 
mg” or “above 600 mg/day to “750 mg/day or above” in the Synopsis and 
Sections 4.2.2.2, 4.2.2.4, 6.4.6.1, 6.5.2, 9.4, and Appendix A Table 8 footnotes. 
Removed the phrase “above 600 mg/day” when referring to additional safety visit 
necessary for certain dose escalations in Sections 4.2.2.4. 
• Added the timing of tablet count increase increments during the Restoration 
Phase titration beginning at RW5 will be “alternating AM and PM per Table 2 
Dosing Titration Scheme” in Section 4.4, and “alternating AM and PM” in the 
Synopsis.   
• Clarified that the DSMB will be assessing “key” safety data in the Synopsis. 
• Added statements that “Any subject who withdraws after randomization will not 
be replaced” and “Withdrawn subjects will not be re-entered into the study”, and 


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clarified the null and alternative hypotheses definitions and sample size 
determination in the Synopsis and Section 12.2.1.  
• Clarified instrument for measurement of QTc interval in Exclusion 11 in the 
Synopsis to be consistent with Section 5.3. 
• Updated to include additional safety visits for subjects currently on 
levoketoconazole requiring re-titrating after TM0 through TM2, dependent on 
dose escalations in Section 9.3 and Appendix A Table 8. 
• Changed Exclusion Criteria 21 serum potassium measurement from “below 3.0 
mEq/L” to “below 4.0 mEq/L” in the Synopsis, and Section 5.3. 
• Updated the SONICS enrollment from “is planned to enroll 90” to “enrolled 94” 
in Section 1.1. 
• Changed the most recent meeting date of the DSMB in Section 1.1 from “October 
2016” to “April 2018” and changed “approximately two thirds of the study 
enrolled” to “the study fully enrolled”.  
• Clarified durability of efficacy in Section 1.2. 
• Removed footnote in Inclusion Criteria for All Others #5 in the Synopsis and 
added text as a note within the Inclusion Criteria for All Others #5 in the 
Synopsis to be in line with Section 5.2. 
• Added a note to Inclusion Criteria for All others #4 and #5 in the Synopsis and in 
Section 5.2 to clarify that these two criteria do not apply to subjects currently on 
levoketoconazole. 
• Alignment of footnote for condition 2 of the Primary Endpoint throughout 
protocol. 
• Clarified timing for rest period prior to ECG measurement in 12-Lead ECG 
Section 6.4.3 from “at least 1 minute” to “at least 5 minutes”. 
• Information added to Blinding Section 8.3.3.1 to account for top line analysis. 
Also clarified use of open-label levoketoconazole for subjects who require early 
rescue.     
• Added Section 12.6 Interim Analyses and Data Monitoring to the Data Analysis 
and Statistical Considerations section.  
• Added statement that “Drug accountability will not be performed during visits by 
HHC professional” in Section 9.3 and statement that “Drug accountability and 
dispensation only to be completed when visits are performed in-clinic and not 
applicable to HHC visits” to Appendix A Table 9.  
• Clarified collection of working shift and sleep hours in Lifestyle and Dietary 
Restrictions Section 7. 
• Clarified the subject population definitions (Intent-to-Treat, Per-Protocol, 
Levoketoconazole-naïve, and SONICS-completer) in the Analysis Populations / 
Populations for Analysis sections in the Synopsis and Section 12.1, respectively. 
• Clarified Definitions of Baseline for some endpoints analyzed during the 
Restoration Phase only in section 12.5.1. 
• Added “TEAEs of special interest” to the Adverse Events in Section 12.5.2.2. 
• Changed the reference from “Hotline” to “Contact Details” and “24 Hour Phone” 
to “24-Hour Call Center Phone” in SAE reporting Section 13.7. 


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• Changed RW5 marked the start of the “Rescue Phase” to RW5 marked the start 
of the “Restoration Phase” in the Synopsis and Section 4.1.  
• Clarified statistical terminology and corrected text pertaining to statistical tests 
throughout protocol and in the Data Analysis and Statistical Considerations in 
Synopsis and Section 12. 
• Changed “lost UFC response” to “lost (lose/loss of) therapeutic response” in the 
Synopsis and Sections 12.2.1 and 12.4. 
• Added additional clarification to the rules to be applied when determining loss of 
therapeutic response when some or all mUFC data are missing in Section 12.4. 
• Clarified the Time to Event Analysis Section 12.5.3.3 to be in alignment with 
statistical terminology and Exploratory Endpoints section. 
• Moved UFC and LNSC Analyses-Partial loss of response section and Time to 
Event Analysis section, Cushing’s Syndrome Quality of Life Questionnaire, and 
Beck’s Depression Questionnaire sections from the Secondary Efficacy Section 
12.5.3.2 to the Exploratory Efficacy Section 12.5.3.3. 
• Changed the header in Section 9.2 to refer to drug as “Investigational Product” 
rather than “Product” to ensure consistency throughout the section. 
• Added the active medication/open-label levoketoconazole drug source for 
subjects rolling over from SONICS and for subjects entering from EAP in 
Section 4.1 and in Appendix A Table 7. 
• Added line item in Appendix A Table 7 to “Dispense study medication/diary” 
during Screening for subjects who completed SONICS within the previous 6 
months and currently receiving levoketoconazole.  
• Updated and added applicable footnotes to clarify text and ensure consistency 
between protocol body and Appendix A Tables 7, 8 and 9.   
• Renumbered and reordered footnotes throughout Appendix A Tables 7, 8, and 9. 
• Removed ‘SONICS-completers cohort’ and ‘Levoketoconazole-naïve cohort’ and 
updated descriptors in the column headers in Appendix A Table 7.  
• Clarified SONICS-completers (subjects who completed SONICS) versus 
SONICS-completers ‘cohort’ throughout the protocol.   
• Clarified that data may overlap between SONICS and LOGICS in the Synopsis 
and Sections 4.2.1 and 6.1.  
• Clarified subjects in levoketoconazole-naïve cohort “must” have their 
Therapeutic Dose established by end of Dose Titration and Maintenance Phase in 
Section 8.3.2. 
• Clarified subjects in SONICS-completers cohort will have their Therapeutic Dose 
confirmed at screening (prior to randomization) in Sections 8.3 and 8.3.2.  
• Clarified timing of UFCs to indicate collections must be collected prior to visits 
in the Dose Titration and Maintenance Phase in the Synopsis, Sections 4.2.2.2., 
4.2.2.2.1, 4.2.2.2.2, and 6.4.5.1, and Appendix A Table 8.  
• Clarified washout must be prior to Baseline Assessments, including UFCs and 
LNSCs in Synopsis, Sections 4.2.2.1, 6.2, and Appendix J Table 12. 
• Added that urine volume can be measure by HHC professional in Section 6.4.5.1. 
• Clarified timing of UFC to indicate collections must be collected prior to the visit 
in the Randomized Withdrawal and Restoration Phases in Appendix A Table 9.  


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• Clarified timing of LNSC to indicate collections must be collected before the visit 
in the Dose Titration and Maintenance, Randomized Withdrawal, and Restoration 
Phases in Section 6.4.5.2 and Appendix A Tables 8 and 9.  
• Added additional details for the use of SONICS M12 UFC and LNSC collection 
samples and required additional collections for LOGICS screening for subjects 
rolling over from SONICS in Sections 6.4.5.1 and 6.4.5.2 and Appendix A Table 
7. 
• Clarified MRI procedures need to be completed if not previously done within 6 
months for “TM0” to “TM0 or RW0” in the Synopsis, Section 4.2.2.1, 6.4.5.5, 
and Appendix A Tables 7 and 8.  
• Added SONICS M12 MRI may be used in Section 6.4.5.5 to ensure consistency 
with Appendix A Table 9. 
• For use of Local ECG machines in Appendix A Tables 7, 8, and 9; removed “not 
operational” or “unavailable” and clarified text to read “…non-operational. Local 
ECGs must be transmitted to Spaulding for central reading via printout.” 
• Added Ammonia to list of other laboratory tests for Liver Panel in Appendix O.   
• Added Lactate Dehydrogenase (LDH) to the list of abbreviations, list of 
laboratory tests for Liver Safety Tests in Section 6.3, Section 6.4.4, and Appendix 
B. 
• Added details for grading and evaluating criteria for acne, hirsutism (females 
only) and peripheral edema to Appendix M. 
• Updated language in Appendix M to include the Assessment of Clinical Signs 
and Symptoms of Cushing’s Syndrome can be completed by qualified trained 
HHC professional, in addition to the Investigator. 
• Modified line item for “Administer/dispense drug/drug accountability/patient 
diary” in Appendix A Table 8 to 2 separate line items “Administer Study 
drug/patient study diary review” and “Drug accountability/dispensation of drug 
and study diary” to clarify that drug accountability and dispensation of drug and 
study diary will not occur at additional safety visits. 
• Modified line item for “Administer/dispense drug/drug accountability/patient 
diary” in Appendix A Table 9 to 2 separate line items “Administer study drug/ 
patient diary review and dispensation” and “Drug accountability/dispensation of 
drug” to clarify activities to be performed in clinic versus during HHC visit.  
• Added a new visit column in Appendix A Table 8 for “Additional safety visit 
(HHC)” and added the caveat “(in office)” to the existing Additional safety visit 
column to distinguish procedures that should be completed by HHC during the 
Dose Titration and Maintenance Phase. 
• Clarified text referring to concomitant drugs that are categorized into multiple 
categories and added text that the restrictions of the “most restrictive” category 
should hold precedent in Appendix J. 
• Removed the duplicate medications (Buproprion and Phentermine) from 
Appendix J Table 16. 
• Changed the reference noted in Appendix J for the drug interaction checker to be 
used for Drug-drug interactions via CYP3A4. 
• Updated “unless no suitable alternative is available after the Baseline Visit” in 


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Appendix J Table 20. 
• Added “Polycystic Ovary Disease (PCOD)” to the list of clinical features of CS 
and moved “Glucocorticoid resistance” from the clinical features list to the 
Unlikely to have any clinical features of CS list in Appendix G. 
• Replaced Appendix O “Instructions for Liver Function Test Abnormalities 
Follow-up” with “Additional Information on Adverse Event of Special Interest 
(QTc Interval, Instructions for Liver Function Test Abnormalities Follow-up and 
Adrenal Insufficiency)” and added additional information schematics and 
instructions.   
• Added additional references to Appendix O in the body of the Protocol.   
• Removed +3-day window from collection of LNSC and UFC collection for 
Baseline measurements in Sections 6.2, 6.4.5.2, and Appendix A Table 8.  
• Clarified RW0 may occur concurrently with TM7 or no more than 11 (+3 days) 
later unless a dose change is required at TM7 in Section 6.2 and Appendix A 
Table 9. 
• Clarified expected creatinine excretion rates in Section 6.4.5.1 and Table 4. 
Amendment 3: 
• Corrected typographical and formatting errors. 
• Updates made to ensure consistency of wording and alignment of information 
between the Protocol Synopsis and the Protocol, as well as alignment between 
sections of the Protocol. 
• Aligned use of terminology throughout the Protocol referencing the Dose 
Titration and Maintenance Phase to TM Phase for consistency. 
• Removed abbreviation for total bilirubin (TBN) and clarified instances where 
bilirubin should have been used instead of total bilirubin in Protocol Synopsis, 
Protocol and Appendices.   
• Increased target number of subjects for randomization to 54 with 27 in each 
treatment group, removed the reference to the target number of completing 
subjects and changed the reference to the number of anticipated 
SONICS-completers to represent a minority of randomized subjects in the 
Synopsis and Section 12.2.1. 
• The secondary and exploratory objectives and endpoints have been realigned and 
clarified.  Only acne, hirsutism and peripheral edema as clinical signs and 
symptoms of CS have remained secondary; the other signs and symptoms have 
been shifted from secondary to exploratory objectives and endpoints.  The health-
related quality of life and symptoms of depression have been shifted from 
exploratory to secondary objectives and endpoints.  The evaluation criteria for 
exploratory endpoint #2 for time from RW0 to first time of loss of response has 
been more clearly defined.  These changes have been made in the Synopsis and 
the corresponding sections for objectives (Section 2.2 and Section 2.3), endpoints 
(Section 3.2 and Section 3.3), and efficacy analyses (Section 12.5.3.2 and Section 
12.5.3.3). 
• Blood pressure and high-density lipoprotein cholesterol (HDL-C) have been 
removed from secondary objectives, endpoints and the related analysis.  These 
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changes have been made in the Synopsis and the corresponding sections for 
objectives (Section 2.2), endpoints (Section 3.2), and efficacy analyses (Section 
12.5.3.2). 
• Clarified that subjects on levoketoconazole from SONICS or the Expanded 
Access Program must have confirmation of their Therapeutic Dose, as defined in 
the SONICS protocol, during the Screening Phase to confirm cohort placement 
for LOGICS in the Synopsis and Section 4.2.1. 
• Added clarification describing the eligibility of subjects who complete SONICS, 
including the Follow-up Visit in Section 4.2.2.1. The potential to use select data 
from the SONICS Follow-up Visit for the LOGICS Screening Visit is also 
described. 
• Clarified that eligibility for entering the Randomized Withdrawal Phase requires 
levoketoconazole-naïve cohort subjects to have established and maintained a 
Therapeutic Dose for at least 4 weeks as confirmed by the average of 3 UFC 
values with results received prior to the RW0 Visit in Section 4.2.2.5. 
• Clarified throughout the document that the TM Phase is open-label and that once 
the Therapeutic Dose is achieved, the dose should generally not be further 
adjusted if the mean UFC levels are within normal limits.  However, the dose 
may be increased if medically necessary to maintain eucortisolemia or decreased 
if needed to address drug intolerance or AE.  Updates were made in the Synopsis 
and Section 4.2.2.  Section 8.3.2.1 was added to include this information. 
• 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 in Section 4.1. 
• Clarified the definition of a stable Therapeutic Dose for the SONICS-completers 
cohort in Section 4.1. 
• Clarified that subjects are not permitted a dose change during the Restoration 
Phase. They should be withdrawn from LOGICS owing to “loss of efficacy” and 
may be considered for enrollment in the OPTICS study or EAP program in the 
Synopsis and Section 4.4. 
• Clarified that subjects withdrawn due to suspected or confirmed drug-induced 
liver injury will not be eligible to enroll in either the OPTICS study or EAP 
program in Section 5.4.2. 
• Clarified that subjects who require early rescue during the Randomized 
Withdrawal Phase, may receive open-label levoketoconazole and continue in the 
study.  The rapid titration of the Restoration Phase should be used to reestablish 
the Therapeutic Dose of open-label levoketoconazole used for the early rescue.  
Dose adjustments may be made, as medically indicated including adjustments to 
dose levels above the previous therapeutic dose to return subjects to 
eucortisolemia.  Updates were made in the Synopsis, Section 4.1, Section 4.3.1, 
and Section 8.3.3.1. Section 8.3.3.3 was added to include this guidance 
information. 
• Clarified that subjects who may require lipid lowering drugs, they should be 
added and stabilized for at least 4 weeks prior to TM0 for the levoketoconazole-
naïve cohort or RW0 for the SONICS-completers cohort in Exclusion 
Criterion #24 in the Synopsis and Section 5.3, and in Sections 10.1 and 10.2.  


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• Clarified that at TM7, subjects may require more than 14 (± 3) days between 
TM7 and RW0 to allow for 4 weeks maintenance if a dose change is required at 
TM7 in the Synopsis and Section 4.2.2.2. 
• Added clarification that blinding to the treatment code should be maintained 
during early rescue in Section 4.3.1 and Section 8.3.3.1. 
• Added study number and name of the open-label extension (OLE) study (Study 
COR-2017-OLE, aka OPTICS). 
• Added clarification that procedures for LOGICS can only be performed during 
SONICS Visit M12 after the informed consent for LOGICS has been signed in 
Section 6.4.5.1 and Section 6.4.5.2. 
• Added clarification that subjects should remain awake within 2 hours before 
collecting the late-night salivary cortisol samples in Section 6.4.5.2. 
• Added clarification of information about the SONICS-completers cohort for 
subjects that finished SONICS within 6 months prior to screening for LOGICS 
and for those subjects who completed SONICS more than 6 months prior to the 
Screening Phase in Section 4.2.1. 
• Clarified in Figure 1 and in the Synopsis that during the screening period for 
subjects that are SONICS-completers IP may be dispensed starting at TM0 (from 
LOGICS for those entering Screening directly from the SONICS study and from 
EAP for those entering Screening directly from the EAP program). 
• Study Hypothesis and Sample Size Determination information was updated to 
align with new assumption that approximately 20% of subjects in each treatment 
group will withdraw prior to RW4 and to decrease the assumption of loss of 
response to 10% in the levoketoconazole arm in the Synopsis and Section 12.2.1. 
• For the Primary Efficacy Analysis, Loss of Therapeutic Response definition, the 
null hypothesis definitions were removed in Section 12.5.3.1. 
• Synopsis Screening Phase wording was clarified to remove the word ‘blood’ to 
align with Section 4.2.2 and Section 6.2 regarding the washout of medications 
that are known to influence cortisol. 
• Added a heading for Eligibility and included statement clarifying that Cortendo 
will review each subject’s enrollment criteria in the Synopsis. 
• Included information in Section 4.2.2.2 and Synopsis to allow for subjects still in 
the TM Phase when the randomization target of 54 subjects has been reached to 
be offered the opportunity to join the OPTICS study and receive open-label 
treatment provided they meet the OPTICS inclusion/exclusion criteria. 
• Included information in Section 4.3 that eligibility for entering the Randomized 
Withdrawal Phase requires subjects to have established and maintained a 
Therapeutic Dose as confirmed by the average of 3 UFC values with results 
received prior to the RW0 visit. 
• Clarified that the interactive randomization system is via interactive response 
technology (IRT) in Section 8.3.3.1. 
• Clarified that the duration of vital signs described in Section 6.4.2 was to occur 
over approximately 10 minutes. 


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• Updated Appendix B to classify fasting glucose and insulin as a CS 
cardiovascular co-morbidity biomarker and updated Appendix A tables (Table 7, 
Table 8, and Table 9) to include these tests as a unique laboratory assessment. 
• Clarified that for urine collections between RW5 and RES1, subjects should have 
received the previously achieved Therapeutic Dose of blinded study medication 
for at least 1 week before collections commence and complete and at least 1 week 
before the RES1 visit.  And for urine collections between RES1 and RES2, urine 
collection should commence at approximately Day 18 of the Restoration Phase.  
These updates were made in Section 6.4.5.1 and Appendix A, Table 9.  
• Clarified Appendix A, Table 7 to match flowchart including providing a diary to 
subjects who were either levoketoconazole naïve or those who completed 
SONICS > 6 months prior to study entry. 
• Clarified Appendix A, Table 9 drug accountability and dispensation to include 
guidance on collection of information in IRT. 
• Clarified Section 6.4.5.5 and Appendix A, Table 9, Footnote 13 to include 
guidance that the MRI for RW0 and RW5 may be performed up to 2 weeks 
BEFORE the study visit. 
• Clarified Appendix M to allow for signature by assessor. 
• Clarified Appendix O, Recommended LFT Management Guidance algorithm 
where ALT or AST > 3X ULN or AP > 2X ULN or Total Bilirubin >2X ULN to 
be present “with” signs or symptoms of liver dysfunction and removed reference 
to Appendix O. 
Amendment 4: 
• Corrected typographical and formatting errors 
• Updates made to ensure consistency of wording and alignment of information 
between the Protocol Synopsis and the Protocol, as well as alignment between 
sections of the protocol. 
• Clarification of the term “SONICS-completer”. “SONICS-completer Cohort” is 
the current term used for the subset of subjects who completed the SONICS study 
and met the description of the cohort as provided in Section 4.1. These updates 
were made in the following sections:  Synopsis (Eligibility, Methodology, 
Number of subjects, Inclusion Criteria, Investigational product, Statistical 
Methods); Section 2.1; Sections 4.1, 4.2.1, 4.3 and 4.3.1; Sections 5.1 and 5.3; 
Sections 6, 6.2, 6.3, 6.4.4.1, and 6.4.5.5; Sections 8.3 and 8.3.2; Section 10.1; 
Sections 12.1, 12.5.1, 12.5.2, and 12.5.3; and Appendix A. 
• Clarification regarding expansion of time to achieve Therapeutic Dose in 
levoketoconazole-naïve subjects in the Dose Titration and Maintenance Phase.  
This change is reflected in the following sections: Synopsis (Methodology, Dose 
Titration and Maintenance Phase [TM] Phase; Duration of treatment); 
Section 4.2.2.2; Section 4.2.2.2.2; and Section 6.2. 
• 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.  The following sections are 
23 Sep 2019 


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impacted by this change:  Synopsis (Methodology, Dose Titration and 
Maintenance [TM] Phase; Number of subjects (planned); and Study Hypothesis 
and Sample Size Determination); Section 4.2.2.2; and Section 12.2.1.  
• Addition of one secondary endpoint that addressed the proportion of subjects with 
normalized mUFC at the end of the Randomized Withdrawal Phase.  This change 
applies to the following sections: Synopsis (Criteria for evaluation) and Section 
3.2. The planned analysis of this endpoint has been added to Section 12.5.3.2. 
• Addition of two exploratory endpoints to analyze normalization rate of mUFC at 
TM7 and the rate of normalized mUFC or partial response at TM7. These 
changes apply to the following sections: Synopsis (Criteria for evaluation) and 
Section 3.4.  The planned analyses of these endpoints have been added to Section 
12.5.3.3. 
• Addition of eligibility of non-responders in the Dose Titration and Maintenance 
Phase to enroll in OPTICS. This change applies to Section 4.2.2.2. 
• Clarification of procedures for subjects requiring early rescue with open-label 
levoketoconazole during the Randomized Withdrawal Phase. This change applies 
to Synopsis (Methodology, Safety monitoring and extended assessment) and 
Section 4.3. 1. 
• Clarification of Early Rescue Criterion 1 (second bullet point).  This change 
applies to Section 4.3.1. 
• Clarification of Early Rescue Criterion 2 (Partial loss of cortisol response). A 
subject must have a partial loss of cortisol response and clinically significant 
worsening of CS symptoms to meet this criterion. This change applies to 
Section 4.3.1. 
• Clarification regarding the abnormal dexamethasone suppression test (DST) 
values required for study inclusion for those subjects who had not previously 
completed the SONICS Study. The following sections are impacted by this 
change:  Synopsis (Inclusion Criteria for All Others) and Section 5.2. 
• Additions to the study withdrawal criteria to include failure to achieve the 
Therapeutic Dose during the TM Phase and closure of randomization while still 
in the TM Phase. These changes impact Section 5.4.  
• Clarification regarding adequacy of urine samples. This change impacts 
Section 6.4.5.1. 
• Clarification on the timing of the LNSC ad UFC sample collections relative to 
dosing with dexamethasone to account for the half-life of dexamethasone. The 
following sections are impacted by this change: Section 6.4.5.3 and Appendix A 
(Table 7). 
• Clarification on the scope of the interim analysis that will be performed and who 
will remain blinded at the individual subject level until the database lock at the 
end of the study. The following sections are impacted by these changes: Section 
8.3.3.1 and Section 12.6. 
• Clarification that the analyses for the SONICS-completer Population will be 
performed only if the size of this cohort is at least 30% of the ITT population. 
This change impacts the Synopsis (Analysis Populations) and Section 12.1. 


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• Clarification that the calculation of study drug compliance will be performed by 
phase and for the study overall instead of by visit. This change impacts 
Section 12.5.2.1. 
• Clarification on the categories to apply to the results from the oral glucose 
tolerance testing. This change impacts Section 12.5.2.6. 
• Clarification on the use of the two-sample t-test to compare the two randomized 
treatment groups.  The two-sample t-test will be performed on the changes from 
Baseline (RW0) at each applicable visit in the Randomized Phase only and will 
not be performed for visits at the Restoration Phase.  This change impacts 
Synopsis (Statistical methods) and Section 12.5.3.2. 
• Clarification on the analysis time points for the Cushing’s Syndrome Quality of 
Life Questionnaire and Beck’s Depression Questionnaire.  The changes from 
Baseline (RW0) will be analyzed at the end of the Randomized Withdrawal Phase 
and Restoration Phase.  This change impacts Section 12.5.3.2.   
• Clarification on Pregnancy test (βhCG) to include all women regardless of 
childbearing potential. This change impacts Appendix B (Other 
analytes/measures).  
 




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Protocol COR-2017-01
 
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INVESTIGATOR AGREEMENT 
I have read this protocol and agree: 
• To conduct the study as outlined herein, in accordance with current International 
Council for Harmonisation (ICH) Tripartite Guideline on Good Clinical Practice 
(GCP), the Declaration of Helsinki and comply with the obligations and requirements 
of Clinical Investigators and all other requirements listed in 21 CFR part 312 and in 
accordance with the study procedures provided by Cortendo and local regulations. 
• Not to implement any changes to the protocol without prior agreement from the 
Sponsor and prior review and written approval from the Investigational Review 
Board (IRB) or Independent Ethics Committee (IEC), except as would be necessary 
to eliminate an immediate hazard to study subject(s), or for administrative aspects of 
the study. 
• To ensure that all persons assisting me with the study are adequately informed about 
the investigational product(s) and of their study-related duties as described in the 
protocol. 
• I agree to completely inform all subjects in this study concerning the pertinent details 
and purpose of the study prior to their agreement to participate in the study in 
accordance with GCP and regulatory authority requirements. 
• I will be responsible for maintaining each subject’s consent form in the study file and 
providing each subject with a signed copy of the consent form. 
• That I am thoroughly familiar with the appropriate use of the investigational 
product(s), as described in the protocol, and any additional information provided to 
me by, or on behalf of Cortendo. 
Investigator Name and Title: 
 
 
 
Institution/Address: 
 
 
 
Contact Information: 
 
 
Signature: ___________________________ 
Date: ________________ 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Cortendo AB 
Name of Investigational Product: Levoketoconazole (previously COR-003) 
Name of Active Ingredient: (2S, 4R)-(-)-cis-Ketoconazole  
{2S,4R cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(IH-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl] 
methoxylphenyl] piperazine} 
Title of Study:  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 
Study center(s): This is a multicenter study at approximately 40 sites in North America, Europe and the 
Middle East.  Additional sites may be added. 
Phase of development:  Phase 3 
Objectives:  
Primary: 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. 
Secondary:  
1. To compare the effects of levoketoconazole with placebo on cortisol status (inferred from mean 
urinary free cortisol [mUFC] and/or late night salivary cortisol [LNSC]) during the Randomized 
Withdrawal (RW) Phase and the subsequent Restoration Phase; 
2. To compare the effects of levoketoconazole with placebo on changes in biomarkers of CS 
comorbidities (fasting glucose, fasting insulin, homeostatic model assessment-insulin resistance 
[HOMA-IR], hemoglobin A1c [HbA1c], total cholesterol, low-density lipoprotein-cholesterol 
[LDL-C], and high-sensitivity C-reactive protein [hsCRP]); 
3. To compare the effects of levoketoconazole with placebo on changes in health-related quality of 
life (QoL) and symptoms of depression; 
4. To compare the effects of levoketoconazole with placebo on changes in acne, hirsutism and 
peripheral edema; 
5. To assess the safety and tolerability of levoketoconazole; 
6. To evaluate the population pharmacokinetics (PK) of levoketoconazole in subjects with CS. 
NOTE: Secondary Objectives 5 and 6 are not subjects of hypothesis tests. 
Exploratory:  
1. To assess changes in anti-diabetic, anti-cholesterol, anti-hypertensive, and chronic 
anti-inflammatory therapies; 
2. To describe the effects and durations of levoketoconazole action with respect to cortisol status and 
clinical signs and symptoms of CS other than acne, hirsutism and peripheral edema; 
3. To describe the dose-response relationship of levoketoconazole with respect to safety and 
tolerability; 
4. To describe the effects of levoketoconazole on glucose tolerance among subjects with impaired 
fasting glucose (IFG). 
 


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Criteria for evaluation: 
Primary endpoint:  
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 1.5X 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. >1.0X ULN)1, OR  
(3)  an early rescue criterion is met. 
Secondary endpoints: 
• 
Changes from Baseline (RW0) in mUFC and LNSC at all post-Baseline visits with these 
assessments through the final study visit (RES2)—applies to Secondary Objective 1; 
• 
Proportion of subjects with normalization of mUFC at RES2—applies to Secondary Objective 1; 
• 
Proportion of subjects with normalization of mUFC at the end of Randomized Withdrawal 
Phase—applies to Secondary Objective 1; 
• 
Changes from Baseline (RW0) in biomarkers of CS comorbidities (fasting glucose, fasting insulin, 
homeostatic model assessment-insulin resistance [HOMA-IR], hemoglobin A1c [HbA1c], total 
cholesterol, low density lipoprotein-cholesterol [LDL-C], and high-sensitivity C-reactive protein 
[hsCRP]) at all post-Baseline visits with these measurements through the final study visit 
(RES2)—applies to Secondary Objective 2; 
• 
Changes from Baseline (RW0) in health-related QoL and symptoms of depression at all post-
Baseline visits with these assessments through the final study visit (RES2) – applies to Secondary 
Objective 3; 
• 
Changes from Baseline (RW0) in acne, hirsutism and peripheral edema at all post-Baseline visits 
with these assessments through the final study visit (RES2) – applies to Secondary Objective 4; 
• 
Incidence and severity of adverse events (AEs), particularly adverse events of special interest 
(AESIs) during levoketoconazole open-label therapy in the Dose-Titration and Maintenance (TM) 
Phase (levoketoconazole-naïve cohort), and during blinded therapy in the Randomized 
Withdrawal Phase and Restoration Phase (both cohorts)—applies to Secondary Objective 5. 
Pharmacokinetic endpoints and pharmacokinetic/pharmacodynamic modeling: 
• 
Estimates of the following PK parameters: clearance (CL/F), volume of distribution (V/F), 
absorption rate constant (Ka), with associated between-subject variability where feasible. These 
parameters will be used to calculate half-life (t½), area under the concentration time curve (AUC) 
and peak concentration (Cmax), if feasible—applies to Secondary Objective 6;   
• 
Estimates of the following pharmacodynamic (PD) parameters: levoketoconazole concentration 
producing half maximal UFC suppression (IC 50), maximal suppression of UFC (Imax) and 
associated estimates of between-subject variability, if feasible. UFC concentrations in relation to 
dose and plasma exposure will be explored—applies to Secondary Objective 6. 
Exploratory endpoints: 
• 
Frequency of usage and changes from Baseline (RW0) in frequency of usage of anti-diabetic, anti-
cholesterol, anti-hypertensive, and chronic anti-inflammatory therapies at all post-Baseline visits; 
changes in corresponding biomarkers accounting for changes in medication usage will also be 
explored—applies to Exploratory Objective 1; 


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• 
Time from RW0 to first time of loss of response, when: 
(1)  mUFC is above 1.5X the ULN of the central laboratory’s reference range, OR 
(2)  mUFC is more than 40% above the RW0 value, if the RW0 value is above the ULN [i.e. 
>1.0X ULN]2, OR 
(3)  an early rescue criterion is met—applies to Exploratory Objective 2;  
• 
Time to first normalization of mUFC beginning from RW5 (subset with mUFC above 1.5X ULN 
at RW5)—applies to Exploratory Objective 2; 
• 
Time to first normalization of LNSC beginning from RW5 (subset with LNSC above ULN at 
RW5)—applies to Exploratory Objective 2; 
• 
Proportion of subjects with normalization of mUFC at the end of Dose Titration and Maintenance 
Phase (TM7)—applies to Exploratory Objective 2;  
• 
Proportion of subjects with either normalization of mUFC or partial response (at least 50% 
decrease in mUFC) at the end of Dose Titration and Maintenance Phase (TM7)—applies to 
Exploratory Objective 2; 
• 
Proportion of subjects with normalization of LNSC at RES2—applies to Exploratory Objective 2; 
• 
Changes from Baseline (RW0) in serum cortisol and adrenocorticotrophic hormone (ACTH) at all 
post-Baseline visits with these assessments through the final study visit (RES2)—applies to 
Exploratory Objective 2; 
• 
Changes from Baseline (RW0) in clinical signs and symptoms of CS excluding acne, hirsutism 
and peripheral edema at all post-Baseline visits with these assessments through the final study 
visit (RES2)—applies to Exploratory Objective 2; 
• 
Frequency and severity of common AEs and laboratory abnormalities in relation to dose of study 
drug administered at the time of the reported AE or laboratory abnormality—applies to 
Exploratory Objective 3; 
• 
Shifts from normality and concentration changes from Baseline (RW0) in serum transaminases, 
alkaline phosphatase, and total bilirubin at all post-Baseline visits in relation to dose of study drug 
administered at the time of the shift or change—applies to Exploratory Objective 3; 
• 
Durations and changes in durations from Baseline (RW0) of the QT interval corrected for heart 
rate (QTc) in relation to dose of study drug administered proximal to the measurement—applies to 
Exploratory Objective 3.  
• 
Change from Baseline in observed and derived glucose and insulin parameters during oral glucose 
tolerance test (OGTT) in the subset of subjects with IFG—applies to Exploratory Objective 4. 
Methodology:  A study schematic follows at the end of this section.  This is a double-blind, 
randomized, placebo-controlled withdrawal and restoration (or as needed early rescue) study in subjects 
with endogenous CS previously treated with single-arm, open-label levoketoconazole that will assess 
efficacy, safety, tolerability, and PK of levoketoconazole.  Two populations or cohorts, are defined for 
analytical and procedural purposes as follows:  
Levoketoconazole-naïve cohort: Subjects who did not participate in the prior clinical study of 
                                               
1 This category applies only to subjects who have completed SONICS, who may have a Therapeutic Dose established 
with UFC above the ULN of the reference range.  Levoketoconazole-naïve subjects must have UFC at or below the 
ULN at RW0 to qualify for randomization. 
2 This category applies only to subjects who have completed SONICS, who may have a Therapeutic Dose established 
with UFC above the ULN of the reference range.  Levoketoconazole-naïve subjects must have UFC at or below the 
ULN at RW0 to qualify for randomization. 


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levoketoconazole (COR-2012-01 aka SONICS) plus subjects who completed Visit M12 of SONICS (final 
scheduled visit prior to safety follow-up) but who have not been treated with a Therapeutic Dose of 
levoketoconazole throughout the 12-week period immediately prior to Screening in the current study.   
SONICS-completer cohort:  Limited to subjects who have completed all visits in the SONICS study 
through M12 (final scheduled visit prior to safety follow-up) at any time prior to the current study and 
who have been treated with a stable Therapeutic Dose of levoketoconazole throughout the 12-week period 
immediately prior to Screening.   
Study methodology varies by cohort prior to randomization (RW0) only.  Following initial Screening 
(washout as needed) and Dose Titration and Maintenance (TM) Phase, as applicable, this study will be 
conducted in two randomized, double-blind treatment phases (a Randomized Withdrawal Phase and a 
Restoration Phase).   
Screening Phase:   
Duration up to approximately 13 weeks to allow for washout, as needed.  
All subjects on levoketoconazole from SONICS or the Expanded Access Program (EAP) must have 
confirmation of their Therapeutic Dose, as defined in the SONICS protocol, during the Screening Phase to 
confirm cohort placement for LOGICS.  During this time, subjects will continue their prescribed dose of 
levoketoconazole to ensure continuity of treatment.  
Subjects who have completed all visits in SONICS, through Visit 12 and have been on a stable 
Therapeutic Dose throughout the 12-week period immediately prior to signing informed consent, will 
enter the Screening Phase to confirm eligibility.   
For subjects who have completed SONICS within 6 months prior to Screening for LOGICS, the Screening 
Phase, relying primarily on data collected during SONICS and completed with data collected in LOGICS, 
will begin after Visit M12 of SONICS completion and end once eligibility is confirmed.  The time from 
confirmation of eligibility to RW0 should be no more than 11 (+3) days later (the minimum time 
requirement for Therapeutic Dose confirmation as dictated by tolerability and UFC results).  As data 
collected from the SONICS study will be used in this study as well, overlapping assessments only need to 
be performed once (e.g. the same vital signs data may be recorded in the eCRFs for both studies).  
For subjects who have completed SONICS more than 6 months prior to the Screening Phase and have 
been on a stable Therapeutic Dose throughout the previous 12-week period, Screening procedures will 
mimic those for the levoketoconazole-naïve subjects to confirm eligibility for the current study.  After 
eligibility has been confirmed during the Screening Phase, subjects should proceed directly to the 
Open-label 
levoketoconazole 
Therapeutic Dose established from Dose Titration and Maintenance (TM) Phase 
for levoketoconazole-naïve cohort, or prior to entry into LOGICS for the 
SONICS-completer cohort 
Randomization 
(RW0) 
 
 
Blinded 
Randomized 
Withdrawal Phase 
Levoketoconazole at Therapeutic Dose 
Placebo at equivalent tablet count to 
Therapeutic Dose 
Blinded Restoration 
Phase 
Placebo added as 1 tablet twice daily 
(BID) at RW5 then add 1 tablet every 2 
days, alternating AM and PM, until the 
total tablet count is double the count at 
RW0 
Levoketoconazole added as 1 tablet 
BID at RW5 then add 1 tablet every 
2 days, alternating AM and PM, until 
the total tablet count is double the 
count at RW0 


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Baseline/Randomization Visit (RW0).  The time between Screening and RW0 should be no more than 
11±3 days.  
Following consent signature, subjects naïve to levoketoconazole receiving previous CS medical therapies 
or other prohibited medications must enter a washout period before completing screening assessments 
detailed in the Time and Events schedule.  The Screening Phase may last up to approximately 13 weeks.  
Baseline measurements will be obtained as part of the Screening assessments (after washout); therefore, 
the time from confirmation of eligibility to TM0 (aka Baseline) should be no more than 11 (+3) days.  
Screening procedures completed within 3 weeks of TM0 (within 2 weeks for LNSC, QTc interval and 
liver safety tests) will be used as the TM0 value.  If Screening procedures were completed more than 3 
weeks prior to TM0, then they will be repeated at TM0 (except for pituitary magnetic resonance imaging 
(MRI), which may be completed up to 6 months of TM0 or RW0).  All blood samples (except for post 
dose PK samples) should be obtained prior to administering the first dose of levoketoconazole.  
Likewise, the final Baseline UFC specimen should be collected close to the date of TM0 and never more 
than 6 weeks prior to TM0.  NOTE: all Baseline UFC and LNSC values must be obtained after washout of 
any medications that are known to influence cortisol levels.   
If a subject does not meet the eligibility requirements on initial Screening, they may be eligible to re-
screen only if worsening of their medical condition has increased the likelihood that they would meet the 
study eligibility criteria.  Such re-screenings will be exceptional circumstances, and all re-screenings 
require prior permission of the study Medical Monitor before they begin.  Repeating a Screening test (e.g. 
UFC) that has been found to be technically flawed will not be considered re-screening.   
For subjects who have completed Visit M12 in SONICS either within the previous 6 months or more than 
6 months prior to the Screening Phase and are NOT on a stable Therapeutic Dose throughout the previous 
12-week period, Screening procedures will mimic those for the levoketoconazole-naïve subjects as noted 
above to confirm eligibility and progress the subject into the Dose Titration and Maintenance (TM) Phase 
of the study.   
 
Dose Titration and Maintenance (TM) Phase (levoketoconazole-naïve cohort ONLY) 
After confirmation of eligibility, members of the levoketoconazole-naïve cohort (including subjects that 
completed SONICS but require re-titration) will enter the TM Phase.  As detailed above, subjects who 
completed visit M12 of SONICS but who have not been treated with a stable Therapeutic Dose of 
levoketoconazole throughout the 12-week period immediately prior to screening must establish their 
Therapeutic Dose in the TM Phase and are thus members of the levoketoconazole-naïve cohort.  The 
starting dose for these subjects may be as high as the dose that was most recently or currently being 
received or next higher dose level, at the discretion of the Investigator. The first dose of open-label therapy 
for this phase will be at TM0.  Dose titration will occur in increments of 150 mg over a period of 
approximately 3 to 19 weeks to achieve an effective and tolerable dose (the Therapeutic Dose). In 
exceptional situations, subjects may require additional time (i.e. greater than 19 weeks) to achieve the 
Therapeutic Dose.  These situations must be approved on a case by case basis by the Medical Monitor. 
Dose increases (and decreases, as needed) will be based on subjective and objective indicators of 
medication tolerance, UFC and other cortisol measures.  Subjects will return to the clinic every 14 (± 3) 
days during the TM Phase (note: to allow for 4 weeks maintenance, additional time may be required in the 
event a dose change is required at TM7).  Additionally, when a dose escalation during the TM Phase is 
required to a total daily dose of 750 mg or above, subjects will be asked to return to the clinic or, 
optionally, will be visited by a qualified home healthcare (HHC) professional for one extra safety 
evaluation 5 days (± 2 days) after each dose escalation.  
Subjects will be advised to contact the Investigator immediately in the event of AESI-suggestive signs or 
symptoms (defined later) regardless of the onset timing relative to a scheduled visit.  


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Once the Therapeutic Dose has been reached and confirmed from the mean of a total of three adequately 
collected 24-hour urine specimens for UFC measurements, subjects will continue that Therapeutic Dose 
(i.e. in Maintenance) until the final open-label study visit (Visit TM7) in the TM Phase.  During the TM 
Phase (while treatment is open-label), once the Therapeutic Dose is achieved, the dose should generally 
not be further adjusted if the UFC levels are within normal limits.  However, the dose may be increased if 
medically necessary to maintain eucortisolemia or decreased to address drug intolerance or AE.  Prior to 
the final open-label visit (Visit TM7), three complete 24-hour urine specimens will be obtained 
(collections need not be repeated if the final open-label visit coincides with the initial establishment of 
UFC normalization) to confirm maintenance of UFC normalization prior to randomization, denoting UFC-
eligibility for the Randomized Withdrawal Phase.  To ensure the TM Phase occurs within the allotted 
timeframe of no more than approximately 19 weeks, urine collections should ideally be made on 
sequential days and prior to the actual scheduled visit for dose assessment, as results are needed to 
determine if dose escalation is required, or whether a confirmatory UFC is needed to establish Therapeutic 
Dose.  The minimum duration of this phase and thus establishment of the Therapeutic Dose will be no less 
than approximately 14 weeks, even among subjects who reach a Therapeutic Dose more quickly.  
Randomization (RW0) should occur as soon as possible after the final Titration-Maintenance visit (TM7) 
and no more than 11 (+3) days later unless a dose change was required at Visit TM7.  Regardless, in all 
cases at least 4 weeks should elapse between reaching the Therapeutic Dose and RW0 to ensure 
tolerability and stability (continued effectiveness) of the Therapeutic Dose. 
Subjects still in the TM Phase when the randomization target of 46 to 54 subjects, depending on the 
observed withdrawal rate trend during the Randomized Withdrawal Phase is reached, will be offered the 
opportunity to join an open-label extension (OLE) study (Study COR-2017-OLE, aka OPTICS) to receive 
open-label treatment.  Subjects must meet the OPTICS inclusion/exclusion criteria to be eligible.  
 
Randomized Withdrawal (RW) Phase (All Subjects) 
In the 8-week, double-blind Randomized Withdrawal Phase, subjects will return to the clinical site at least 
twice: on RW3 {Day 30(-4)} and RW5 {Day 58(-4)} relative to the Randomization Visit (RW0) for safety 
and efficacy evaluations to determine if they are still responding to therapy, or if they have relapsed or if 
an early rescue criterion has otherwise been met. 
Three additional visits, either at-home (by a qualified HHC professional) OR on-site, will be conducted for 
all subjects on RW1 {Day 10(-2)}, RW2 {Day 20(-2)} and RW4 {Day 40(-2)} relative to Randomization 
(RW0).  These interim visits will be primarily for determining cortisol status as well as to monitor safety 
and tolerability associated with the possible withdrawal of medication.  Partial loss of response or relapse 
should be confirmed by a repeat 24-hour urine sample or LNSC sample, which should be collected and 
analyzed as soon as possible.  Courier services will be provided, as desired, to collect UFC specimens for 
transport to the site on days when a qualified HHC professional is not present or if subjects prefer courier 
pickup of collected samples prior to visit. 
NOTE: Early rescue criteria are described that provide for immediate substitution of blinded study drug 
with open-label levoketoconazole treatment directed by the study Investigator if continued use of blinded 
treatment is regarded as unacceptable owing to significant or rapid clinical deterioration.  Criteria to guide 
the Investigator as to the possible need for early rescue medication are described in this protocol.  
Although UFC will be the primary measure of loss of therapeutic efficacy, cortisol status will be assessed 
through additional measures as described.  The rapid titration schedule used in the Restoration Phase 
should be used to reestablish the Therapeutic Dose if a subject requires early rescue with open-label 
levoketoconazole.  As treatment is open-label during early rescue, dose adjustments may be made, as 
medically indicated.  This includes adjustments to dose levels above the previous therapeutic dose if 
required to return subject to eucortisolemia. 
 
Restoration Phase (All Subjects) 


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All subjects completing the 8-week Randomized Withdrawal Phase who do not meet early rescue criteria, 
will enter the Double-blind Restoration Phase, wherein they will continue to receive the randomly assigned 
blinded treatment regimen and in addition will receive blinded restoration study medication (placebo for 
those already receiving levoketoconazole; levoketoconazole for those already receiving placebo), 
beginning with 1 tablet BID and titrated in 1 tablet increments every 2 days alternating AM and PM, as 
described above, in order to return their treatment regimen to its status quo prior to randomization (i.e. 
subjects will resume the Therapeutic Dose of levoketoconazole if randomized to placebo in the 
Randomized Withdrawal Phase).  The total tablet number received during blinded Restoration Phase will 
ultimately be twice the number received prior to randomization.  If, in the opinion of the Investigator, an 
increased dose of study drug is required for subjects who are unable to restore their prior cortisol control 
(i.e. mUFC >ULN) during the Restoration Phase at their prior Therapeutic Dose, those subjects should be 
withdrawn from this study owing to “loss of efficacy”.  Such subjects may be considered for enrollment in 
the long-term OPTICS study or EAP if they otherwise qualify. 
Safety monitoring and extended assessment 
Throughout the study, safety data will be collected at regular intervals of approximately: 5 to 17 days 
during Titration and Maintenance, 6 to 20 days during Randomized Withdrawal and 23 to 33 days during 
Restoration Phase (except for interim, remote [via telephone], safety checks during rapid titration), per the 
Time and Events Schedule.  Adequate medical coverage must be provided by the study site continuously 
during the study to ensure that prompt safety decisions can be made and appropriate medical interventions 
provided.  The Investigator will provide subjects with instructions for accessing medical staff at any hour 
to obtain prompt medical care.  An independent Data Safety Monitoring Board (DSMB) will review key 
safety data at regular intervals throughout the study, including review of serious adverse events (SAEs) 
and AESIs shortly after they have been reported to the Sponsor.  
Study completion is defined as having:  completed all scheduled visits in the Restoration Phase OR 
required early rescue with open-label levoketoconazole (or another rescue medication) during the 
Randomized Withdrawal Phase.  If early rescue is deemed appropriate with open-label levoketoconazole, 
subjects continue in the study using Blinded Restoration Phase procedures.  Subjects requiring rescue 
medication should complete all procedures for visit RW5 prior to entering the Restoration Phase. All 
subjects who complete the study will be eligible to enter the open-label extension (OLE) OPTICS study to 
continue open-label treatment with levoketoconazole and enable assessment of the long-term effects on 
efficacy and safety.  The OPTICS study is described in a separate protocol. 


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Levoketoconazole-naïve cohort 
[Levoketoconazole-naïve subjects (or re-titrations)] 
 
 
SONICS-completer cohort 
 
Note: RW5, the last visit of the Randomized Withdrawal, marks the start of the Restoration Phase  
NOTE: If there is a time gap between completion of Screening and TM0 or RW0 for subjects 
currently receiving levoketoconazole, then open-label levoketoconazole should be continued between 
Screening and TM0 or RW0 to maintain the Therapeutic Dose. If rolling over from SONICS, subjects 
will be dispensed LOGICS medication starting at the screening visit.  If entering from the expanded 
access program (EAP), subjects will stay on open-label levoketoconazole dispensed from EAP until 
the Baseline visit. 
Number of subjects (planned):  Forty-six (46) to 54 subjects, 23 to 27 in each treatment group, will be 
enrolled into the Randomized Withdrawal Phase of the study.  A minority of randomized subjects are 
anticipated to be subjects in the SONICS-completer cohort.  Any subject who withdraws after 
randomization will not be replaced.  Withdrawn subjects will not be re-entered into the study.       
Study Hypothesis and Sample Size Determination:  The null hypothesis is that the proportion of 
subjects with loss of therapeutic response, upon withdrawing to placebo compared with continued 
levoketoconazole, is not different between levoketoconazole and placebo.  The alternative hypothesis is 
that the two proportions are different, specifically that there is an increased loss of response for the 
placebo arm.  For the purpose of sample size estimation, it is assumed that among subjects in the ITT 
population who complete at least the RW4 visit in the Randomized Withdrawal Phase, 10% will lose 
therapeutic response in the levoketoconazole arm vs. 75% in the placebo arm.  For the analysis of the 
primary endpoint, subjects in the ITT population who withdraw prior to RW4 will be considered as losing 
therapeutic response.   
A minimum of 46 subjects (23 per arm) and a maximum of 54 subjects (27 per arm) will be targeted to be 
enrolled into the Randomized Withdrawal Phase based on the observed withdrawal rate trend for the 


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phase. If the withdrawal rate is 10% per arm, a sample size of 46 subjects (23 per arm) randomized and 
treated during the Randomized Withdrawal Phase corresponds to 42 subjects (21 per arm) completing 
RW4 and provides approximately 99% power to detect the alternative hypothesis of a loss of therapeutic 
response rate of 17% in the levoketoconazole arm and 78% in the placebo arm vs. the null hypothesis. If 
the withdrawal rate is 20% per arm, a sample size of 54 subjects (27 per arm) randomized and treated 
during the Randomized Withdrawal Phase corresponds to 44 subjects (22 per arm) completing RW4 and 
provides approximately 98% power to detect the alternative hypothesis of a loss of therapeutic response 
rate of 26% in the levoketoconazole arm and 81% in the placebo arm vs. the null hypothesis.  
 
Eligibility for Enrollment 
Cortendo will review each subject’s enrollment criteria to ensure that subjects meet the eligibility criteria. 
Inclusion Criteria for Specified Subjects Completing the SONICS Study:  
Subjects who have completed the SONICS study, within 6 months of the screening visit, including those 
receiving open-label treatment after SONICS as part of an EAP, may be eligible for the study if the 
following criteria are met: 
1. Completed the final SONICS visit (M12) and have demonstrated maintenance of clinical response 
(partial or complete, as defined in the SONICS protocol, COR-2012-01) on a stable Therapeutic Dose 
of levoketoconazole for at least 12 weeks prior to study entry (i.e. Visit RW0).  
2. Able and willing to provide written informed consent prior to any study procedures being performed; 
eligible subjects must be able to understand the informed consent form prior to inclusion into the 
study.   
Inclusion Criteria for All Others: 
The following categories of potential subjects, categorized by prior use of levoketoconazole, may be 
eligible if the following 11 inclusion criteria are all met: 
• 
Naïve to levoketoconazole (defined as having never participated in SONICS); 
• 
Completers of SONICS visit M12 more than 6 months of the screening visit of the current study; 
• 
Completers of SONICS visit M12 within 6 months of the screening visit who have not been 
receiving a stable Therapeutic Dose of levoketoconazole for at least 12 weeks prior to the start of 
screening. 
1. Male or female and at least 18 years of age. 
2. Able and willing to provide written informed consent prior to any study procedures being performed; 
eligible subjects must be able to understand the informed consent form prior to inclusion into the 
study. 
3. Confirmed newly diagnosed, persistent or recurrent endogenous Cushing’s syndrome of any etiology, 
except secondary to malignancy (including pituitary or adrenal carcinoma).  Persistence will not be 
considered confirmed until 6 weeks or more post-surgery. 
The following historical evidence will be considered as sufficient to establish the cause of endogenous 
Cushing’s syndrome as being due to Cushing’s disease (i.e. ACTH-dependent of pituitary origin) 
specifically: 
• 
Pathological (e.g. adrenocorticotropic hormone [ACTH]-staining) or post-surgical confirmation of 
the diagnosis of CD (i.e. documented adrenal insufficiency post-adenomectomy or post-
hypophysectomy) OR 
• 
Intermediate, normal or elevated plasma ACTH (i.e. at least 5 pg/mL [1.1 pmol/L]) PLUS 
For tumors 6 mm and above by imaging: 
a) Inferior petrosal sinus sampled (IPSS) ACTH central:plasma gradient at least 2 before 
corticotropin-releasing hormone (CRH) or at least 3 after CRH, OR in the absence of 
IPSS, either: 


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b) Positive ACTH and/or cortisol response to CRH or desmopressin or combined CRH-
desmopressin stimulation plus high-dose (8 mg) dexamethasone suppression of blood 
cortisol, ideally on more than one occasion OR 
c) Other adequate diagnostic testing.  Such cases must be discussed with and explicitly 
approved by the Medical Monitor, and the specific diagnostic criteria used to establish the 
diagnosis of CD must be documented. 
For tumors below 6 mm or not visible by Magnetic Resonance Imaging (MRI): 
a) IPSS with ACTH central:plasma gradient at least 2 before CRH or at least 3 after CRH. 
b) Other adequate diagnostic testing.  In the absence of IPSS, an individual might be eligible 
if CD was otherwise confirmed via adequate testing.  Such cases must be discussed with 
and explicitly approved by the Medical Monitor, and the specific diagnostic criteria used 
to establish the diagnosis of CD must be documented. 
4. Elevated mean 24-hour UFC levels at least 1.5X ULN of the normative range of the study’s central 
laboratory assay and from a minimum of three measurements from adequately collected urine; the 
study’s central laboratory must be used for all qualifying measurements.  
NOTE: This criterion does not apply to subjects currently on levoketoconazole.   
5. Presence of abnormal values from at least one of these two diagnostic tests (discrepancies between test 
findings will not be investigated nor considered exclusionary) 
• 
Abnormal Dexamethasone Suppression Test (DST): Elevated 8 AM blood cortisol at least 
1.8 µg/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior with 
concurrent dexamethasone blood concentration greater than 5.6 nmol/L (220 ng/dL) (results from 
within the 2 months prior to start of Screening or newly tested with results available by the 
Baseline Visit [TM0]). If the DST cortisol is elevated and the dexamethasone value is at least 
3.9 nmol/L (153 ng/dL), then the subject could qualify if at least 1 LNSC is greater than the ULN 
of the study’s central laboratory normative range (the study’s test kit and lab must be used for all 
qualifying measurements), whereas a non-suppressed cortisol during DST with a dexamethasone 
value of at least 5.6 nmol/L (220 ng/dL) would be required if LNSC is not done or if both LNSC 
values are low (≤ ULN of the study’s central laboratory normative range; the study’s test kit and 
lab must be used for all qualifying measurements).  
OR 
• 
Elevated LNSC concentrations (at least two measurements) each greater than the ULN of the 
study’s central laboratory normative range; the study’s test kit and lab must be used for all 
qualifying measurements. 
NOTE: Abnormal LNSC is required among eligible subjects with estimated glomerular filtration rate 
(eGFR as determined by Modified Diet in Renal Disease MDRD equation) above 40 and below 
60 mL/min/1.73 m2. 
NOTE: This criterion does not apply to subjects currently on levoketoconazole. 
6. Non-candidates for CS-specific surgery, refuse surgery or surgery will be delayed until after study 
completion and agree to complete this study prior to surgery.  
7. If post-surgical for CS-specific surgery, then no significant post-operative sequelae remain and the 
risk of such sequelae is considered negligible. 
8. Agree to the following minimum washout periods prior to the Baseline Visit (TM0) (as applicable): 
• 
Ketoconazole or metyrapone: 2 weeks;  
• 
Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks); 
• 
Octreotide acetate LAR, lanreotide Autogel®, pasireotide LAR: 12 weeks; 
• 
Lanreotide SR: 8 weeks; 
• 
Octreotide acetate (immediate release) or short-acting pasireotide: 1 week; 


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• 
Mifepristone (RU 486, KORLYM®): 4 weeks; 
• 
Megestrol acetate or medroxyprogesterone acetate (and selected other synthetic progestins): 
6 weeks. 
9. Females who are either of non-child bearing potential (i.e. incapable of becoming pregnant): 
• 
Post-menopausal, defined as age 50 or older with amenorrhea for more than 1 year or any age with 
serum follicle stimulating hormone (FSH) at least 23 mIU/mL and estradiol no more than 
40 pg/mL (140 pmol/L) OR  
• 
Surgically sterile—documented hysterectomy and/or bilateral oophorectomy or tubal ligation  
OR 
• 
Females of child-bearing potential who agree to use highly effective methods of birth control 
while participating and for 2 weeks after participation has completed (abstinence is considered 
acceptable if routinely practiced). 
10. Men who, if fertile, agree to use an acceptable form of birth control, including abstinence if routinely 
practiced, while enrolled and for 2 weeks after participation has completed. 
11. Able to comprehend and comply with all procedures. 
Exclusion Criteria 
Subjects will be excluded from the study if ANY of the following criteria are met (NOTE: exclusion 
criteria apply to and must be assessed in both cohorts): 
1. Enrolled in SONICS but have not completed SONICS through Visit M12.  
2. Pseudo-Cushing’s syndrome based on assessment of the Investigator.  
3. Cyclic Cushing’s syndrome with multi-week periods of apparent spontaneous CS remission. 
4. Non-endogenous source of hypercortisolism, including pharmacological corticosteroids or ACTH. 
5. Radiotherapy of any modality directed against the source of hypercortisolism within the last 5 years. 
6. Treatment with mitotane within 6 months of enrollment. 
7. History of malignancy, including adrenal or pituitary carcinomas (other than low-risk, well-
differentiated carcinomas of thyroid, breast or prostate that are very unlikely to require further 
treatment in the opinion of the treating physician, or squamous cell or basal cell carcinoma of the 
skin). 
8. Clinical or radiological signs of compression of the optic chiasm. 
9. Major surgery within 1 month of Screening (or within 6 weeks for pituitary surgery). 
10. Clinically significant abnormality in 12-lead electrocardiogram (ECG) during the Screening Phase 
requiring medical intervention (may be eligible once stable, to be determined case by case). 
11. QTc interval above 470 msec during the Screening Phase via central reader interpretation. 
12. History of Torsades des Pointes, ventricular tachycardia, ventricular fibrillation, history of prolonged 
QT syndrome (including first-degree family history). 
13. Use of medications associated with possible, probable, or definite QT/QTc prolongation (unless 
subsequently washed out). 
14. Pre-existing hepatic disease (except for mild to moderate non-alcoholic fatty liver disease documented 
by imaging or biopsy and with transaminase values within allowed limits). 
15. Hepatitis B surface antigen (HbsAg) or hepatitis C-positive. 
16. Human immunodeficiency virus (HIV)-positive. 
17. History of symptomatic cholelithiasis with intact gallbladder. 
18. History of pancreatitis. 
19. Liver safety tests during the Screening Phase as follows:  


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• 
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) above 3X ULN 
• 
Alkaline phosphatase or Total bilirubin above 2X ULN. 
Subjects with isolated indirect bilirubin up to 3X ULN are presumed to have Gilbert’s syndrome 
and may be enrolled if all other liver safety tests are within normal levels. 
20. History of documented or suspected drug-induced liver injury to ketoconazole or any other azole drug. 
21. Serum potassium below 4.0 mEq/L (unless subsequently corrected and stable). 
22. Abnormal free thyroxine (FT4), unless subsequently corrected and stable for at least 4 weeks. Subjects 
with thyroid-stimulating hormone (TSH) less than the lower limit of normal (LLN) and normal FT4 
are potentially eligible without intervention. 
23. History of persistent, uncontrolled hypertension despite medical intervention. 
24. Hypercholesterolemia currently treated with atorvastatin, lovastatin or simvastatin and unwilling or 
unable to change to alternative therapy with: pravastatin, fluvastatin, pitavastatin or rosuvastatin (must 
switch statin at least 2 weeks prior to dosing) or another allowed therapy.  For subjects for whom lipid 
reduction therapy is being considered, all lipid lowering drugs should be added and stabilized for at 
least 4 weeks prior to TM0 for the levoketoconazole-naïve cohort or RW0 for the SONICS-completer 
cohort, as improvements in lipids are being assessed as an endpoint for levoketoconazole treatment in 
this study. 
25. More than one hospitalization for hyperglycemia or complication of diabetes during the last 12 months 
26. Decreased renal function as defined by eGFR below 40 mL/min/1.73 m2, using MDRD equation for 
eGFR. 
27. Pregnant or lactating. 
28. Body habitus preventing repeated venipuncture as required by protocol. 
29. Any other clinically significant medical condition, as determined by the Investigator that precludes 
enrollment and participation in the study through completion, including conditions that would 
preclude the subject from being able to follow instructions or perform necessary procedures (for 
example, psychiatric instability or severe disability).  
30. History of alcohol or drug abuse in the 6-month period prior to Screening. 
31. Currently participating in another study or has received any investigational treatment (drug, biological 
agent or device) other than levoketoconazole (COR-003), within prior 30 days or five half-lives of 
treatment, whichever is longer. 
32. Current use of any H2-receptor antagonists, proton-pump inhibitors, or sucralfate (all inhibit 
absorption of levoketoconazole; subjects may be allowed to enroll after washout).  A list of acceptable 
oral antacids will be provided; if used, antacids must be ingested at least 2 hours after dosing of 
levoketoconazole. 
33. Current use of any prohibited concomitant medication that cannot be discontinued safely and washed 
out completely prior to the Baseline Visit (TM0 or RW0, for the levoketoconazole-naïve and 
SONICS-completer cohorts, respectively), including but not limited to the following (a more complete 
list is included in Appendix J): 
• 
Weight loss medications (prescription or over the counter); 
• 
Acetaminophen (paracetamol) above 2 g total daily dose; 
• 
Strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with the metabolism 
of levoketoconazole and cannot be discontinued prior to first dose; 
• 
Herbal preparations: St John’s Wort, echinacea, gingko, goldenseal, yohimbe, red rice yeast, 
danshen, silybum marianum, Asian ginseng, schissandra sphenanther, shankhapushi, and Asian 
herb mixture (Xiao chai hu tang and Salboku-to); 
• 
Topical or inhaled corticosteroids; 
• 
Carbamazepine, fenofibrate, carbenoxolone; 


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• 
Drugs that pose unacceptable risk due to overlapping or exaggerated toxicities or pharmacological 
action due to presumed PK or PD interactions with levoketoconazole; 
• 
Genuine licorice. 
Investigational product, dosage and mode of administration:  
Levoketoconazole (2S,4R-ketoconazole); 150 mg immediate release tablets for oral administration.   
For the levoketoconazole-naïve subjects, the total daily dose will be titrated in 150 mg increments from a 
starting dose of 300 mg (dosed as 150 mg BID) up to a maximal daily dose of 1200 mg (dosed as 600 mg 
BID) until a Therapeutic Dose is established.  Subjects re-establishing their Therapeutic Dose via re-
titration may begin titration at their current or most recently received dose at the discretion of the 
Investigator.  The minimum daily dose is 150 mg once daily (QD) for subjects who cannot tolerate 150 mg 
BID.  For all subjects in the levoketoconazole-naïve cohort, the Therapeutic Dose will be established by 
the end of the TM Phase.   
For the SONICS-completer cohort, the stable Therapeutic Dose will have been established prior to 
enrollment in this study.   
The Therapeutic Dose will be used as the target dose and dose-regimen during the Restoration Phase. 
Duration of treatment:  
Prior to treatment, subjects in the levoketoconazole-naïve cohort (including subjects who completed 
SONICS Visit M12 but who have not been treated with a stable Therapeutic Dose of levoketoconazole 
throughout the 12 weeks immediately prior to screening) will undergo Screening for up to approximately 
13 weeks (to allow for prior medication washout and to complete screening procedures); there is no 
required minimum Screening interval.  Dose titration is variable depending on clinical response.  
However, all subjects in the levoketoconazole-naïve cohort will be treated for not less than 14 weeks in 
total and for no more than approximately 19 weeks (except on a case by case basis with approval by the 
Medical Monitor) in total during the TM Phase to confirm the Therapeutic Dose and to establish 
tolerability to levoketoconazole.  The Randomized Withdrawal Phase and the Restoration Phase are each 
approximately 8 weeks’ duration (maximum 9½ weeks), with the total of the two treatment phases not to 
exceed approximately 19 weeks.  Therefore, the longest anticipated exposure to active study medication in 
this study is no more than approximately 38 weeks and the shortest approximately 8 weeks.  The longest 
anticipated exposure to placebo monotherapy is no more than 9½ weeks.  The longest anticipated total 
study participation duration is approximately 51 weeks. 
Reference therapy, dosage and mode of administration:  
An active reference therapy will not be used.  Placebo tablets identical in appearance to levoketoconazole 
will be administered during the Randomized Withdrawal Phase using the same regimen as the Therapeutic 
Dose of levoketoconazole established during the TM Phase (levoketoconazole-naïve cohort) or at study 
entry (SONICS-completer cohort).  During the Restoration Phase, blinded placebo to be added onto the 
levoketoconazole regimen will be started at 1 tablet BID and titrated every 2 days in 1 tablet increments 
per the Dosing Titration Scheme until the Therapeutic Dose-equivalent is achieved unless the Therapeutic 
dose is DL0.  The total final tablet count (active + placebo) during Restoration Phase will equal twice the 
total tablet count of the Therapeutic Dose, not to exceed 8 tablets BID. 
Analysis Populations: 
Intent-to-Treat Population (ITT): The ITT population will include all subjects who are randomized and 
receive at least one dose of blinded study medication during the Randomized Withdrawal Phase.  The ITT 
population will be used for the primary analysis of efficacy and secondary analyses of efficacy and safety.   


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Per Protocol (PP) Population:  The PP population will consist of all subjects in the ITT population who 
have no major protocol deviations during the Randomized Withdrawal Phase that could affect the primary 
endpoint.  This population will be used in supportive analyses of the primary endpoint and secondary 
efficacy endpoints. 
Levoketoconazole-naïve Population:  The levoketoconazole- naïve population will consist of all subjects 
in the levoketoconazole-naïve cohort who receive at least one dose of study medication during the TM 
Phase.  This population will be used for supportive evaluations of safety and for exploratory efficacy, 
safety, and PK analyses.   
SONICS-completer Population:  The SONICS-completer population will consist of all subjects in the 
SONICS-completer cohort who receive at least one dose of blinded study medication during the 
Randomized Withdraw Phase.  This population will be used for supportive evaluations of safety and for 
exploratory efficacy, safety, and PK analyses.  Because only a minority of the subjects are anticipated to 
be in the SONICS-completer cohort, the analyses will be performed only if the size of this cohort is at 
least 30% of the ITT population. 
Statistical methods: 
Primary Efficacy Analysis:   The primary analysis will use the ITT population and supportive analysis will 
be repeated in the PP population.   
Statistical significance testing will be conducted using a logistic regression model containing fixed effect 
terms for Randomized Withdrawal treatment group (levoketoconazole, placebo) and subject cohort 
(SONICS-completer cohort, levoketoconazole-naïve cohort) and confirmed using a two-sided Fisher’s 
Exact test.   
Secondary Efficacy Analysis:  Inferences derived from secondary efficacy analyses will be gated on 
results from the primary efficacy analysis.  Secondary efficacy analyses will be hierarchically structured to 
ensure control of the family-wise type I error rate at the 0.05 level.  Hypothesis tests for secondary 
endpoints will be based on null hypotheses that assume no a priori differences between placebo and 
levoketoconazole treatments.  All secondary endpoints will be analyzed using the ITT population (primary 
analyses) and the PP population (supportive analyses). 
Changes from Baseline (RW0) in mUFC and LNSC during the Randomized Withdrawal Phase will be 
analyzed using repeated measures mixed effects models with fixed effect terms for treatment group, 
subject cohort, time (i.e. visit) and treatment-by-time interaction, with Baseline value as a covariate and 
subject as a random effect. The treatment groups will be compared using least squares mean differences 
between treatment groups and associated 95% confidence intervals (CIs) for each time point will be 
derived from the model.  Two-sample t-tests will also be performed to compare the two treatment groups 
for the mean change from Baseline to each nominal visit during the Randomized Withdrawal Phase.   
Normalization of mUFC at RES2 will be calculated for each treatment group and presented as shift tables 
from RW5 to RES2 using three strata of mUFC status: at or below ULN, more than ULN and no more 
than 1.5X ULN, above 1.5X ULN. 
The number and proportion of subjects with normalization of mUFC (at or below ULN) at the end of the 
Randomized Withdrawal Phase (RW5) will be summarized for each treatment group and compared using 
Fisher’s Exact test (with corresponding 95% CIs).  
Changes and percentage changes from Baseline (RW0) in the biomarkers of CS comorbidities (fasting 
glucose, fasting insulin, HOMA-IR, Hb1Ac, total cholesterol, LDL-C, and hsCRP) during the Randomized 
Withdrawal Phase and Restoration Phase will be summarized by treatment group and time point and 
assessed using two-sample t-test comparison at each visit in the Randomized Withdrawal Phase.  For CS 
comorbidities measured at more than one visit after RW0 during the Randomized Withdrawal Phase, 
changes from Baseline during the Randomized Withdraw Phase will also be analyzed using repeated 
measures mixed effects models.  


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Changes from Baseline (RW0) in health-related QoL, symptoms of depression, acne, hirsutism and 
peripheral edema during the Randomized Withdrawal Phase and Restoration Phase will be summarized by 
treatment group and time point and mean changes from Baseline assessed using two-sample t-test 
comparison at the end of the Randomized Withdrawal Phase. 
Safety Analyses: Safety assessments, including AEs, vital signs, ECGs (inclusive of QTc), laboratory 
parameters, and physical examination results will be summarized descriptively by study phase and/or by 
time point, as applicable. 


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TABLE OF CONTENTS 
 
SPONSOR APPROVAL....................................................................................................................... 15 
INVESTIGATOR AGREEMENT ....................................................................................................... 16 
PROTOCOL SYNOPSIS ..................................................................................................................... 17 
TABLE OF CONTENTS ...................................................................................................................... 32 
TABLE OF TABLES............................................................................................................................ 34 
TABLE OF FIGURES .......................................................................................................................... 35 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................... 36 
1 
INTRODUCTION ............................................................................................................ 39 
1.1 DISEASE BACKGROUND ............................................................................................................. 39 
1.2 RATIONALE FOR STUDY DESIGN ................................................................................................. 41 
2 
OBJECTIVES .................................................................................................................. 43 
2.1 PRIMARY OBJECTIVE ................................................................................................................. 43 
2.2 SECONDARY OBJECTIVES ........................................................................................................... 43 
2.3 EXPLORATORY OBJECTIVES ....................................................................................................... 43 
3 
ENDPOINTS .................................................................................................................... 44 
3.1 PRIMARY ENDPOINT .................................................................................................................. 44 
3.2 SECONDARY ENDPOINTS ............................................................................................................ 44 
3.3 PHARMACOKINETIC ENDPOINTS AND PHARMACOKINETIC/PHARMACODYNAMIC MODELING......... 45 
3.4 EXPLORATORY ENDPOINTS ........................................................................................................ 45 
4 
STUDY DESIGN .............................................................................................................. 46 
4.1 OVERVIEW OF STUDY DESIGN .................................................................................................... 46 
4.2 PRE-RANDOMIZATION ............................................................................................................... 50 
4.2.1 
SONICS-Completer Cohort Screening Phase .................................................................... 50 
4.2.2 
Levoketoconazole-Naïve Cohort ....................................................................................... 51 
4.3 RANDOMIZED WITHDRAWAL PHASE (ALL SUBJECTS) ................................................................. 58 
4.3.1 
Early Rescue Criteria and Procedures ............................................................................. 59 
4.4 DOUBLE-BLIND RESTORATION PHASE ........................................................................................ 62 
5 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ........................................ 63 
5.1 INCLUSION CRITERIA FOR SPECIFIED SUBJECTS COMPLETING THE SONICS STUDY ...................... 63 
5.2 INCLUSION CRITERIA FOR ALL OTHERS: ..................................................................................... 64 
5.3 EXCLUSION CRITERIA ................................................................................................................ 66 
5.4 WITHDRAWAL CRITERIA ............................................................................................................ 69 
5.4.1 
Withdrawal due QTc Interval Prolongation ...................................................................... 70 
5.4.2 
Withdrawal due to Suspected or Confirmed Drug-induced Liver Injury ............................. 70 
5.4.3 
Withdrawal due to Adrenal Insufficiency .......................................................................... 72 
6 
STUDY ASSESSMENTS AND PROCEDURES ............................................................. 72 
6.1 SONICS-COMPLETER COHORT .................................................................................................. 73 
6.2 LEVOKETOCONAZOLE-NAÏVE COHORT ....................................................................................... 73 
6.3 DEMOGRAPHIC/MEDICAL HISTORY ASSESSMENTS ...................................................................... 74 
6.4 SAFETY AND EFFICACY ASSESSMENTS ....................................................................................... 75 
6.4.1 
Physical Examination and Assessment of Clinical Signs and Symptoms of CS ................... 75 
6.4.2 
Vital Signs ....................................................................................................................... 75 


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6.4.3 
12-Lead Electrocardiograms (ECG) ................................................................................. 76 
6.4.4 
Clinical Laboratory Tests................................................................................................. 79 
6.4.5 
Disease-Related Assessments ........................................................................................... 81 
6.4.6 
Situations Requiring Additional Safety Monitoring ........................................................... 86 
6.4.7 
Pharmacokinetics ............................................................................................................ 87 
6.5 ADDITIONAL CONSIDERATIONS FOR RISK MANAGEMENT ............................................................ 88 
6.5.1 
Instructions for Subjects ................................................................................................... 88 
6.5.2 
Considerations for the Investigator .................................................................................. 88 
6.5.3 
Adrenal Insufficiency ....................................................................................................... 89 
7 
LIFESTYLE AND DIETARY RESTRICTIONS ............................................................ 90 
8 
INVESTIGATIONAL PRODUCTS ................................................................................ 91 
8.1 DESCRIPTION OF INVESTIGATIONAL PRODUCT ............................................................................ 91 
8.2 DESCRIPTION OF REFERENCE THERAPY ...................................................................................... 91 
8.3 DOSAGE AND ADMINISTRATION ................................................................................................. 91 
8.3.1 
Dose Rationale ................................................................................................................ 92 
8.3.2 
Dose Titration and Maintenance (TM) Phase (levoketoconazole-naïve cohort) ................. 92 
8.3.3 
Randomized Withdrawal Phase and Restoration Phase..................................................... 94 
9 
DRUG SUPPLIES, DISPENSING, STORAGE AND ACCOUNTING .......................... 95 
9.1 PRODUCT STORAGE ................................................................................................................... 95 
9.2 INVESTIGATIONAL PRODUCT ACCOUNTABILITY .......................................................................... 96 
9.3 COMPLIANCE ASSESSMENT ........................................................................................................ 96 
9.4 TREATMENT OF INVESTIGATIONAL PRODUCT OVERDOSE ............................................................ 96 
10 
CONCOMITANT MEDICATIONS ................................................................................ 96 
10.1 PERMITTED MEDICATIONS ......................................................................................................... 96 
10.2 PROHIBITED MEDICATIONS ........................................................................................................ 97 
10.3 MEDICATIONS TO BE USED WITH CAUTION ................................................................................. 98 
11 
SUBJECT COMPLETION AND WITHDRAWAL ........................................................ 99 
11.1 SUBJECT COMPLETION ............................................................................................................... 99 
11.2 SUBJECT WITHDRAWAL PROCEDURES ........................................................................................ 99 
12 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .................................... 99 
12.1 POPULATIONS FOR ANALYSIS ..................................................................................................... 99 
12.2 HYPOTHESIS ............................................................................................................................ 100 
12.2.1 
Sample Size Determination ............................................................................................ 100 
12.3 GENERAL CONSIDERATIONS FOR DATA ANALYSIS .................................................................... 101 
12.4 STUDY COMPLETION, PREMATURE WITHDRAWAL AND MISSING DATA ..................................... 101 
12.5 FINAL ANALYSES .................................................................................................................... 102 
12.5.1 
Definitions of Baseline ................................................................................................... 102 
12.5.2 
Safety Analyses .............................................................................................................. 103 
12.5.3 
Efficacy Analyses ........................................................................................................... 106 
12.5.4 
Pharmacokinetics Analysis ............................................................................................. 111 
12.5.5 
Pharmacodynamics Analysis .......................................................................................... 111 
12.5.6 
Subgroup Analyses......................................................................................................... 112 
12.6 INTERIM ANALYSES AND DATA MONITORING ........................................................................... 112 
13 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) .................... 113 
13.1 DEFINITION OF AN AE.............................................................................................................. 113 
13.2 DEFINITION OF A SAE .............................................................................................................. 114 
13.2.1 
Disease-Related Events .................................................................................................. 115 
13.2.2 
Adverse Events of Special Interest (AESI) ....................................................................... 115 
13.3 TIME PERIOD, FREQUENCY, AND METHOD OF COLLECTING AES AND SAES............................... 116 


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13.4 RECORDING OF AES AND SAES ................................................................................................ 116 
13.5 EVALUATING AES AND SAES .................................................................................................. 116 
13.5.1 
Severity Rating .............................................................................................................. 116 
13.5.2 
Relationship to Study Drug ............................................................................................ 117 
13.6 FOLLOW-UP OF AES AND SAES ............................................................................................... 117 
13.7 PROMPT REPORTING OF SAES TO SPONSOR .............................................................................. 118 
14 
REFERENCES............................................................................................................... 119 
APPENDIX A 
TIME AND EVENTS SCHEDULES ................................................................. 123 
APPENDIX B 
LABORATORY ANALYTES ............................................................................ 130 
APPENDIX C 
STUDY MANAGEMENT AND MATERIALS ................................................. 132 
APPENDIX D 
ADMINSTRATION AND REGULATORY POLICIES ................................... 133 
APPENDIX E 
PUBLICATION POLICY .................................................................................. 135 
APPENDIX F 
PROTOCOL AMENDMENT(S) ........................................................................ 136 
APPENDIX G 
CONDITIONS ASSOCIATED WITH PSEUDO-CUSHING’S SYNDROME . 137 
APPENDIX H 
CRITERIA FOR DIAGNOSES OF PREDIABETES AND DIABETES .......... 138 
APPENDIX I 
GUIDELINES FOR HYPERTENSION ............................................................. 139 
APPENDIX J 
CONCOMITANT MEDICATIONS PROHIBITED OR TO BE USED ONLY 
WITH PRIOR PERMISSION ............................................................................ 140 
APPENDIX K 
SIGNS AND SYMPTOMS OF CONDITIONS FOR RISK MANAGEMENT 
PURPOSES ......................................................................................................... 148 
APPENDIX L 
QUALITY OF LIFE QUESTIONNAIRE .......................................................... 149 
APPENDIX M 
ASSESSMENT OF CLINICAL SIGNS AND SYMPTOMS OF CUSHING’S 
SYNDROME ...................................................................................................... 152 
APPENDIX N 
BECK DEPRESSION INVENTORY (BDI-II) .................................................. 156 
APPENDIX O 
ADDITIONAL INFORMATION ON ADVERSE EVENT OF SPECIAL 
INTEREST (QTC INTERVAL, INSTRUCTIONS FOR LIVER FUNCTION 
TEST ANORMALITIES FOLLOW-UP AND ADRENAL INSUFFICIENCY)
............................................................................................................................. 158 
 
TABLE OF TABLES 
Table 1 
Study Design ...................................................................................... 47 
Table 2 
Dosing Titration Scheme .................................................................... 53 
Table 3 
Minimum Visit-to-Visit Serial Change in Biomarker that Could be 
Considered Potentially Relevant ......................................................... 62 
Table 4 
Expected Normal 24-Hour Creatinine Excretion from Adequate Urine 
Collections ......................................................................................... 83 
Table 5 
Vital Sign Values of Clinical Importance ......................................... 105 
Table 6 
QTc Interval Values of Clinical Importance ..................................... 105 
Table 7 
Time and Events Schedule for Screening Procedures ....................... 123 


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Table 8 
Time and Events Schedule for Dose Titration and Maintenance Phase 
(levoketoconazole-naïve Cohort) ...................................................... 125 
Table 9 
Study Time and Events Schedule for Randomized Withdrawal Phase 
and Restoration Phase (Both Cohorts) .............................................. 127 
Table 10 
Blood Pressure Classification (for Adults Over 18 Years of Age) ..... 139 
Table 11 
Recommendations for Follow-up Based on Initial Blood Pressure 
Measurements for Adults without Acute End Organ Damage ........... 139 
Table 12 
Steroidogenesis Inhibitors and Systemic Corticosteroids .................. 141 
Table 13 
Dopamine Agonists .......................................................................... 141 
Table 14 
Synthetic Progestins that Bind with Moderate to High Affinity to 
Glucocorticoid Receptor (GR) or Mineralocorticoid Receptor (MR) 142 
Table 15 
Somatostatin Analogs ....................................................................... 142 
Table 16 
Weight Loss Medications ................................................................. 142 
Table 17 
Drugs Predicted to Interfere with Levoketoconazole Absorption ...... 142 
Table 18 
Drugs Whose Systemic Exposure is Predicted to be Significantly 
Increased by Levoketoconazole via CYP3A4 Inhibition ................... 143 
Table 19 
Drugs That Are Predicted to Reduce (Top) or Increase Significantly 
(Bottom) the Plasma Concentration of Levoketoconazole via CYP3A4 
Induction or Inhibition, Respectively and Are Prohibited ................. 144 
Table 20 
Drugs that can Cause QTc Prolongation ........................................... 145 
Table 21  
Drugs Whose Systemic Exposure is Predicted to be Increased 
Moderately by Levoketoconazole ..................................................... 146 
Table 22 
Topical or Inhaled Steroids .............................................................. 146 
Table 23 
Other Medications Contraindicated or Relatively Contraindicated with 
Ketoconazole ................................................................................... 147 
TABLE OF FIGURES 
Figure 1 
Study Design Schematics ................................................................... 48 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACTH 
Adrenocorticotropic hormone 
ADA 
American Diabetes Association 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
ANA 
Antinuclear antibody 
AP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
βhCG 
Beta human chorionic gonadotropin 
BDI-II 
Beck Depression Inventory  
BID 
Twice daily 
BMI 
Body mass index 
CBG 
Cortisol-binding globulin 
CFR 
Code of Federal Regulations 
CD 
Cushing’s disease 
CI 
Confidence Interval 
CL/F 
Apparent clearance following oral administration 
Cmax 
Peak concentration 
CRF 
Case Report Form 
CRH 
Corticotropin-releasing hormone 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CS 
Cushing´s syndrome 
CYP 
Cytochrome P450 
GCP 
Good Clinical Practice 
DBP 
Diastolic blood pressure 
DCCT 
Diabetes Control and Complications Trial 
DL 
Dose level 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
DST 
Dexamethasone Suppression Test 
EAP 
Expanded Access Program 
E/T 
Early termination 
ECG 
Electrocardiogram/electrocardiograph 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GR 
Glucocorticoid receptor 
HBsAg 
Hepatitis B surface antigen 
HbA1c 
Hemoglobin A1C 
HDL-C 
High density lipoprotein cholesterol 
HDPE 
High Densitiy polyethylene 


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HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HHC 
Home health care agency 
HIV 
Human immunodeficiency virus 
HOMA-IR 
Homeostatic Model Assessment-Insulin Resistance 
HPLC/MS/MS 
High pressure liquid chromatography tandem mass spectroscopy 
HR 
Heart rate 
hsCRP 
High sensitivity C-reactive protein 
IC50 
Half-maximal suppression (50% inhibitory concentration) 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IFG 
Impaired Fasting Glucose 
IgG 
Immunoglobulin G 
IGT 
Impaired Glucose Tolerance 
IgM 
Immunoglobulin M 
Imax 
Maximal suppression of UFC 
IPSS 
Inferior petrosal sinus sampling 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
Ka 
Absorption rate constant 
LDH 
Lactate Dehydrogenase 
LDL-C 
Low density lipoprotein cholesterol 
LLN 
Lower limit of normal 
L-N 
Levoketoconazole-naïve cohort (or population) 
LNSC 
Late night salivary cortisol 
LSMEAN 
Least Squares Mean 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDRD 
Modified Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Mineralocorticoid receptor 
MRI 
Magnetic Resonance Imaging 
mUFC 
Mean of three 24-hour UFC samples 
NCI-CTCAE 
National Cancer Institute Common Terminology for Adverse Events,  
NGSP 
National Glycohemoglobin Standardization Program 
OGTT 
Oral glucose tolerance test 
OLE 
Open-label extension 
OPTICS 
Acronym for Study COR-2017-OLE, an open-label extension study 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per protocol 
PT 
Prothrombin time 
PTT 
Prothromboplastin time 
QD 
Once daily 


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QoL 
Quality of life 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected using Bazett’s correction  
QTcF 
QT interval corrected using Fridericia’s correction 
RBC 
Red blood cell 
RES 
Restoration Phase 
RCV 
Reference change value 
RW 
Randomized Withdrawal Phase 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
S-C 
SONICS-completer cohort (or population) 
SD 
Standard deviation 
SONICS 
Acronym for Study COR-2012-01 
SPM 
Study procedures manual 
t½ 
Half-life 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitors 
TM 
Dose Titration and Maintenance Phase 
Tmax 
Time of peak concentration 
TSH 
Thyroid stimulating hormone 
UFC 
Urinary free cortisol  
ULN 
Upper limit of normal 
V/F 
Apparent volume of distribution following oral administration 
WBC 
White blood cell 


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1 
INTRODUCTION  
1.1 Disease Background 
Endogenous Cushing´s syndrome (CS) is a rare, serious and potentially lethal endocrine 
disease caused by chronically elevated cortisol.  The incidence of CS has been estimated 
to be 0.7 to 2.4 cases per million per year [Sharma 2015].  The prevalence of CS has been 
reported to be approximately 79 cases per million [Bolland 2011].  Patients with 
incompletely controlled disease are seriously ill and have a higher mortality rate than 
age-and gender matched controls, mainly due to metabolic and cardiovascular 
complications [Bolland 2011, Clayton 2016, Dekkers 2013, Pivonello 2016]. 
Treatment options for CS include surgery, radiation therapy and medical treatment 
[Pivonello 2015].  Medical treatment is used to suppress excessive cortisol production or 
activity and ameliorate its clinical manifestations prior to surgery, while awaiting the 
effects of radiation therapy [Nieman 2015], or in cases when surgery is delayed, 
contraindicated, or unsuccessful.  As such, normalization of 24-hour urinary free cortisol 
(UFC) is considered a reliable marker of disease remission [Bertherat 2016, Bochicchio 
1995].  More recently, late night salivary cortisol (LNSC) has also been shown to reflect 
remission but is not yet considered to be as reliable as UFC [Amlashi 2015, Findling 
2016].  Conversely, the persistence of high or only modestly reduced UFC levels argues 
for treatment failure, i.e. persistent disease.  
Ketoconazole (Nizoral®, a true racemate comprised of two enantiomers: cis-2S,4R- and 
cis-2R,4S-ketoconazole) is an antifungal agent that reduces adrenal steroid production via 
inhibition of multiple steroidogenic enzymes, notably 11β-hydroxylase (CTYP11B1) and 
C17,20-lyase / 17α-hydroxylase (CYP17A1) [Engelhardt 1991, Sonino 1987, Nizoral 
2013].  One publication has reported a direct effect of ketoconazole on ectopic 
adrenocorticotropic hormone (ACTH) secretion [Steen 1991].  Because of these 
properties, ketoconazole is a commonly used off-label drug for treatment of CS in the US 
and is approved for the treatment of CS in Europe and elsewhere [DeMartin 2006, Daniel 
2015, Castinetti 2014, Nizoral 2013 Product Insert, Ketoconazole 2014 HRA Assessment 
Report]. 
Adrenal insufficiency is avoided by adjusting the dose of ketoconazole to normalize 
cortisol production.  The most frequent adverse effects of ketoconazole are nausea, 
vomiting, abdominal pain and pruritus.  When used orally as a treatment for fungal 
infection, ketoconazole has been associated with acute liver injury, typically 
asymptomatic elevated transaminasemia.  Rarely, however, acute severe hepatotoxicity 
has been reported, leading the Food and Drug Administration (FDA) to caution that use 
of oral ketoconazole should be restricted to serious fungal infection when no suitable 
alternative exists (Outeiro 2016, Lo Re 2016, FDA 2016).  Early markers for azole-
related liver toxicities include elevations in serum alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST), which are recommended to be monitored at regular 
intervals during treatment [Ketoconazole 2014 HRA Assessment Report, Nizoral 2013 
Product Insert, Lake-Bakaar 1987, Lewis 1984].  In addition to its adverse effects on 
liver, ketoconazole has dose-related effects to prolong the ECG QT interval (Darpo 2013) 
and is associated with numerous potential drug-drug interactions, principally via its 


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inhibitory effects on certain cytochromes P450 (CYPs) responsible for xenobiotic 
metabolism (Nizoral 2013 Product Insert). 
Cortendo AB is developing levoketoconazole, also known as COR-003, the cis-2S,4R 
enantiomer of ketoconazole, as an investigational new drug for the treatment of cortisol 
hypersecretion in CS.  It is hypothesized that levoketoconazole may prove to be both 
safer and more efficacious than ketoconazole.  Levoketoconazole has a significantly 
lower IC50 (50% inhibitory concentration) towards key enzymes regulating cortisol 
synthesis (11β -hydroxylase, IC50 = 150 nM; 17-α-hydroxylase, IC50 = 48 nM) than the 
2R,4S enantiomer of ketoconazole (IC50 = 680 nM and 1800 nM, respectively), thus 
potentially allowing a lower dose of drug to achieve the same efficacy [Rotstein 1992, 
Moulder Centre, 2012]. In rats, levoketoconazole reduced corticosterone (the major 
glucocorticoid in rodents) more potently and effectively than either 2R,4S-ketoconazole 
or ketoconazole [Cortendo Report 2002-02-21]. 
Preclinical data suggest that levoketoconazole may pose less risk to impair hepatic 
function than ketoconazole.  Levoketoconazole has 12-fold higher IC50 towards CYP7A 
(IC50 = 2.4 μM), i.e. lower potency, than does 2R,4S-ketoconazole (IC50 = 0.195 μM) 
[Rotstein 1992].  CYP7A is the first and rate-limiting enzyme in the major (classical) 
liver pathway for production of bile acids, catalyzing 7α-hydroxylation of cholesterol and 
other oxysterols.  Inhibition of this enzyme can lead to functional cholestasis and 
consequent accumulation of potentially toxic metabolites such as bilirubin and 
xenobiotics, including ketoconazole itself.  Another property that suggests potentially 
improved safety of levoketoconazole compared to ketoconazole relates to the 
pharmacokinetics (PK) of the 2S,4R- and 2R,4S-enantiomers, which have been studied in 
humans after oral administration of ketoconazole or levoketoconazole [Gerber 2003, 
Schindler 2003, Schwartz 2008].  The enantiomers of ketoconazole are present in equal 
amounts, but following ketoconazole oral administration plasma concentrations of the 
2S,4R-enantiomer exceed those of the 2R,4S-enantiomer by approximately 3-fold 
[Gerber 2003], suggesting preferred extraction of the 2R,4S enantiomer by the liver.  
Assuming that liver injury is a function of hepatocyte exposure to drug, reduced hepatic 
exposure to the 2S,4R enantiomer (i.e. levoketoconazole) would be expected to be 
associated with reduced propensity for toxicity dose-for-dose compared ketoconazole; 
however, there are no published studies that directly address this hypothesis. 
Levoketoconazole has been previously administered to healthy volunteers and human 
subjects with Type 2 Diabetes Mellitus (T2DM).  Doses of levoketoconazole over the 
range of 200 mg to 600 mg once daily (QD) for up to 14 days and 150 mg to 450 mg for 
up to 4 months were shown to be generally well tolerated in these studies, with an 
adverse effect profile similar to ketoconazole, including sporadic cases of elevated 
transaminases in the Phase 2b study in T2DM.   
The first pivotal clinical trial investigating the safety and efficacy of levoketoconazole in 
subjects with endogenous CS, Study COR-2012-01 (aka SONICS) is ongoing, having 
begun in 2014.  This is an open-label, single-arm study with a Screening Phase, a Dose 
Titration Phase, a 6-month Maintenance Phase, and a 6-month Extended Evaluation 
Phase.  SONICS enrolled 94 subjects in total.  SONICS is monitored by an independent 
Data Safety Monitoring Board (DSMB), which reviews all serious adverse events (SAEs) 
and adverse events of special interest (AESI) as they are reported and meets twice yearly 


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to review all available efficacy and safety data.  At the most recent meeting in 
April 2018, with the study fully enrolled, the DSMB indicated that the SONICS study 
should continue as planned.  The current study will include subjects who have previously 
completed SONICS as well as subjects who have not been previously exposed to 
levoketoconazole. 
Please refer to the Investigator’s Brochure for a detailed description of all prior 
preclinical and clinical studies conducted with levoketoconazole. 
1.2 Rationale for Study Design 
This study, the second pivotal clinical trial investigating the safety and efficacy of 
levoketoconazole in subjects with endogenous CS, is a double-blind, randomized, 
placebo-controlled withdrawal following single-arm, open-label, trial of therapy with 
levoketoconazole that will assess efficacy, safety, tolerability, and PK of 
levoketoconazole in subjects with endogenous CS. 
Randomization and blinding are used to minimize biases.  A blinded-treatment 
Restoration Phase, in which all subjects are returned to active treatment with their 
Therapeutic Dose of levoketoconazole, is included for subjects who do not require early 
rescue and who tolerate the 8-week blinded, randomized withdrawal to completion.  
Masking study drug during the Restoration Phase eliminates any potential for bias 
introduction via knowledge of the treatment assignment in the Randomized-withdrawal 
Phase.  An add-on of study medication (doubling the number of tablets ingested) during 
the blinded Restoration Phase was chosen over a direct substitute of blinded medication 
(holding the number of tablets ingested constant), owing to the desire to titrate the 
Restoration Phase medication to minimize adverse effects of rapid re-introduction of 
levoketoconazole.  Titrating from Dose Level (DL1) during Restoration Phase could 
potentially result in functional unblinding of subjects assigned to receive 
levoketoconazole during the Withdrawal Phase. 
Two populations, or cohorts, have been defined for analytical purposes: subjects who 
have completed all visits in SONICS through M12 (the final scheduled visit prior to 
safety follow-up) at any time in the past and who have been receiving a stable 
Therapeutic Dose throughout the 12-weeks prior to Screening, hereafter referred to as the 
SONICS-completer cohort, and subjects who did not participate in the prior clinical study 
of levoketoconazole (COR-2012-01 aka SONICS), plus subjects who completed Visit 
M12 of SONICS but who have not been treated with a stable Therapeutic Dose of 
levoketoconazole throughout the 12-week period immediately prior to Screening in the 
current study, hereafter known as the levoketoconazole-naïve cohort.   
There is also a procedure-only distinction made between those who have completed 
SONICS recently (those completing within 6 months prior to screening) and distant 
completers of SONICS (those completing more than 6 months from screening).  Distant 
completers of the SONICS study will need to undergo additional Screening procedures to 
confirm eligibility. 
The concept of Therapeutic Dose originates in the parent SONICS study, wherein the 
Therapeutic Dose is considered established when: (a) mean UFC levels determined from 
a total of four adequate 24-hour urine collections are at or below the ULN of the central 


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laboratory’s reference range, or (b) the maximum dose allowed has been reached, or (c) a 
partial UFC response has been determined and the maximal tolerated dose has been 
reached.  Although this definition of Therapeutic Dose shall suffice for subjects who 
complete the SONICS study entering LOGICS, for subjects in the levoketoconazole-
naïve cohort, the definition of Therapeutic Dose will be restricted to the dose of 
levoketoconazole associated with normalization of UFC (at or below the ULN of the 
reference assay) only.  The choice to restrict the definition of Therapeutic Dose among 
subjects in the levoketoconazole-naïve cohort was determined based on the design of the 
current study—interpreting the effects of withdrawal from active drug is “cleaner” when 
the Therapeutic Dose (i.e. a prior response to therapy) is defined singularly. 
The chosen design has considered the reported experience treating CS patients with 
ketoconazole [Castinetti 2014].  Like ketoconazole, dosing of levoketoconazole needs to 
be individualized, since therapeutic need varies considerably among patients.  Response 
to therapy (e.g. as determined by reduction in UFC and improved clinical signs and 
symptoms) is equally variable and results in a wide range of effective doses, each tailored 
to an individual patient.  As such, the design of this study includes a Dose-Titration and 
Maintenance (TM) Phase for subjects in the levoketoconazole-naïve cohort, including 
subjects who completed all visits in SONICS but who have not been treated with a stable 
Therapeutic Dose of levoketoconazole throughout the 12 weeks prior to Screening that 
will identify a Therapeutic Dose for each subject (see Section 4.2.2 for details).   
Post-randomization, the blinded, randomized withdrawal design employs a placebo 
comparator to establish the efficacy and safety of levoketoconazole based on the 
expectation of loss of prior-established response upon administration of placebo, and 
maintenance of response with active treatment.  The time allowance—approximately 
8 weeks (maximum 9 ½ weeks)—provided for the demonstration of loss of efficacy is 
considered adequate based on the relationship between withdrawal of ketoconazole and 
loss of efficacy, as documented in published case reports and series.  A longer period of 
withdrawal is neither necessary nor advisable, considering the higher risk of exposure to 
unrecognized hypercortisolemia as the withdrawal interval increases.  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 may be “rescued” with 
open-label treatment at any time prior to the completion of the 8-week Randomized 
Withdrawal phase if the Investigator determines such rescue is needed based on pre-
defined criteria as set forth in Section 4.3.1. 
The enrollment of subjects who have completed the SONICS study will allow for 
controlled assessment of the durability of efficacy of levoketoconazole beyond 1 year.  
The randomized-withdrawal design can provide an inference concerning the duration of 
drug effect based on the active-therapy period preceding the Randomized Withdrawal 
phase.  Specifically, when the following conditions are met, the duration of preceding 
active therapy is inferred as the demonstrated duration of efficacy durability: (1) the 
duration of active therapy was verified; (2) the therapy was dispensed and used 
continuously (within expected normal variability in adherence), and (3) the effect of 


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active drug on the disease state was measured regularly using a validated biomarker or 
clinical outcome.  In the current study, all subjects who have completed SONICS will 
have received levoketoconazole continuously for more than 1 year, with drug use and 
effect on UFC and LNSC monitored at regular intervals by the same Investigators.  
Therefore, if efficacy is demonstrated in the overall study population, and the efficacy 
trend within the SONICS-completer cohort drives the overall study population effect, it 
will be reasonable to infer that the efficacy of levoketoconazole is reliably durable for up 
to the average (or median) time of drug exposure within the SONICS-completer cohort. 
2 
OBJECTIVES 
2.1 Primary Objective 
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. 
2.2 Secondary Objectives 
1. To compare the effects of levoketoconazole with placebo on cortisol status 
(inferred from mean urinary free cortisol [mUFC] and/or late night salivary 
cortisol [LNSC]) during the Randomized Withdrawal Phase and the subsequent 
Restoration Phase; 
2. To compare the effects of levoketoconazole with placebo on changes in 
biomarkers of CS comorbidities (fasting glucose, fasting insulin, homeostatic 
model assessment-insulin resistance [HOMA-IR], hemoglobin A1c [HbA1c], 
total cholesterol, low-density lipoprotein-cholesterol [LDL-C], and high-
sensitivity C-reactive protein [hsCRP]); 
3. To compare the effects of levoketoconazole with placebo on changes in 
health-related quality of life (QoL) and symptoms of depression; 
4. To compare the effects of levoketoconazole with placebo on changes in acne, 
hirsutism and peripheral edema; 
5. To assess the safety and tolerability of levoketoconazole; 
6. To evaluate the population pharmacokinetics (PK) of levoketoconazole in 
subjects with CS. 
NOTE: Secondary Objectives 5 and 6 are not subjects of hypothesis tests. 
2.3 Exploratory Objectives 
1. To assess changes in anti-diabetic, anti-cholesterol, anti-hypertensive, and chronic 
anti-inflammatory therapies; 
2. To describe the effects and durations of levoketoconazole action with respect to 
cortisol status and clinical signs and symptoms of CS other than acne, hirsutism 
and peripheral edema; 
3. To describe the dose-response relationship of levoketoconazole with respect to 
safety and tolerability; 


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4. To describe the effects of levoketoconazole on glucose tolerance among subjects 
with impaired fasting glucose (IFG). 
3 
ENDPOINTS 
3.1 Primary Endpoint 
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 
UFC measurements obtained at any visit from second through final Randomized 
Withdrawal Phase visits (RW1 through RW5 inclusive) when:  
(1)  mUFC is above 1.5X 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. >1.0X ULN)1, OR  
(3)  an early rescue criterion is met. 
3.2 
Secondary Endpoints 
• Changes from Baseline (RW0) in mUFC and LNSC at all post-Baseline visits 
with these assessments through the final study visit (RES2)—applies to 
Secondary Objective 1; 
• Proportion of subjects with normalization of mUFC at RES2—applies to 
Secondary Objective 1; 
• Proportion of subjects with normalization of mUFC at the end of Randomized 
Withdrawal Phase—applies to Secondary Objective 1; 
• Changes from Baseline (RW0) in biomarkers of CS comorbidities (fasting 
glucose, fasting insulin, homeostatic model assessment-insulin resistance 
[HOMA-IR], hemoglobin A1c [HbA1c], total cholesterol, low-density 
lipoprotein-cholesterol [LDL-C], and high-sensitivity C-reactive protein [hsCRP]) 
at all post-Baseline visits with these measurements through the final study visit 
(RES2)—applies to Secondary Objective 2; 
• Changes from Baseline (RW0) in health-related QoL and symptoms of depression 
at all post-Baseline visits with these assessments through the final study visit 
(RES2)—applies to Secondary Objective 3; 
• Changes from Baseline (RW0) in acne, hirsutism and peripheral edema at all post-
Baseline visits with these assessments through the final study visit (RES2)—
applies to Secondary Objective 4; 
• Incidence and severity of adverse events (AEs), particularly adverse events of 
special interest (AESIs) during levoketoconazole open-label therapy in the TM 
                                               
1 This category applies only to subjects who have completed SONICS, who may have a Therapeutic Dose 
established with UFC above the ULN of the reference range.  Levoketoconazole-naïve subjects must have 
UFC at or below the ULN at RW0 to qualify for randomization. 


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Phase (levoketoconazole-naïve cohort) and during blinded therapy in the 
Randomized Withdrawal Phase and Restoration Phase (both cohorts)—applies to 
Secondary Objective 5. 
3.3 Pharmacokinetic Endpoints and Pharmacokinetic/Pharmacodynamic 
Modeling 
• Estimates of the following PK parameters: clearance (CL/F), volume of 
distribution (V/F), absorption rate constant (Ka), with associated between-subject 
variability where feasible. These parameters will be used to calculate half-life 
(t½), area under the concentration time curve (AUC) and peak concentration 
(Cmax), if feasible—applies to Secondary Objective 6; 
• Estimates of the following pharmacodynamic (PD) parameters: levoketoconazole 
concentration producing half maximal UFC suppression (IC50), maximal 
suppression of UFC (Imax) and associated estimates of between-subject 
variability, if feasible. UFC concentrations in relation to dose and plasma 
exposure will be explored—applies to Secondary Objective 6. 
3.4 Exploratory Endpoints 
• Frequency of usage and changes from Baseline (RW0) in frequency of usage of 
anti-diabetic, anti-cholesterol, anti-hypertensive, and chronic anti-inflammatory 
therapies at all post-Baseline visits; changes in corresponding biomarkers 
accounting for changes in medication usage will also be explored—applies to 
Exploratory Objective 1; 
• Time from RW0 to first time of loss of response, when:  
(1)  mUFC is above 1.5X the ULN of the central laboratory’s reference range, OR  
(2)  mUFC is more than 40% above the RW0 value, if the RW0 value is above the 
ULN (i.e. >1.0X ULN)2, OR  
(3)  an early rescue criterion is met—applies to Exploratory Objective 2; 
• Time to first normalization of mUFC beginning from RW5 (subset with mUFC 
above 1.5X ULN at RW5)—applies to Exploratory Objective 2; 
• Time to first normalization of LNSC beginning from RW5 (subset with LNSC 
above ULN at RW5) —applies to Exploratory Objective 2; 
• Proportion of subjects with normalization of mUFC at the end of Dose Titration 
and Maintenance Phase (TM7)—applies to Exploratory Objective 2;  
• Proportion of subjects with either normalization of mUFC or partial response (at 
least 50% decrease in mUFC) at the end of Dose Titration and Maintenance Phase 
(TM7)—applies to Exploratory Objective 2; 
                                               
2 This category applies only to subjects who have completed SONICS, who may have a Therapeutic Dose 
established with UFC above the ULN of the reference range.  Levoketoconazole-naïve subjects must have 
UFC at or below the ULN at RW0 to qualify for randomization. 


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• Proportion of subjects with normalization of LNSC at RES2—applies to 
Exploratory Objective 2; 
• Changes from Baseline (RW0) in serum cortisol and ACTH at all post-Baseline 
visits with these assessments through the final study visit (RES2)—applies to 
Exploratory Objective 2; 
• Changes from Baseline (RW0) in clinical signs and symptoms of CS excluding 
acne, hirsutism and peripheral edema at all post-Baseline visits with these 
assessments through the final study visit (RES2)—applies to Exploratory 
Objective 2; 
• Frequency and severity of common AEs and laboratory abnormalities in relation 
to dose of study drug administered at the time of the reported AE or laboratory 
abnormality—applies to Exploratory Objective 3; 
• Shifts from normality and concentration changes from Baseline (RW0) in serum 
transaminases, alkaline phosphatase (AP), and total bilirubin at all post-Baseline 
visits in relation to dose of study drug administered at the time of the shift or 
change—applies to Exploratory Objective 3; 
• Durations and changes in durations from Baseline (RW0) of the QTc interval in 
relation to dose of study drug administered proximal to the measurement—applies 
to Exploratory Objective 3. 
• Change from Baseline in observed and derived glucose and insulin parameters 
during oral glucose tolerance test (OGTT) in the subset of subjects with IFG—
applies to Exploratory Objective 4. 
4 
STUDY DESIGN 
4.1 Overview of Study Design 
This is a double-blind, randomized, placebo-controlled withdrawal and restoration (or as-
needed early rescue) study in subjects with endogenous CS previously treated with 
single-arm, open-label levoketoconazole that will assess efficacy, safety, tolerability, and 
PK of levoketoconazole.  
Two populations or cohorts, are defined for analytical and procedural purposes, 
levoketoconazole-naive and SONICS-completer, defined as follows:  
Levoketoconazole-naïve cohort: Subjects who did not participate in the prior clinical 
study of levoketoconazole (COR-2012-01, aka SONICS) plus subjects who completed 
Visit M12 of SONICS (final scheduled visit prior to safety follow-up) but who have not 
been treated with a Therapeutic Dose of levoketoconazole throughout the 12-week period 
immediately prior to Screening in the current study.   
SONICS-completer cohort:  Limited to subjects who have completed all visits in the 
SONICS study through M12 (final scheduled visit prior to safety follow-up) at any time 
prior to the current study and who have been treated with a stable Therapeutic Dose of 
levoketoconazole throughout the 12-week period immediately prior to Screening. (Note: 


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A stable dose is defined as a Therapeutic Dose that has been received by the subject for 
12 weeks without requiring a change in dose.) 
Subjects completing all visits in SONICS who have not been treated with a Therapeutic 
Dose of levoketoconazole throughout the 12-week period immediately prior to Screening 
must re-establish their Therapeutic Dose in the TM Phase as part of the 
levoketoconazole-naïve cohort.  Subjects re-establishing the Therapeutic Dose via re-
titration may begin titration at their current or next higher level most recently received at 
the discretion of the Investigator.  However, all SONICS subjects re-titrating must follow 
the 14-week minimum Dose Titration and Maintenance schedule.  
Study methodology varies by cohort prior to randomization (RW0) only.  Following 
initial Screening (washout as necessary) and Dose Titration and Maintenance phases, as 
applicable, this study will be conducted in two randomized, double-blind treatment 
phases (a Randomized Withdrawal Phase and a Restoration Phase).  The overall design 
and the designs for each cohort are described and schematized in Table 1 and Figure 1 
below. 
Table 1 
Study Design 
Open-label 
levoketoconazole 
Therapeutic Dose established in Dose Titration and Maintenance (TM) Phase 
for levoketoconazole-naïve cohort, or prior to entry into LOGICS for the 
SONICS-completer cohort 
Randomization 
(RW0) 
 
 
Blinded Randomized 
Withdrawal Phase 
Levoketoconazole at 
Therapeutic Dose 
Placebo at equivalent tablet count to 
Therapeutic Dose 
Blinded Restoration 
Phase 
Placebo added as 1 tablet twice daily 
(BID) at RW5 then add 1 tablet every 
2 days, alternating AM and PM, until 
the total tablet count is double the 
count at RW0 
Levoketoconazole added as 1 tablet 
BID at RW5 then add 1 tablet every 
2 days, alternating AM and PM, until 
the total tablet count is double the 
count at RW0 


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Figure 1 
Study Design Schematics 
Levoketoconazole-naïve cohort 
[Levoketoconazole-naïve subjects (or re-titrations)] 
 
SONICS-completer cohort 
 
Note: RW5, the last visit of the Randomized Withdrawal Phase marks the start of the Restoration 
Phase  
NOTE: If there is a time gap between completion of Screening and TM0 or RW0 for subjects currently 
receiving levoketoconazole, then open-label levoketoconazole should be continued between Screening 
and TM0 or RW0 to maintain the Therapeutic Dose. If rolling over from SONICS, subjects will be 
dispensed LOGICS medication starting at the screening visit.  If entering from the expanded access 
program (EAP), subjects will stay on open-label levoketoconazole dispensed from EAP until the 
Baseline visit. 
• Screening Phase:  For the levoketoconazole-naïve cohort, screening duration 
may last up to approximately 13 weeks to allow for as-needed wash out of 
Cushing’s syndrome medications. For the SONICS-completer cohort, screening 
duration is estimated to be 2 weeks and may begin concurrently with Visit M12; 
see Sections 4.2.1 and 4.2.2 for details.   
• Dose Titration and Maintenance Phase (TM Phase) [levoketoconazole-
naïve subjects and re-titrations ONLY]:  Duration is a minimum of 
14 weeks and up to approximately 19 weeks to achieve an effective and 
tolerable dose of levoketoconazole (i.e. the Therapeutic Dose); see 
Section 4.2.2.2 for details.  Note that subjects who completed SONICS but 
are being treated as part of the levoketoconazole-naïve cohort (see above) 
and must re-titrate, must complete at least 14 weeks of dose titration and 


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maintenance, regardless of the duration needed to re-establish their 
Therapeutic Dose according to the LOGICS definition. 
• Double-blind, Randomized Withdrawal Phase (RW0-RW5; all eligible 
subjects): Duration is approximately 8 weeks (maximum 9½ weeks) to evaluate 
the efficacy and safety of continued treatment with the established Therapeutic 
Dose of levoketoconazole compared to withdrawal to a matched placebo 
(administered in same regimen as the established Therapeutic Dose). Early rescue 
criteria are established to provide immediate use of active medication (open-label 
levoketoconazole) at any time during this phase if the subject’s clinical condition 
warrants it; see Section 4.3 for details. 
• Double-blind, Restoration Phase (RW5-RES2; all eligible subjects):  Duration 
is approximately 8 weeks (maximum 9½ weeks).  To maintain the blind and 
ensure subjects are managed at their established Therapeutic Dose, subjects will 
be additionally dosed with either placebo or levoketoconazole until the addition of 
tablets equals the original levoketoconazole tablet count (i.e. total tablet count will 
be twice the tablet count of levoketoconazole at the established Therapeutic 
Dose).  Specifically, for those subjects randomized to placebo during the 
Randomized Withdrawal Phase, levoketoconazole will be added during 
Restoration Phase, and for those subjects randomized to levoketoconazole, 
matched placebo will be added during Restoration Phase see Section 4.4 for 
details.   
The longest anticipated exposure to active study medication is no more than 
approximately 38 weeks and the shortest approximately 8 weeks; these exposure 
durations exclude any exposure in SONICS or in an EAP.  If rolling over from SONICS, 
subjects will be dispensed LOGICS medication during screening phase which should be 
no more than 11 (±3) days.  If entering from EAP, subjects will stay on open-label 
levoketoconazole dispensed through EAP during the screening phase which should be no 
more than 11 (±3) days.  The longest anticipated exposure to placebo monotherapy is no 
more than 9½ weeks, with provisions for earlier rescue with active drug in case of 
decompensation.  The longest anticipated total study participation duration is 
approximately 51 weeks. 
Efficacy will be assessed by measuring UFC levels and other endpoints at the times 
indicated in the Time and Events Schedules (Appendix A). 
Blood samples for PK determination will be collected as described in Section 6.4.7.1.  
Note that the times indicated in the Time and Events Schedules (Appendix A) are 
indicative of potential collection times. 
Safety data will be collected at the times indicated in the Time and Events Schedules and 
as described in Section 6.4.   
Adequate medical coverage shall be provided by the Investigator throughout the study 
(including nights, weekends and holidays) to ensure that prompt safety decisions can be 
made and appropriate medical interventions provided.  The Investigator should provide 
all subjects with instructions how to access the site’s medical staff regardless of day and 
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An independent DSMB will review key safety data throughout the study.  The DSMB 
will be composed of experts in aspects of drug safety and benefit-risk assessment 
germane to the therapeutic area and the known safety issues associated with 
levoketoconazole (e.g. liver injury, QT prolongation).   
All subjects who complete the study, where completion is defined as having completed 
Visit RES2 in the Restoration Phase OR having required use of early rescue with open-
label levoketoconazole during the Randomized Withdrawal Phase, will be eligible to 
enter an open-label extension (OLE) study (Study COR-2017-OLE, aka OPTICS) to 
allow open-label treatment with levoketoconazole and assess its long-term effects on 
efficacy and safety.  The OPTICS study is described in a separate protocol. Subjects who 
are not eligible for or who do not consent to participate in the OPTICS study or the EAP 
for levoketoconazole will be promptly referred to their endocrinologist (if not the 
Investigator) for further management. 
Early rescue procedures and visit schedule will mimic those described for the rapid 
titration during the Blinded Restoration Phase (Section 4.4), except that therapy will be 
administered as open-label therapy, assuming the Investigator determines open-label 
therapy with levoketoconazole remains in the best interests of the subject.  It should be 
noted that during the early rescue period, as treatment is open-label, dose adjustments 
may be made as medically indicated.  This includes adjustments to dose levels above the 
previous therapeutic dose if required to return subject to eucortisolemia. 
4.2 Pre-Randomization  
4.2.1 SONICS-Completer Cohort Screening Phase 
All subjects on levoketoconazole from SONICS or the EAP must have confirmation of 
their Therapeutic Dose, as defined in the SONICS protocol, during the Screening Phase 
to confirm cohort placement for LOGICS.  During this time, subjects will continue their 
prescribed dose of levoketoconazole to ensure continuity of treatment.  Subjects who 
have completed all visits in SONICS, through Visit M12 and have been on a stable 
Therapeutic Dose throughout the 12-week period immediately prior to signing informed 
consent, will enter the Screening Phase to confirm eligibility.   
For subjects who have completed SONICS within 6 months prior to screening for 
LOGICS, the Screening Phase, relying primarily on data collected during SONICS and 
completed with data collected in LOGICS, will begin after Visit M12 of SONICS 
completion and end once eligibility is confirmed.  The time from confirmation of 
eligibility to RW0 should be no more than 11 (+3) days later (the minimum time 
requirement for Therapeutic Dose confirmation as dictated by tolerability and UFC 
results).  As data collected from the SONICS study will be used in this study as well, 
overlapping assessments only needs to be performed once (e.g. the same vital signs data 
may be recorded in the eCRFs for both studies).    
For subjects who have completed SONICS more than 6 months prior to the Screening 
Phase, the screening procedures will mimic those for the levoketoconazole-naïve subjects 
to confirm eligibility for the current study (see inclusion criteria in Section 5).  After 
eligibility has been confirmed during the Screening Phase, subjects should proceed 


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directly to the Baseline/Randomization Visit (RW0).  The time between Screening and 
RW0 should be no more than approximately 11±3 days. 
4.2.2 Levoketoconazole-Naïve Cohort  
4.2.2.1 Screening Phase for Levoketoconazole-naïve Cohort 
Following consent signature, subjects naïve to levoketoconazole receiving previous CS 
medical therapies or other prohibited medications must enter a washout period (see 
Section 5.2) before completing the screening assessments detailed in the Time and Events 
schedule (Appendix A).  The Screening Phase will last up to approximately 13 weeks. 
Baseline measurements will be obtained as part of the Screening assessments; therefore, 
the time from confirmation of eligibility to TM0 (aka baseline) should be no more than 
11 (+3) days.  Screening procedures completed within 3 weeks of TM0 (within 2 weeks 
for LNSC, QTc interval and liver safety tests) will be used as the TM0 value.  If 
Screening procedures were completed more than 3 weeks prior to TM0, then they will be 
repeated at TM0, (except for pituitary magnetic resonance imaging (MRI), which may be 
completed up to 6 months prior to TM0 or RW0). All blood samples (except for post 
dose PK samples) should be obtained prior to administering the first dose of 
levoketoconazole. 
Likewise, the final Baseline UFC specimen must be collected close to the date of TM0 
and never more than 6 weeks prior to TM0 (NOTE: all Baseline UFC and LNSC values 
must be obtained after washout of any medications (except levoketoconazole) that are 
known to influence cortisol).   
If a subject does not meet the eligibility requirements described in Section 5 on initial 
Screening, they may be eligible to re-screen only if worsening of their medical condition 
has increased the likelihood that they would meet the study eligibility criteria. Such re-
screenings will be exceptional circumstances, and all re-screenings require prior 
permission of the study Medical Monitor before they begin. Repeating a Screening test 
(e.g. UFC) that has been found to be technically flawed will not be considered re-
screening. 
For subjects who have completed Visit M12 in SONICS either within 6 months or more 
than 6 months prior to the Screening Phase and are NOT on a stable Therapeutic Dose 
throughout the previous 12-week period, screening procedures will mimic those for the 
levoketoconazole-naïve subjects as noted above to confirm eligibility and progress the 
subject into the TM Phase of the study as indicated in Section 4.2.2.2.  In such cases, the 
latest available data from SONICS (e.g. Visit M12 or the Follow-up Visit) may be 
applied to the LOGICS Screening Visit. 
4.2.2.2 Dose Titration and Maintenance Phase (levoketoconazole-naïve 
cohort only) 
After confirmation of eligibility, subjects in the levoketoconazole-naïve cohort (including 
subjects that completed SONICS but require re-titration) will enter the TM Phase.  The 
first dose of open-label therapy for this phase will be at TM0.  Subjects who did not 


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complete Visit M12 of SONICS will always begin titration at Dose Level 1 (150 mg 
BID). 
Subjects who have completed Visit M12 in SONICS who have not been treated with a 
Therapeutic Dose of levoketoconazole throughout the 12-week period immediately prior 
to Screening must also re-establish a Therapeutic Dose and remain in the TM Phase for 
the full 14-week period, regardless of the duration needed to establish their Therapeutic 
Dose for this study (i.e. even if it takes less than 14 weeks).  As stated earlier, these 
subjects are considered as part of the levoketoconazole-naïve cohort for this study, 
despite not being naïve to levoketoconazole in the strict sense at the time of entry in the 
current study.  Note that subjects in this category may begin dose-titration at their current 
or most recently received dose of levoketoconazole, rather than Dose Level 1, at the 
discretion of the Investigator.   
Dose titration will occur in increments of 150 mg over a period of approximately 3 to 
19 weeks to achieve an effective and tolerable dose (the Therapeutic Dose).  Dose 
increases (and decreases, as needed) will be based on subjective and objective indicators 
of medication tolerance, UFC and other cortisol measures (see Section 4.2.2.2.1).  
In exceptional situations, subjects may require additional time (i.e. greater than 19 weeks) 
to achieve the Therapeutic Dose.  These situations must be approved on a case by case 
basis by the Medical Monitor. 
Subjects must return to the clinic at least every 14 (± 3) days during the TM Phase (note: 
to allow for 4 weeks maintenance, additional time may be required in the event a dose 
change is required at TM7).  However, several additional safety checks, which may be 
performed outside the clinic, will also be scheduled: (1) 5 days (± 2 days) after the first 
dose (DL1) and after dose escalations to DL2 and DL3 during the TM Phase (if needed), 
subjects will be contacted by site personnel remotely (e.g. by phone or email) to inquire 
about the subject’s condition and note any adverse events.  (2) If the total daily dose is 
escalated to 750 mg (DL4) or above, subjects will be asked to return to the clinic or, 
optionally, will be visited by a qualified home healthcare (HHC) professional for one 
extra safety evaluation to occur 5 days (± 2 days) after each dose escalation.  
Subjects will be advised to contact the Investigator immediately in the event of AESI-
suggestive signs or symptoms (see Section 13.2.2) regardless of the onset timing relative 
to a scheduled visit.  
Once the Therapeutic Dose has been reached and confirmed from the mean of three 
adequately collected 24-hour urine specimens for UFC measurements (i.e. from mUFC), 
subjects will continue that Therapeutic Dose (i.e. remain in Maintenance) until the final 
open-label study visit (Visit TM7) in the TM Phase, which shall be a minimum of 
14 weeks from TM0. During the TM Phase (while treatment is open-label), once the 
Therapeutic Dose is achieved, the dose should generally not be further adjusted if the 
UFC levels are within normal limits.  However, the dose may be increased if medically 
necessary to maintain eucortisolemia or decreased to address drug intolerance or AE.   
Prior to the final open-label visit (Visit TM7), three adequate 24-hour urine specimens 
will again be obtained (NOTE: collections need not be repeated if the final open-label 
visit coincides with the initial establishment of UFC normalization) to confirm 


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maintenance of UFC normalization prior to randomization, denoting UFC-eligibility for 
the Randomized Withdrawal Phase.  To ensure the TM Phase occurs within the allotted 
timeframe of no more than approximately 19 weeks, urine collections should ideally be 
made on sequential days and prior to the actual scheduled visit for dose assessment, as 
results are needed to determine if dose escalation is required, or whether a confirmatory 
UFC is needed to establish Therapeutic Dose.  The minimum duration of this phase and 
thus establishment of the Therapeutic Dose will be no less than approximately 14 weeks, 
even among subjects who reach a Therapeutic Dose more quickly.  Randomization 
(RW0) should occur as soon as possible after the final TM Phase visit (TM7) and no 
more than 11 (+3) days later unless a dose change was required at Visit TM7.  
Regardless, in all cases, at least 4 weeks should elapse between reaching the Therapeutic 
Dose and RW0 to ensure tolerability and stability (continued effectiveness) of the 
Therapeutic Dose. 
Subjects still in the TM Phase when the randomization target (approximately 46 to 
54 subjects, depending on the observed withdrawal rate trend in the Randomized 
Withdrawal Phase) is reached, will be offered the opportunity to join the OPTICS study 
to receive open-label treatment.  While randomization is still open, non-responders may 
also be eligible for OPTICS only if they achieve a partial UFC response, do not expect to 
require additional medication other than levoketoconazole to control cortisol, and 
levoketoconazole is well tolerated.  Subjects must meet the OPTICS inclusion/exclusion 
criteria to be eligible. 
4.2.2.2.1 Dose Titration and Adjustment Criteria 
Levoketoconazole will be administered BID beginning at TM0 per the titration scheme in 
Table 2 until one of the following criteria has been met:  
• Mean 24-hour UFC levels no higher than ULN as established for the assay being used 
at a central laboratory; 
• Highest protocol-specified dose (i.e. DL7) reached; 
• Highest tolerated dose reached (in the opinion of the Investigator). 
Table 2 
Dosing Titration Scheme 
Dose Level (DL)* 
Morning dosing 
Evening Dosing 
DL1 
150 mg 
150 mg 
DL2 
150 mg 
300 mg 
DL3 
300 mg 
300 mg 
DL4 
300 mg 
450 mg 
DL5 
450 mg 
450 mg 
DL6 
450 mg 
600 mg 
DL7 
600 mg 
600 mg 
*DL0, permitted for dose reductions, is a dose of 150 mg QD administered in the evening, except 
on the day of the in-clinic or at-home visit procedures, when the dose should be administered 
during the visit (see Section 8.3.2). 
 


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All subjects will be asked to collect two adequate 24-hour urine specimens for UFC 
measurements prior to their next scheduled visit that will be used to determine the need 
for continued dose titration.  The first 24-hour urine collection will be on Day 8 
(± 2 days) and the second collection will be on Day 9 (± 2 days) after start of each dose 
level.  Subjects should be asked to bring or, preferably, ship per courier service, their two 
urine collections to the clinic, as soon as possible (by approximately Day 10) for 
measurement of 24-hour UFC levels from each sample.  The UFC results are needed 
prior to the next scheduled visit in order to determine the need to escalate dose. Urine 
volume and creatinine will be measured as markers of the adequacy of each collection 
(see Section 6.4.5.1 for definition).  Subjects will continue their current dose of 
levoketoconazole until the UFC results have been obtained from the central laboratory 
(expected within 2-4 days of shipment) and reviewed by the Investigator.  Subjects 
should be contacted as soon as feasible after the results from the two 24-hour urine 
samples are received.  Based on these UFC results and reported tolerability to 
levoketoconazole, subjects will be asked to do one of the following:  
• If UFC exceeds the ULN of the central lab reference range:  Return to the clinic for 
scheduled assessments and, as applicable, receive the first dose of drug for the next 
Dose Titration interval; OR 
• If UFC is at or below the ULN of the central lab reference range:  Collect one 
additional 24-hour urine sample for confirmatory UFC testing to determine if the 
Therapeutic Dose of levoketoconazole has been reached; Section 4.2.2.2.2).   
4.2.2.2.2 Determination of the Therapeutic Dose of Levoketoconazole 
When normalized UFC results from the mean of the first two adequately collected 
24-hour urine samples are returned, one additional 24-hour urine sample will be 
collected and returned to the clinic for submission to the central laboratory.  The UFC 
results must be received prior to the actual scheduled visit, as they are needed to 
determine if dose escalation is required. The mean of the three UFC results will be used 
to determine if UFC normalization has occurred. 
A Therapeutic Dose will be considered established only when the mUFC levels are no 
higher than the ULN of the assay (i.e. mUFC has been normalized).  Once the 
Therapeutic Dose has been reached the subject should continue with that dose (i.e. in 
Maintenance) until the end of the TM Phase of the study (Visit TM7).  During the TM 
Phase (while treatment is open-label), once the Therapeutic Dose is achieved, the dose 
should generally not be further adjusted if the UFC levels are within normal limits. 
However, the dose may be increased if medically necessary to maintain eucortisolemia or 
decreased to address drug intolerance or AE.  The Therapeutic Dose must be stable (i.e. 
fixed), with normal mUFC established, for at least 4 weeks before a subject may be 
eligible for the Randomized Withdrawal Phase. 
Detailed Steps for Determination of Therapeutic Dose 
• If the mean value of UFC from at least two (up to three if indicated by the first two 
tests being no higher than ULN—see below) adequate 24-hour urine collections is 
greater than the ULN of the central lab’s reference range, the subject should 
continue to dose-escalate by 150 mg approximately once every 2 weeks until a 


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Therapeutic Dose, a maximally tolerated dose, or maximally allowed dose (DL7) is 
reached.   
• If the mean value for the first two UFC tests from two adequate 24-hour urine 
collections is at or below the ULN from the central laboratory’s reference range, the 
subject should be notified immediately and asked to begin the additional 24-hour 
urine collection as soon as possible to confirm a biochemical response by mUFC 
normalization.  When UFC response-confirmatory urine sample collection is required, 
the subsequent visit should be scheduled no later than 18 (± 3 days) days after the 
prior dose-escalation visit.  Investigators must ensure that the subject has an adequate 
supply of levoketoconazole to cover the duration between visits.  Refer to the Study 
Procedures Manual (SPM) for other confirmatory urine collection-day guidelines. 
• All subjects who achieve a Therapeutic Dose, evidenced by the mean of three UFC 
values at or below the ULN, must complete all 7 TM Phase visits regardless of the 
Therapeutic Dose.  Thus, the total duration of the TM Phase should not be less than 
14 weeks and should not exceed approximately 19 Weeks. In exceptional situations, 
subjects may require additional time (i.e. greater than 19 weeks) to achieve the 
Therapeutic Dose. These situations must be approved on a case by case basis by the 
Medical Monitor.  
Failure to Achieve Therapeutic Dose 
If the subject has reached the highest allowed (i.e. DL7) or highest tolerated dose level 
and mUFC levels remain greater than the ULN of the central laboratory’s reference 
range, the subject will be considered a non-responder, will not be eligible for 
randomization (RW0) and should be withdrawn from the study.  Non-responders may be 
eligible for OPTICS only if they achieve a partial UFC response, do not expect to require 
additional medication other than levoketoconazole to control cortisol, and 
levoketoconazole is well tolerated. 
4.2.2.3 Safety Factors to be Considered During the Dose Titration Phase 
4.2.2.3.1 Possible Prolongation of QTc Interval 
Subjects will have electrocardiogram (ECG) evaluations at Baseline (Visit TM0) and 
within approximately 1 to 2 hours after each monitored drug administration during the 
TM Phase, ideally using the provided Spaulding ECG device (Section 6.4.3).  If 
persistent levoketoconazole-related QTc interval prolongation is observed (value above 
500 msec or more than 60 msec increase from Baseline TM0), study medication will be 
temporarily held and/or the dose level reduced.  Refer to Section 5.4.1 and Appendix O, 
where guidance to the Investigator for assessing apparently prolonged QTc interval is 
provided in detail. In all cases, a PK sample should be collected as close to the time of the 
event as possible.   
4.2.2.3.2 Possible Adrenal Insufficiency 
If the subject develops signs and/or symptoms of adrenal insufficiency (e.g., 
hypoglycemia, hyperkalemia, orthostatic hypotension, nausea, vomiting, abdominal 
pain), based on further investigation (see Section 6.5.3 and Appendix O for assessment of 


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signs and symptoms of adrenal insufficiency) and clinical judgment, the Investigator may 
temporarily interrupt study medication to allow resolution.  In such cases, at the 
discretion of the Investigator, the dose will be restarted at the preceding dose level.  
When adrenal insufficiency is observed at DL1, subjects may be provided a lower dose of 
150 mg QD (DL0) following agreement with the Sponsor.  Subjects may resume the 
Dose Titration scheme after a dose reduction at the discretion of the Investigator and 
agreement of the Sponsor.  In all cases, a PK sample should be collected as close to the 
time of the event as possible. 
4.2.2.3.3 Possible Liver Injury  
Criteria have been developed to guide the Investigator towards frequent monitoring, 
temporary drug interruption, dose reduction, rechallenge, or permanent study medication 
cessation and study withdrawal in cases when liver injury is suspected or confirmed.   
Recommendations from the FDA Guidance on Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation (July 2009) have been adopted for use in this study to monitor for 
evidence of early liver injury.  Per FDA guidance, discontinuation of investigational 
therapy should be considered in the case of: 
• ALT or AST above 8X ULN; 
• ALT or AST rises to above 5X ULN in less than 4 weeks or persists for over 
2 weeks; 
• ALT or AST above 3X ULN and total bilirubin above 2X ULN or International 
Normalized Ratio (INR) above 1.5 not explained by any other cause such as viral 
hepatitis;  
• ALT or AST above 3X ULN with new onset of or worsening of fatigue, nausea, 
vomiting, fever, rash or eosinophilia, in the absence of other evident cause; 
• Signs and /or symptoms suggestive of hepatic dysfunction (any of the following: 
nausea, anorexia, fever, fatigue, right upper quadrant discomfort, pruritus, dark 
urine or acholic stool) coupled with ALT and/or AST above 3X ULN and/or AP 
above 2X ULN, and/or total bilirubin above 2X ULN in the absence of evidence 
for obstruction or Gilbert syndrome.  NOTE: An ultrasound evaluation of the 
gallbladder and bile duct should be conducted to exclude cholestasis as the cause 
for elevated AP and/or total bilirubin. 
• Not included in FDA guidance but additionally specified for this study as a 
finding that should prompt evaluation and possible action:  Subjects with ALT or 
AST above 3X ULN or AP above 2X ULN (in the absence of evidence for 
cholestasis) or total bilirubin above 2X ULN (in the absence of evidence for 
cholestasis and except for subjects enrolled with presumed Gilbert’s syndrome). 
The above criteria are also found in Section 5.4.2. and Appendix O, which describes 
considerations for study withdrawal due to suspected or confirmed drug-induced liver 
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When a clinically significant liver test abnormality is observed, the battery of liver 
screening tests should be repeated as soon as possible after initial determination of the 
abnormality and thereafter at 3- to 4-day intervals or as the clinical situation dictates.   
The need for levoketoconazole interruption will be influenced by the Baseline (TM0 for 
levoketoconazole-naïve) liver safety test values and the subject’s clinical condition at the 
time of the abnormal liver safety test finding.  For example, small increases in ALT/AST 
above a subject’s Baseline concentration that are unaccompanied by symptoms may not 
warrant any medication interruption, whereas large increases from a subject’s Baseline, 
even if not to high absolute concentrations, might warrant withholding medication 
temporarily.  Even if ALT and/or AST continue to rise slowly (but only if 
unaccompanied by a concurrent rise in total bilirubin exceeding the cut-offs for study 
drug cessation/early withdrawal), asymptomatic subjects may continue to receive study 
medication uninterrupted with cautious monitoring, depending on the clinical condition.   
If ALT and/or AST levels at any time exceed 8X ULN or if AST/ALT are 
persistently higher than 5X ULN and are accompanied by a concurrent rise on total 
bilirubin, or if abnormal liver safety test studies are accompanied by clinical signs 
or symptoms referable to liver injury, the study medication must be interrupted 
immediately.   
In all cases, a PK sample should be collected as close to the time of the event as possible.  
If abnormally elevated liver safety tests return near to the subject’s Baseline while the 
subject continues to be dosed with study medication, serial, frequent liver safety test 
measurements may be discontinued, with usual safety monitoring thereafter.   
Appropriate diagnostic evaluations and interventions should be implemented based on the 
clinical presentation of the subject and following the instructions for AESI-liver safety 
test abnormality follow-up (Appendix O).   
Rechallenge with Study Medication 
If levoketoconazole dosing has been interrupted and liver safety tests normalize, subjects 
may be re-challenged (i.e. restarted on medication at prior or lower dose) at the discretion 
of the Investigator AND following discussion with and approval by the Medical Monitor.  
Note that rechallenge has been associated with relatively more severe liver injury among 
some patients treated with ketoconazole who interrupted medication temporarily 
(Ketoconazole 2014 HRA Assessment Report).  Therefore, it is important to re-check 
liver safety tests within 4 days after rechallenge or earlier if the subject develops 
symptoms referable to acute liver injury and recheck them again 7 to 10 days later.  
Subjects who are uneventfully rechallenged may remain in the study with usual safety 
monitoring thereafter. 
4.2.2.3.4 Stopping Criteria During Dose Titration and Maintenance 
Dosing with study medication will cease permanently due to any of the following 
observations: 
• Intolerability to the study medication based on the subjects’ signs or symptoms in 
accordance with the Investigator’s medical judgment; 


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• Lack of clinically relevant response at the maximally tolerated dose, in the 
opinion of the Investigator; 
• QTc prolongation as specified in Section 5.4.1 at 150 mg/day; 
• Liver safety test abnormalities as specified in Section 5.4.2; 
• Adrenal insufficiency at the lowest dose of study medication (equivalent to 
150 mg daily)—See Sections 5.4.3 and 6.5.3 for details; 
• Any withdrawal criteria met as specified in Section 5.4. 
4.2.2.4 Dose Titration at 750 mg/day or Above  
The safety of levoketoconazole at doses 750 mg/day or above is less established than at 
lower daily doses.  For this reason, in addition to the assessments that are carried out at 
each dose-escalation, subjects that reach total daily doses of 750, 900, 1050, and 
1200 mg/day (dose levels DL4 to DL7) will be asked to return to the clinic or will be 
visited by a qualified HHC professional for one extra safety evaluation 5 days (± 2 days) 
after each dose escalation to include the following assessments: AEs, vital signs, routine 
safety laboratory assessments (including liver safety tests), ECGs and morning serum 
cortisol levels, as outlined in Time and Events Schedule (Appendix A) and in 
Section 6.4.6.1.  Subjects should also be advised to contact the Investigator immediately 
in the event of suspected adrenal insufficiency (see Section 6.5) or other AEs between 
high-dose titration visits.   
Consult Section 4.2.2.2.2 for determination of the Therapeutic Dose via confirmatory 
urine collection for UFC, which is the same for the high-dose range. 
4.2.2.5 Transition from Dose Titration and Maintenance (TM) Phase to 
Randomized Withdrawal Phase  
Eligibility for entering the Randomized Withdrawal Phase requires the levoketoconazole-
naïve cohort subjects to have established and maintained a Therapeutic Dose for at least 
4weeks as confirmed by the average of  UFC values with results received prior to the 
RW0 Visit.  Prior to the final open-label visit in the Dose Titration and Maintenance 
(TM) Phase (Visit TM7), three complete 24-hour urine specimens will be obtained 
(collections need not be repeated if the final open-label visit coincides with the initial 
establishment of UFC normalization, i.e. Therapeutic Dose) to confirm UFC-eligibility 
for the Randomized Withdrawal Phase.  Randomization (RW0) should occur as soon as 
possible after the final Titration-Maintenance visit (TM7) and no more than 11 (+3) days 
later unless a dose change was required at Visit TM7.  At least 4 weeks should elapse 
between reaching the Therapeutic Dose and RW0 to ensure tolerability and stability of 
effectiveness. 
4.3 Randomized Withdrawal Phase (All Subjects) 
In order to qualify for randomization, ALL subjects must have established and 
maintained a Therapeutic Dose for at least 4 weeks as confirmed by the average of 3 UFC 
values with results received prior to the RW0 Visit.   


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All eligible subjects (from both the SONICS-completer and levoketoconazole-naïve 
cohorts) will enter the 8-week, double-blind Randomized Withdrawal Phase.  At this 
point in the study, SONICS-completer and levoketoconazole-naïve cohorts are treated 
identically.  In the Randomized Withdrawal Phase, subjects will return to the clinical site 
at least twice: on RW3 {Day 30 (-4)} and RW5 {Day 58 (-4)} relative to the 
Randomization Visit (RW0) for safety and efficacy evaluations, to determine if they are 
still responding to therapy (i.e. have maintained mUFC within normal range or, for 
certain SONICS-completer cohort subjects, within previously established therapeutic 
range) or if they have partial loss of response or relapse, as defined in Section 4.3.1.  
In addition, all subjects will complete three further visits either at-home (by a qualified 
HHC professional) or on-site (if qualified HHC professional is unavailable or not 
allowed/preferred) on RW1 {Day 10 (-2)}, RW2 {Day 20 (-2)} and RW4 {Day 40 (-2)} 
relative to Randomization (RW0).  These interim visits will be primarily for determining 
cortisol status as well as to monitor safety and tolerability associated with the possible 
withdrawal of medication. Although UFC will be the primary measure determining loss 
of therapeutic efficacy, cortisol status will also be assessed through additional measures, 
including LNSC.  Partial loss of response or relapse should be confirmed by a repeat (i.e. 
one additional) 24-hour urine sample (or LNSC sample), which should be collected and 
analyzed as soon as possible after the preliminary mUFC value is known.  Courier 
services will be provided, as desired, to collect UFC and LNSC specimens for transport 
to the site on days when a qualified HHC professional is not present or if subjects prefer 
courier pickup of collected samples prior to visit (Appendix A).  
Early-rescue criteria are described that provide for immediate substitution of blinded 
study drug with open-label levoketoconazole treatment directed by the study Investigator 
whenever continued use of blinded treatment in the Randomized Withdrawal Phase is 
regarded as unacceptable owing to significant or rapid clinical deterioration.  Criteria to 
guide the Investigator as to the possible need for early rescue medication are described in 
Section 4.3.1.   
4.3.1 Early Rescue Criteria and Procedures 
Early rescue is a key safety component of the study that is 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.  It is anticipated 
that at least several subjects who are randomized to receive placebo will require early 
rescue treatment prior to completion of the Randomized Withdrawal Phase.  Before 
proceeding with early rescue, the Principal Investigator must discuss with the Medical 
Monitor.  If early rescue is needed, such subjects will be deemed Study Completers and 
may be considered as eligible for enrollment in the long-term OPTICS study or for EAP 
if they otherwise qualify.  If early rescue is deemed appropriate with open-label 
levoketoconazole, subjects continue in the study using Blinded Restoration Phase 
procedures described in Section 4.4. Subjects requiring rescue medication should 
complete all procedures for visit RW5 prior to entering the Restoration Phase (see 
Table 9). 
Early rescue procedures and visit schedule will mimic those described for the Blinded 
Restoration Phase (Section 4.4), except that therapy will be administered as open-label 


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therapy, assuming the Investigator determines open-label therapy with levoketoconazole 
remains in the best interests of the subject.  The rapid titration schedule used in the 
Restoration Phase should be used to reestablish the Therapeutic Dose if a subject requires 
early rescue with open label levoketoconazole.  During early rescue, the titration will 
increase in 1 tablet increments every 2 days alternating AM and PM per Table 2.  As 
treatment is open-label during early rescue, dose adjustments may be made, as medically 
indicated.  This includes adjustments to dose levels above the previous therapeutic dose if 
required to return the subject to eucortisolemia.  Blinding to the treatment code should be 
maintained as described in Section 8.3.3.1, so as not to reveal the dosing assignment 
made during Randomized Withdrawal.  If the subject and Investigator choose to 
administer a treatment other than levoketoconazole as early rescue therapy, such 
treatment will be administered outside of the study (i.e. the subject must be withdrawn 
from the study at that time).  
Subjects who require and choose early rescue with open-label levoketoconazole will 
undergo RW5 procedures (Table 9) immediately prior to administration of open-label 
drug (except ECG to be done 1-2 hours after administration of rescue medication).   
Early rescue during the Randomized Withdrawal Phase must be considered when a 
subject demonstrates one or more of the following criteria at any time after 
randomization: 
1. Relapse of hypercortisolemia (i.e. loss of therapeutic response). Defined as:  
o mUFC from three urine collections that is above 1.5X ULN  
OR 
o mUFC from three urine collections that was above 1X ULN at Baseline 
(RW0) and increases by more than 40% above the baseline value for 
SONICS-completer cohort subjects. 
NOTE:  Relapse as per UFC criterion should always trigger early rescue as soon 
as it is observed 
2. Partial loss of cortisol response. Defined as:   
o mUFC from three urine collections that increases from Baseline (RW0) to 
greater than 1X ULN but no more than 1.5X ULN  
OR  
o LNSC that was normal at Baseline (RW0; both values ≤ULN) and 
becomes abnormal (>ULN) based on each of two LNSC collections 
obtained on different nights  
AND 
In addition to one of the above partial-loss criteria, the subject must exhibit 
clinically significant worsening of signs and symptoms of CS, as determined 
by: 
 Clinically significant deterioration in disease-related signs or 
symptoms (using the signs and symptoms validated instrument 


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and/or physical examination). 
OR 
 Relevant deterioration in one or more disease-related biomarkers 
(see Table 3). 
3. In the absence of loss or partial loss of cortisol response as defined above, 
clinically significant deterioration in disease-related signs or symptoms (using the 
signs and symptoms validated instrument and/or physical examination) AND 
clinically relevant deteriorations in two or more disease-related biomarkers (see 
Table 3).   
The justification for early rescue must fall under one of the three scenarios above and 
must be described in the Case Report Form (CRF). 


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Table 3 
Minimum Visit-to-Visit Serial Change in Biomarker that Could be 
Considered Potentially Relevant 
 
Reference Change Value (RCV)* 
Source 
Fasting Blood Glucose1 17.9% 
(e.g. an increase from 6.1 mmol/L to 7.2 
mmol/L is an 18% change and meets the RCV 
threshold) 
Santaguida 2005 
Fasting Insulin2 
79% 
(e.g. an increase from 173 pmol/L to 310 
pmol/L is a 79% increase and meets the RCV 
threshold) 
Borai 2013 
Potassium 
10%  
(e.g. a decrease from 4.0 to 3.6 mmol/L is a 
10% change and meets the RCV threshold) 
Turner 2012 
Blood Leukocytes 
(WBCs) 
33.8% 
(e.g. an increase from 7.0 to 9.4 x109/L is an 
increase of 34% and meets the RCV threshold) 
Ricos 2004 
Systolic/Diastolic 
blood pressure  
Exceeds threshold for intervention3 
 
*The analyte reference change values (or intervention thresholds) are the minimum 
within-subject, between-visit (from RW0) change values that are to be considered 
potentially relevant for purposes of early rescue. A value exceeding the Reference 
Change Value (RCV) need not be considered clinically relevant, as such a change might 
not be predicted to be associated with clinical sequelae.  Expert interpretation is therefore 
required beyond the minimum requirement. 
4.4 Double-blind Restoration Phase 
All subjects completing the Randomized Withdrawal Phase who do not meet early rescue 
criteria, will enter the 8-week Double-blind Restoration Phase, wherein they will 
continue to receive the randomly assigned blinded treatment regimen and in addition will 
receive blinded restoration study medication (placebo for those already receiving 
                                               
1  Glucose must be fasting for at least 12 hours 
2 Must be fasting for at least 12 hours.  Biological variability in serum insulin reportedly depends upon the 
state of glucose tolerance. The RCV shown reflects an intermediate RCV, between the published RCVs for 
normal glucose tolerance and impaired glucose tolerance, i.e. equivalent to that for impaired fasting 
glucose. Subjects with impaired glucose tolerance (IGT) or diabetes may have higher expected variability 
in fasting serum insulin. 
3 Visit-to-visit variability is known to vary substantially between people, regardless of actual SBP or DBP.  
Therefore, a clinically relevant deterioration cannot be based on a single reference change value or other 
threshold that is applicable to all study subjects.  Clinically relevant deterioration in mean SBP or DBP 
should be justified by exceeding an established intra-patient range of variability in blood pressure, ideally 
established with prior values from the current study or COR-2012-01.   


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levoketoconazole, or levoketoconazole for those receiving placebo), in order to restore all 
subjects to a Therapeutic Dose of levoketoconazole while concealing from subjects and 
study personnel the identity of study medications used during Randomized Withdrawal.    
If, in the opinion of the Investigator, an increased dose of study drug is required for 
subjects who are unable to restore their prior cortisol control (i.e. mUFC >ULN) during 
the Restoration Phase at their prior Therapeutic Dose, those subjects should be withdrawn 
from this study owing to “loss of efficacy”.  Such subjects may be considered for 
enrollment in the long-term OPTICS study or EAP if they otherwise qualify. 
Subjects who complete all Randomized Withdrawal visits will undergo RW5 procedures 
immediately prior to administration of blinded Restoration Phase study medication 
(except ECG to be done 1-2 hours after administration of rescue medication).  Subjects 
will return to the clinical site every 28 (± 5) days (i.e., between Visits RW5 and RES1 
and between Visits RES1 and RES2) for safety and efficacy evaluations as indicated in 
the Time and Events Schedule (Appendix A).  During the Restoration Phase starting at 
Visit RW5, approximately weekly contact will be made between visits (method 
unspecified) to inquire regarding AEs, subject status and to ensure compliance with study 
medication. 
The titration with blinded restoration therapy will begin at RW5 with 1 tablet BID and 
will increase in 1 tablet increments every 2 days alternating AM and PM per Table 2 until 
the prior-established Therapeutic Dose regimen is matched unless the Therapeutic Dose 
is DL0.  Thus, for illustration, a subject with a Therapeutic Dose of 300 mg BID 
(2 tablets BID) randomized to levoketoconazole during the Randomized Withdrawal 
Phase would rapidly titrate over 8 days to a total of 4 tablets BID during the Restoration 
Phase to include the addition of 2 tablets BID of placebo. 
The reason for adding blinded study medication (as opposed to open-label) to the 
regimen during Restoration Phase is to maintain the blinded treatment assignment that 
occurred via randomization.  This eliminates the risk of bias introduction from this 
knowledge. 
RES2 procedures will also be performed by subjects who prematurely withdraw from the 
study during Restoration Phase. 
5 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
Cortendo will review each subject’s enrollment criteria to ensure that subjects meet the 
eligibility criteria. 
5.1 Inclusion Criteria for Specified Subjects Completing the SONICS Study 
Subjects who have completed the SONICS study, within 6 months of the screening visit, 
including those receiving open-label treatment after SONICS as part of an EAP, may be 
eligible for the study if the following criteria are met:  
1. Completed the final SONICS visit (M12) and have demonstrated maintenance of 
clinical response (partial or complete, as defined in the SONICS protocol, COR-
2012-01) on a stable Therapeutic Dose of levoketoconazole for at least 12 weeks 
prior to study entry (i.e. Visit RW0).  


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2. Able and willing to provide written informed consent prior to any study 
procedures being performed; eligible subjects must be able to understand the 
informed consent form prior to inclusion into the study.   
5.2 
Inclusion Criteria for All Others: 
The following categories of potential subjects, categorized by prior use of 
levoketoconazole, may be eligible if the following 11 inclusion criteria are all met: 
• Naïve to levoketoconazole (defined as having never participated in SONICS); 
• Completers of SONICS visit M12 more than 6 months of the screening visit of 
the current study; 
• Completers of SONICS visit M12 within 6 months of the screening visit who 
have not been receiving a stable Therapeutic Dose of levoketoconazole for at 
least 12 weeks prior to the start of screening. 
1. Male or female and at least 18 years of age. 
2. Able and willing to provide written informed consent prior to any study 
procedures being performed; eligible subjects must be able to understand the 
informed consent form prior to inclusion into the study. 
3. Confirmed newly diagnosed, persistent or recurrent endogenous CS of any 
etiology, except secondary to malignancy (including pituitary or adrenal 
carcinoma).  Persistence will not be considered confirmed until 6 weeks or more 
post-surgery. 
The following historical evidence will be considered as sufficient to establish the 
cause of endogenous CS as being due to Cushing’s Disease (CD) (i.e. ACTH-
dependent of pituitary origin) specifically: 
• Pathological (e.g. ACTH-staining) or post-surgical confirmation of the 
diagnosis of CD (i.e. documented adrenal insufficiency post-adenomectomy 
or post-hypophysectomy) OR 
• Intermediate, normal or elevated plasma ACTH (i.e. at least 5 pg/mL 
[1.1 pmol/L]) PLUS 
For tumors 6 mm and above by imaging: 
a. Inferior petrosal sinus sampled (IPSS) ACTH central:plasma gradient 
at least 2 before corticotropin-releasing hormone (CRH) or at least 3 
after CRH, OR in the absence of IPSS, either: 
b. Positive ACTH and/or cortisol response to CRH or desmopressin or 
combined CRH-desmopressin stimulation plus high-dose (8 mg) 
dexamethasone suppression of blood cortisol, ideally on more than one 
occasion OR 
c. Other adequate diagnostic testing.  Such cases must be discussed with 
and explicitly approved by the Medical Monitor, and the specific 
diagnostic criteria used to establish the diagnosis of CD must be 
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For tumors below 6 mm or not visible by Magnetic Resonance Imaging: 
a. IPSS with ACTH central:plasma gradient at least 2 before CRH or at 
least 3 after CRH. 
b. Other adequate diagnostic testing.  In the absence of IPSS, an 
individual might be eligible if CD was otherwise confirmed via 
adequate testing.  Such cases must be discussed with and explicitly 
approved by the Medical Monitor, and the specific diagnostic criteria 
used to establish the diagnosis of CD must be documented. 
4. Elevated mean 24-hour UFC levels at least 1.5X ULN of the normative range of 
the study’s central laboratory assay and from a minimum of three measurements 
from adequately collected urine; the study’s central laboratory must be used for 
all qualifying measurements. NOTE: This criterion does not apply to subjects 
currently on levoketoconazole. 
5. Presence of abnormal values from at least one of these two diagnostic tests: 
(discrepancies between test findings will not be investigated nor considered 
exclusionary) 
• Abnormal Dexamethasone Suppression Test (DST): Elevated 8 AM blood 
cortisol at least 1.8 µg/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 
PM the evening prior with concurrent dexamethasone blood concentration 
greater than 5.6 nmol/L (220 ng/dL) (results from within the 2 months prior to 
start of Screening or newly tested with results available by the Baseline Visit 
[TM0]). If the DST cortisol is elevated and the dexamethasone value is at least 
3.9 nmol/L (153 ng/dL), then the subject could qualify if at least 1 LNSC is 
greater than the ULN of the study’s central laboratory normative range (the 
study’s test kit and lab must be used for all qualifying measurements), 
whereas a non-suppressed cortisol during DST with a dexamethasone value of 
at least 5.6 nmol/L (220 ng/dL) would be required if LNSC is not done or if 
both LNSC values are low (≤ ULN of the study’s central laboratory normative 
range; the study’s test kit and lab must be used for all qualifying 
measurements). OR 
• Elevated LNSC concentrations (at least two measurements) each greater than 
the ULN of the study’s central laboratory normative range; the study’s test kit 
and lab must be used for all qualifying measurements. 
NOTE: Abnormal LNSC is required among eligible subjects with estimated 
glomerular filtration rate (eGFR as determined by Modified Diet in Renal Disease 
[MDRD] equation) above 40 and below 60 mL/min/1.73 m2. 
NOTE: This criterion does not apply to subjects currently on levoketoconazole. 
6. Non-candidates for CS-specific surgery, refuse surgery or surgery will be delayed 
until after study completion and agree to complete this study prior to surgery.  
7. If post-surgical for CS-specific surgery, then no significant post-operative 
sequelae remain and the risk of such sequelae is considered negligible. 


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8. Agree to the following minimum washout periods prior to the Baseline Visit 
(TM0) (as applicable): 
• Ketoconazole or metyrapone: 2 weeks;  
• Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks); 
• Octreotide acetate LAR, lanreotide Autogel®, pasireotide LAR: 12 weeks; 
• Lanreotide SR: 8 weeks; 
• Octreotide acetate (immediate release) or short-acting pasireotide: 1 week; 
• Mifepristone (RU 486, KORLYM®): 4 weeks; 
• Megestrol acetate or medroxyprogesterone acetate (and selected other 
synthetic progestins): 6 weeks. 
9. Females who are either of non-child bearing potential (i.e. incapable of becoming 
pregnant), defined as: 
• Post-menopausal—age 50 or older with amenorrhea for more than 1 year or 
any age with serum follicle stimulating hormone (FSH) at least 23 mIU/mL 
and estradiol no more than 40 pg/ml (140 pmol/L) OR  
• Surgically sterile—documented hysterectomy and/or bilateral oophorectomy 
or tubal ligation.  
OR 
• Females of child-bearing potential who agree to use highly effective methods 
of birth control while participating and for 2 weeks after participation has 
completed (abstinence is considered acceptable if routinely practiced). 
10. Men who, if fertile, agree to use an acceptable form of birth control, including 
abstinence if routinely practiced, while enrolled and for 2 weeks after 
participation has completed. 
11. Able to comprehend and comply with all procedures. 
 
5.3 Exclusion Criteria 
Subjects will be excluded from the study if ANY of the following criteria are met 
(NOTE: exclusion criteria apply to and must be assessd in both cohorts): 
1. Enrolled in SONICS but have not completed SONICS through Visit M12.  
2. Pseudo-Cushing’s syndrome based on assessment of the Investigator (for details 
see Appendix G).  
3. Cyclic Cushing’s syndrome with multi-week periods of apparent spontaneous CS 
remission. 
4. Non-endogenous source of hypercortisolism, including pharmacological 
corticosteroids or ACTH. 


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5. Radiotherapy of any modality directed against the source of hypercortisolism 
within the last 5 years. 
6. Treatment with mitotane within 6 months of enrollment. 
7. History of malignancy, including adrenal or pituitary carcinomas (other than low-
risk, well-differentiated carcinomas of thyroid, breast or prostate that are very 
unlikely to require further treatment in the opinion of the treating physician, or 
squamous cell or basal cell carcinoma of the skin). 
8. Clinical or radiological signs of compression of the optic chiasm. 
9. Major surgery within 1 month of Screening (or within 6 weeks for pituitary 
surgery). 
10. Clinically significant abnormality in 12-lead ECG during the Screening Phase 
requiring medical intervention (may be eligible once stable, to be determined case 
by case). 
11. QTc interval above 470 msec during the Screening Phase via central reader 
interpretation. 
12. History of Torsades des Pointes, ventricular tachycardia, ventricular fibrillation, 
history of prolonged QT syndrome (including first-degree family history). 
13. Use of medications associated with possible, probable, or definite QT/QTc 
prolongation (unless subsequently washed out). 
14. Pre-existing hepatic disease (except for mild to moderate non-alcoholic fatty liver 
disease documented by imaging or biopsy and with transaminase values within 
allowed limits). 
15. Hepatitis B surface antigen (HbsAg) or hepatitis C-positive. 
16. Human immunodeficiency virus (HIV)-positive. 
17. History of symptomatic cholelithiasis with intact gallbladder. 
18. History of pancreatitis. 
19. Liver safety tests during the Screening Phase as follows:  
• ALT and/or AST above 3X ULN 
• AP or Total bilirubin above 2X ULN. 
Subjects with isolated indirect bilirubin up to 3X ULN are presumed to have 
Gilbert’s syndrome and may be enrolled if all other liver safety tests are within 
normal levels. 
20. History of documented or suspected drug-induced liver injury to ketoconazole or 
any other azole drug. 
21. Serum potassium below 4.0 mEq/L (unless subsequently corrected and stable). 
22. Abnormal free thyroxine (FT4), unless subsequently corrected and stable for at 
least 4 weeks. Subjects with thyroid-stimulating hormone (TSH) less than the 


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lower limit of normal (LLN) and normal FT4 are potentially eligible without 
intervention. 
23. History of persistent, uncontrolled hypertension despite medical intervention. 
24. Hypercholesterolemia currently treated with atorvastatin, lovastatin or simvastatin 
and unwilling or unable to change to alternative therapy with: pravastatin, 
fluvastatin, pitavastatin or rosuvastatin (must switch statin at least 2 weeks prior 
to dosing) or another allowed therapy.  For subjects for whom lipid reduction 
therapy is being considered, all lipid lowering drugs should be added and 
stabilized for at least 4 weeks prior to TM0 for the levoketoconazole-naïve cohort 
or RW0 for the SONICS-completer cohort, as improvements in lipids are being 
assessed as an endpoint for levoketoconazole treatment in this study. 
25. More than one hospitalization for hyperglycemia or complication of diabetes 
during the last 12 months 
26. Decreased renal function as defined by eGFR below 40 mL/min/1.73 m2, using 
MDRD equation for eGFR. 
27. Pregnant or lactating. 
28. Body habitus preventing repeated venipuncture as required by protocol. 
29. Any other clinically significant medical condition, as determined by the 
Investigator that precludes enrollment and participation in the study through 
completion, including conditions that would preclude the subject from being able 
to follow instructions or perform necessary procedures (for example, psychiatric 
instability or severe disability).  
30. History of alcohol or drug abuse in the 6-month period prior to Screening. 
31. Currently participating in another study or has received any investigational 
treatment (drug, biological agent or device) other than levoketoconazole (COR-
003), within prior 30 days or five half-lives of treatment, whichever is longer. 
32. Current use of any H2-receptor antagonists, proton-pump inhibitors, or sucralfate 
(all inhibit absorption of levoketoconazole; subjects may be allowed to enroll 
after washout).  A list of acceptable oral antacids will be provided; if used, 
antacids must be ingested at least 2 hours after dosing of levoketoconazole. 
33. Current use of any prohibited concomitant medication that cannot be discontinued 
safely and washed out completely prior to the Baseline Visit (TM0 or RW0, for 
the levoketoconazole-naïve and SONICS-completer cohorts, respectively), 
including but not limited to the following (a more complete list is included in 
Appendix J): 
• Weight loss medications (prescription or over the counter); 
• Acetaminophen (paracetamol) above 2 g total daily dose; 
• Strong inducers or inhibitors of CYP3A4 enzyme system that may interfere 
with the metabolism of levoketoconazole and cannot be discontinued prior to 
first dose; 


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• Herbal preparations: St John’s Wort, echinacea, gingko, goldenseal, yohimbe, 
red rice yeast, danshen, silybum marianum, Asian ginseng, schissandra 
sphenanther, shankhapushi, and Asian herb mixture (Xiao chai hu tang and 
Salboku-to); 
• Topical or inhaled corticosteroids; 
• Carbamazepine, fenofibrate, carbenoxolone; 
• Drugs that pose unacceptable risk due to overlapping or exaggerated toxicities 
or pharmacological action due to presumed PK or pharmacodynamic 
interactions with levoketoconazole; 
• Genuine licorice. 
 
5.4 Withdrawal Criteria 
Subjects have the right to discontinue participation in the study at any time.  Reasons for 
withdrawal during the study may include but are not limited to the following: 
• Withdrawal of informed consent; 
• Safety reasons, as stipulated in Sections 5.4.1, 5.4.2, and 5.4.3 either at the 
discretion of the Investigator or at the subject’s request (see also 
Section 4.2.2.3.4); 
• Protocol violations at the discretion of the Sponsor; 
• Concomitant therapy that could interfere with the results of the study (the 
Investigator will report all such information on the CRFs and decide, in 
accordance with the Sponsor, whether the subject is to be withdrawn);  
• Failure to achieve the Therapeutic Dose during the TM Phase; 
• Closure of randomization while still in the TM Phase. 
All study withdrawals and their causes must be carefully documented by the Investigator 
on the CRF, and, if need be, on the AE page.  The reason for withdrawal will be entered 
in the CRF.  All data gathered prior to withdrawal will be made available to the Sponsor.  
All withdrawn subjects will be asked to report to the clinic to complete the assessments at 
the end of the relevant study phase at either Visit TM7 or RW5 or RES2, as appropriate 
(see Appendix A).  All AEs will be followed until resolution or at least 30 days after the 
last dose of study medication.   
Consult Section 11.2 for study additional withdrawal procedures. 
Consideration of study withdrawals due specifically to QTc interval prolongation or 
suspected or confirmed liver injury are described in Sections 5.4.1 and 5.4.2, 
respectively. 


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5.4.1 Withdrawal due QTc Interval Prolongation 
See Section 6.4.3.1 for guidance on the assessment of QTc interval prolongation, 
including gathering evidence of persistence and confirmation of causal relationship to 
study medication.  
Persistent, Confirmed as Related QTc Prolongation During Titration and Maintenance 
Phase 
If persistent and confirmed levoketoconazole-related QTc interval prolongation greater 
than 500 msec or increase from Baseline (TM0) more than 60 msec is identified, an 
attempt may be made to manage it by temporarily holding the dose or dose reduction, as 
described in Section 6.4.3.1.  However, if such prolongation is observed at the lowest 
levoketoconazole dose (150 mg/day), administration of the study drug must cease 
permanently and the subject must be withdrawn.  In all cases, a PK sample should be 
collected as close to the time of the event as possible. 
Persistent, Confirmed QTc Prolongation During Randomized Withdrawal Phase or 
Restoration Phase 
QTc prolongation is unexpected during these phases owing to prior establishment of the 
Therapeutic Dose.  However, in the event of a persistent confirmed as related, QTc 
prolongation greater than 500 msec or increase from Baseline (RW0) more than 60 msec 
is identified, blinded study medication should be temporarily held, electrolytes and other 
correctable confounding factors addressed, and QTc re-checked within 2 to 4 days.  
Consideration should also be given to cardiology referral if the prolongation is considered 
clinically urgent. 
If QTc interval prolongation does not respond to temporary blinded study medication 
stoppage or recurs after restarting study medication, the subject should stop study 
medication permanently and withdraw from the study.  If the QTc interval returns to a 
normal value and remains normal, the subject may continue in the study per the usual 
visit schedule, with interim QTc interval checks added for monitoring purposes. 
5.4.2 Withdrawal due to Suspected or Confirmed Drug-induced Liver 
Injury 
Although newly recognized liver abnormalities will be less likely for subjects who have 
completed the SONICS study than for levoketoconazole-naïve subjects, both cohorts will 
be monitored in the same way for liver abnormalities during the Randomized Withdrawal 
Phase and the Restoration Phase.  Study withdrawal due to abnormal liver-safety tests 
will likewise be prompted using the same criteria and evaluation procedures, as described 
below.  See Section 4.2.2.3 for details describing management of suspected liver injury 
other than study withdrawal. 
Recommendations from the FDA Guidance on Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation (May 2009) have been adopted for use in this study to monitor for 
evidence of early liver injury.  Per the FDA guidance, discontinuation of investigational 
therapy should be considered in the case of: 
• ALT or AST above 8X ULN 


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• ALT or AST rises to above 5X ULN in less than 4 weeks or persists for over 
2 weeks 
• ALT or AST above 3X ULN and total bilirubin above 2X ULN or 
International Normalized Ratio (INR) above 1.5 not explained by any other 
cause such as viral hepatitis  
• ALT or AST above 3X ULN with new onset of or worsening of fatigue, 
nausea, vomiting, fever, rash or eosinophilia, in the absence of other evident 
cause 
• Signs and /or symptoms suggestive of hepatic dysfunction (any of the 
following: nausea, anorexia, fever, fatigue, right upper quadrant discomfort, 
pruritus, dark urine or acholic stool) coupled with ALT and/or AST above 
3X ULN and/or AP above 2X ULN, and/or total bilirubin above 2X ULN in 
the absence of evidence for obstruction or Gilbert syndrome.  NOTE: An 
ultrasound evaluation of the gallbladder and bile duct should be conducted to 
exclude cholestasis as the cause for elevated AP and/or total bilirubin. 
• Not included in FDA guidance but additionally specified for this study as a 
finding that should prompt evaluation and possible action:  Subjects with ALT 
or AST above 3X ULN or AP above 2X ULN (in the absence of evidence for 
cholestasis) or total bilirubin above 2X ULN (in the absence of evidence for 
cholestasis and except for subjects enrolled with presumed Gilbert’s 
syndrome) 
Guidelines for dose interruption, follow-up and rechallenge with study medication in 
cases meeting the above criteria are found in Section 4.2.2.3. 
Upon reporting liver-safety lab test observations as AESIs, the Sponsor will provide 
Investigators with suggested evaluation procedures to determine the etiology of the 
abnormalities as outlined in Appendix O.  While liver safety tests may be assayed at a 
local laboratory for immediate medical intervention, simultaneous samples must be sent 
to the central laboratory to ensure consistency of assay and interpretation.  In all cases, a 
PK sample should be collected as close to the time of the event as possible. 
Withdrawal from Study 
Prior to considering study withdrawal, but after interrupting use of study medication, 
subjects meeting the above criteria at any visit should be evaluated with serial (repeated) 
liver safety test and INR evaluations and potentially additional diagnostic evaluative 
testing to establish an etiology of the abnormalities so that the etiology might be 
determined definitively while the subject remains available for evaluation.   
If liver safety test abnormalities persist for more than 4 weeks following interruption of 
study medication or demonstrate a trend of worsening following interruption, then the 
subject should remain off study medication permanently and be withdrawn from the 
study.  The subject will continue to be followed post-withdrawal until resolution or near-
normalization of the laboratory abnormality that resulted in the premature study 
withdrawal.  The withdrawn subject will not be eligible to enroll in either the OPTICS 
study or the EAP program. 


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5.4.3 Withdrawal due to Adrenal Insufficiency 
Guidelines for dose interruption, follow-up and rechallenge with study medication in 
cases meeting the above criteria are found in Section 4.2.2.3. 
If adrenal insufficiency is suspected and the subject is taking the lowest levoketoconazole 
dose of 150 mg/day, the subject might be exhibiting exquisite sensitivity to the cortisol-
lowering effects of levoketoconazole.  In such cases, the subject should be informed of 
the heightened risk of future occurrences of adrenal insufficiency before resuming study 
medication, with consideration given to permanent drug discontinuation. In all cases, a 
PK sample should be collected as close to the time of the event as possible. 
6 
STUDY ASSESSMENTS AND PROCEDURES 
There are two cohorts of subjects potentially eligible (SONICS-completer and 
levoketoconazole-naïve); study methodology varies by cohort only prior to 
randomization as outlined in Section 6.1 (SONICS-completer cohort) and Section 6.2 
(levoketoconazole-naïve cohort).   
The Baseline visit for purposes of the primary efficacy endpoint for both cohorts is the 
first visit in the Double-blind Randomized Withdrawal Phase (RW0).  RW0 may 
coincide temporally with Visit M12 (in SONICS), or RW0 may occur after this visit, 
depending on the specific circumstances of the subject.   
For purposes of comparing findings from post-Baseline safety assessments to Baseline 
findings, TM0 should be used as the Baseline if the change or finding occurs during the 
TM Phase; otherwise RW0 will serve as the Baseline.  For purposes of comparing the 
QTc interval to Baseline for determining if an AESI is has occurred the shorter QTc 
interval from the two baselines (TM0 and RW0) will serve as the QTc Baseline.  Refer to 
Section 13.2.2 for information regarding the assessment of QTc prolongation for 
determining AESIs. 
All subjects must meet eligibility criteria prior to randomization.  A screen failure occurs 
when a signed informed consent has been obtained, but the subject fails to meet some or 
all eligibility criteria at the Baseline visit (Visit RW0 for the SONICS-completer cohort 
or, Visit TM0 for the levoketoconazole-naïve cohort.   
The exact timings of each assessment are provided in the Time and Events Schedules 
(Appendix A).  Detailed procedures are provided in the SPM.  The study is being 
conducted as described in Appendix C and reported in accordance with the guidelines 
presented in Appendix D and Appendix E.  Any changes to the study design are managed 
in accordance with Appendix F. 
In addition to the protocol-specified procedures, at any time during the study 
appropriate medical evaluations and safety interventions should be implemented, as 
necessary, based on the clinical presentation of the subject per local standard of 
care.  Changes to a subject’s medical condition or concomitant therapies resulting from 
such interventions, must be documented in the CRF as an unscheduled visit. 


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6.1 SONICS-completer Cohort 
For the SONICS-completer cohort, the study will consist of the following Phases with 
approximate timings: 
• A Screening Phase (of approximately 2 weeks’ duration) 
• Double-blind Randomized Withdrawal Phase (approximately 8 weeks’ total 
duration, maximum 9½ weeks) 
• Double-blind Restoration Phase (approximately 8 weeks’ total duration, 
maximum 9½ weeks) 
After signing the informed consent, subjects will attend the Screening/Baseline visit to 
check eligibility and, if eligible, proceed to be randomized and complete Baseline 
procedures as detailed in the Time and Events Schedules (Appendix A).  Visit RW0 may 
occur concurrently with SONICS Visit M12 or afterward, depending on the time when 
the subject exited SONICS and the availability of UFC data to confirm that UFC 
response has been maintained.  Data from the SONICS study and assessments that 
overlap may be utilized for this study for purposes of determining eligibility and 
establishing Baseline values (e.g. data from vital signs may be recorded in the eCRF for 
both studies. 
NOTE: The duration between exiting SONICS and enrolling in the current study may in 
unusual cases be more than 6 months.  In such cases, subjects must undergo the same 
Screening procedures as levoketoconazole-naïve cohort to confirm eligibility.  However, 
such subjects will NOT have to dose-titrate if they have been receiving levoketoconazole 
therapy at their stable Therapeutic Dose throughout the 12 weeks immediately prior to 
Screening. 
6.2 Levoketoconazole-naïve Cohort 
For the levoketoconazole-naïve cohort, the study will consist of the following Phases 
with approximate timings: 
• Screening Phase (approximately 13 weeks’ duration to allow for prior medication 
washout; there is no required minimum Screening interval). 
• Dose Titration and Maintenance Phase (not less than 14 weeks in total and for no 
more than approximately up to 19 weeks’ total duration). In exceptional 
situations, subjects may require additional time (i.e. greater than 19 weeks) to 
achieve the Therapeutic Dose.  These situations must be approved on a case by 
case basis by the Medical Monitor.  
• Double-blind Randomized Withdrawal Phase (approximately 8 weeks’ total 
duration, maximum 9½ weeks). 
• Double-blind Restoration Phase (approximately 8 weeks’ total duration, 
maximum 9½ weeks). 
After signing written informed consent, subjects will enter the Screening Phase.  After 
performing the initial Screening assessments, subjects on previous CS therapies or other 
prohibited therapies must enter a washout period, as applicable (see Section 4.2.2) before 


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completing all Screening assessments detailed in the Time and Events Schedules 
(Appendix A).   
Baseline evaluations for the TM Phase will be obtained as part of the Screening 
assessments and should be conducted AFTER completion of all initial Screening 
procedures and after subjects have undergone a sufficient washout period from previous 
CS therapies (see Section 5.2), if applicable.  Collections of LNSC and UFC obtained 
during Screening will provide the Baseline measurements if collected within 14 days of 
receiving first dose of levoketoconazole.  NOTE: all Baseline UFC and LNSC values 
must be obtained after washout of any medications (except levoketoconazole) that are 
known to influence cortisol. LNSC results that are unavailable from Screening within 2 
weeks of dosing should be re-collected prior to dosing at TM0.  Results from the Baseline 
assessments are necessary to determine if the subject remains eligible for participation in 
the TM Phase of the study.  
Visit TM0 is the Baseline visit for the TM Phase of the study for purposes of establishing 
QTc interval and safety laboratory Baseline values, as well as certain secondary efficacy 
endpoint values.  TM0 is not the Baseline for purposes of the primary efficacy endpoint.  
RW0 is the Baseline for purposes of the primary endpoint. 
At the end of the TM Phase, subjects will attend the randomization Baseline visit (RW0) 
to check eligibility and, if eligible, proceed to be randomized and complete Baseline 
procedures as detailed in the Time and Events Schedules (Appendix A).  Visit RW0 may 
occur concurrently with TM7 or no more than 11 (+3) days later unless a dose change is 
required at TM7.   
6.3 Demographic/Medical History Assessments 
NOTE: Subjects who have recently completed the SONICS study (within 6 months of 
Screening) will undergo demographic and medical history assessments to confirm 
eligibility. Historical information from all SONICS visits will be used for this purpose 
and captured in the current study database, including ECG, imaging and laboratory data. 
While subjects who have distantly completed the SONICS study (i.e. more than 6 months 
since completing Visit M12) will also have historical SONICS data available for use and 
import into the current study database, they must also have a complete Screening 
assessment with updated testing, the same as the levoketoconazole-naïve cohort.   
The following demographic characteristics will be captured at Screening:   
• Date of birth; 
• Gender; 
• Race and ethnicity. 
Medical and medication history will be assessed and collected as related to the Eligibility 
Criteria in Section 5), and will include but not be limited to the following: 
• Documentation of diagnosis of CS, including but not limited to evaluations for CS 
during the previous 6 months. 
• Documentation of current CS co-morbidities. 


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• Documentation of prior management of CS during the previous 6 months, 
including medications, diagnostic tests (including imaging), surgical or radiation 
therapies. 
• Documentation of clinical laboratory data from the previous 3 months, if 
available; specifically: liver safety tests (ALT, AST, AP, LDH, direct and total 
bilirubin), HbA1c, fasting serum glucose and glucose following an oral glucose 
tolerance test (OGTT), serum lipid panel (LDL-C, HDL-C, total cholesterol, 
triglycerides), hsCRP, urinary albumin/creatinine ratio, and testosterone 
concentration. 
• Documentation of blood pressure data for the previous 3 months, if available. 
• Medication history during the previous 3 months, asking specifically about blood 
pressure, anti-diabetic, cholesterol lowering and anti-inflammatory drugs. 
• Drug and alcohol use. 
6.4 Safety and Efficacy Assessments 
6.4.1 Physical Examination and Assessment of Clinical Signs and Symptoms 
of CS 
Full physical examinations will be performed by a study physician at the times indicated 
in the Time and Events Schedules (Appendix A).  The physical examinations will be 
inclusive of all body systems, except that genitourinary and rectal examinations may be 
waived at the discretion of the Investigator, and should include height (cm) and weight 
(kg).  Abdominal girth (cm) will be measured in triplicate and body habitus will be 
assessed at the times indicated in the Time and Events Schedule and as described in the 
SPM.  Body mass index (BMI) will be calculated based on data entered in the CRF 
during that visit.   
The examining physician or a qualified HHC professional with training will be asked to 
complete a questionnaire related to the assessment of Clinical Signs and Symptoms of CS 
(see Appendix M).  The person completing the Signs and Symptoms of Cushing’s 
assessments should, when possible, remain consistent for individual subjects.  The results 
will be used to quantify changes in Clinical Signs and Symptoms of CS. In cases of 
clinically significant deterioration of clinical signs and symptoms of CS, HHC 
professionals should refer the subject back to the physician for corroboration prior to 
initiation of early rescue therapy.  
6.4.2 Vital Signs 
Vital sign measurements will include temperature, sitting systolic blood pressure (SBP), 
sitting diastolic blood pressure (DBP) and heart rate (HR) at Baseline and at each visit 
throughout the study (see Time and Events Schedules in Appendix A).   
For proper measurement of blood pressure, the following procedures should be followed: 
• An appropriately sized cuff for the size of the subject’s arm circumference should 
be used to minimize inaccurate readings.  


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• Subjects should not smoke or exercise for at least 30 minutes before blood 
pressure measurements. 
• Subjects should sit in a chair with a back support and the arm supported at heart 
level with feet flat on the floor.  
• Subjects should void prior to the measurement. 
• Blood pressure measurements will be made in triplicate, at least 3 minutes apart, 
over approximately 10 minutes, after the subject has rested in a sitting position for 
at least 10 minutes.   
 
Heart rate will also be recorded in triplicate, also approximately 3 minutes between each 
assessment.  The three measurements for heart rate and blood pressure will each be 
recorded individually in the CRF and a mean value for heart rate and blood pressure for 
that visit calculated. 
Vital sign measurements must be repeated if reported as clinically significant or if 
machine/equipment errors occur.  Not clinically significant, out-of-range blood pressure 
or HR measurements may be repeated at the Investigator’s discretion.  Any confirmed, 
clinically significant adverse change from Baseline in vital signs must be recorded as an 
AE. 
Guidelines for classification of blood pressure readings and recommendations for follow-
up of abnormal values are provided in Appendix I. 
6.4.3 12-Lead Electrocardiograms (ECG) 
Male patients with CS have been reported to have prolongation of the QT interval 
[Giraldi 2011].  Thus, inclusion criteria have allowed for this possibility; both males and 
females with mild QTc prolongation will be allowed into the study if Baseline QTc is not 
greater than 470 msec.  The potential risk of protracted prolongation of the QTc interval 
is the development of an arrhythmia called Torsade de Pointes.  The development of 
Torsade de Pointes in the face of QTc interval prolongation is rare, and appears to occur 
primarily when the QTc interval is particularly prolonged and generally longer than 
500 msec or more than 60 msec above Baseline.  
Therefore, subjects with prolonged QTc intervals above 500 msec or above 60 msec 
increase over the QTc interval at the Screening or Baseline visit must not receive study 
medication until the QTc has returned to a value no more than 500 msec or no more 
than 60 msec change from Baseline.  For purposes of comparing the QTc interval to 
Baseline, TM0 should be used as the Baseline value if the QTc prolongation occurs 
during the TM Phase; otherwise RW0 will serve as the QTc Baseline.  If the QTc does 
not shorten sufficiently and stably, the subject will be ineligible for dosing.  Note that 
QTc interval is highly variable during the day, and food intake can transiently shorten 
QTc interval.  Nausea, vomiting, upset stomach, dizziness and electrolyte abnormalities 
(including hypokalemia/hypomagnesemia) can also cause prolongation in the QTc 
interval.  Such factors should be considered and avoided during QTc measurements.  
Many drugs can prolong the QTc interval directly or indirectly through interference with 
the metabolism of QT-prolonging drugs.  Levoketoconazole appears to have the potential 
to prolong QTc both directly and indirectly. 


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In this study, ECG monitoring is being performed at the designated times (see Time and 
Events Schedules in Appendix A), using a Spaulding ECG device that acquires a 12-lead 
ECG continuously over a pre-programmed period (minimum time of 1 minute to 
maximum time of 5 minutes).  A summary of the ECG assessment will be generated by a 
cardiologist employed by Spaulding, with the results serving as the definitive 
measurement of QTc.  Additionally, the Spaulding device will provide a real-time 
automated analysis (using the University of Glasgow diagnostic 12-lead algorithm, 
Macfarlane 2005) of the ECG that can serve as an unconfirmed measurement of QTc 
interval for purposes of safety monitoring. 
NOTE: The Spaulding ECG device should be used for all assessments during the study 
unless it is non-operational, in which case another ECG may be performed locally and 
transmitted to Spaulding for central reading via printout. 
The following procedures will apply to all ECG recordings: 
• ECGs will be obtained within approximately 1 to 2 hours after drug 
administration (i.e., at approximately Tmax of levoketoconazole) 
• No food should be consumed for a total of at least 2 hours prior to ECG 
acquisition, unless necessary to avoid hypoglycemia or to relieve nausea.  Food 
intake must be recorded in the CRF.   
• ECGs will be obtained after the subject has rested in a supine position for at least 
5 minutes. 
6.4.3.1 Procedures for Evaluating and Managing Prolonged QTc Interval 
Greater than 500 Msec or More than 60 Msec Above Baseline 
If at any time during the study, the Spaulding automated ECG reading indicates a QTc 
interval greater than 60 msec above Baseline or an absolute QTc interval more than 
500 msec: 
• The other ECG findings and the subject’s clinical condition must be considered to 
determine the plan of action.  QTc prolongation that is accompanied by Torsades 
de Pointes, polymorphic ventricular tachycardia, or ECG abnormalities 
accompanied by clinical signs/symptoms of serious arrhythmia might require 
urgent intervention and inpatient monitoring; immediate cardiology consultation 
is recommended.   
• With one abnormal ECG reading, the subject should first be questioned about: 
o Recent ingestion of food within the preceding 2 hours. If the subject has eaten, 
a repeat ECG evaluation should be conducted following a proper 2-hour fast 
and rest.  
o The use of any other medications that may have increased QTc interval, either 
directly (via direct effect on the QTc interval) or indirectly because of a drug 
interaction that may have increased the concentrations of study medication 
(see Appendix J).  If such a drug is identified, it should be stopped 
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o Symptoms of nausea or vomiting just prior to the ECG assessment, or 
lightheadedness or similar symptoms that may influence the QTc interval.  In 
such cases, an ECG evaluation should be repeated once the subject's 
symptoms have abated.  Study medication may have to be withheld if the 
symptoms are protracted and the QTc interval prolongation remains evident. 
The Investigator should ensure that the symptoms as well as the ECG results 
are not due to a cardiovascular event, such as a myocardial infarction. 
• If the subject has not eaten, has no confounding medical symptoms/events, does 
not have a concomitant medication that may be increasing the QTc interval, and 
there are no other significant abnormalities on the ECG warranting immediate 
medical intervention then: 
o A repeat ECG evaluation should be undertaken within approximately 
30 minutes of the observed ECG prolongation or as soon as it is practical.  
• If the repeat ECG evaluation continues to demonstrate a QTc interval more than 
60 msec above Baseline or an absolute value more than 500 msec, blood samples 
should be obtained from the subject for evaluation of electrolyte abnormalities, 
including potassium, magnesium and calcium concentrations and for PK 
(levoketoconazole concentration) evaluation. 
o If electrolyte abnormalities are subsequently identified, these should be 
corrected before re-evaluation of the ECG.  Study medication may be 
temporarily withheld until electrolytes can be normalized.  It is recommended 
to keep serum potassium concentration in the high-normal range. 
o If electrolytes are normal and no other cause can be identified to account for 
the absolute QTc interval above 500 msec (or above 60 msec above Baseline), 
and the ECG evaluation on repeat determination demonstrates persistent QTc 
prolongation, a causal relationship to study medication should be assumed and 
study medication should be withheld.  If the ECG is otherwise benign, the 
ECG should be monitored approximately once per week until resolution of the 
QTc prolongation or until another etiology is identified if the QTc 
prolongation does not correct.  
• In all cases, abnormal morphology of the ECG (especially T wave changes), if 
present, must be recorded in the CRF.  
• Whenever persistent and confirmed QTc prolongation is observed (defined 
below), an additional PK sample should be collected as close to the time of the 
event as possible. 
Persistent, confirmed QTc prolongation  
Persistent and confirmation of QTc prolongation is defined as follows: 
• Persistence:  An ECG repeated (ideally) within 30 minutes of the first ECG that also 
reveals QTc prolongation. 
• Confirmation:  The Investigator should consider alternative possibilities as causative 
or contributory to the QTc prolongation as described above.  Once alternative 


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possibilities are ruled out and persistence is documented by automated interpretation, 
QTc prolongation may be considered as preliminarily confirmed for safety reporting 
and immediate-intervention purposes.  Final confirmation of QTc prolongation, 
however, will be based on the Spaulding cardiologist over-read of the integrated 
ECG.  Final confirmation data will be used to summarize QTc findings. 
Regardless of seriousness or causality, instances of persistent, preliminarily or 
definitively confirmed QTc prolongation should be reported to the Sponsor’s designated 
Pharmacovigilance group as an AESI within 24 hours from the time the persistence has 
been preliminarily confirmed, similar to the reporting for SAEs (see Section 13.7). 
6.4.3.1.1 Temporarily Stopping Study Medication for Prolonged QTc and 
Considerations for Restarting 
If the subject is on the lowest possible dose of study medication (150 mg/day) in the TM 
Phase and has persistent and presumed study medication-related QTc interval 
prolongation of more than 500 msec or a change from Baseline longer than 60 msec, 
administration of the study drug will cease permanently and the subject will be 
withdrawn.  See also Section 5.4.1 for withdrawal criteria for persistent, confirmed QTc 
prolongation. 
During any other phase of the study, or if the subject is receiving doses greater than 
150 mg/day in the TM Phase, persistent and presumed study medication-related QTc 
changes may be managed by temporarily withholding study medication.  Subsequently, if 
a confounding etiology is eventually identified, study medication may be restarted.   
During the TM Phase, withheld study medication may be resumed at the same or lower 
dose after resolution of QTc prolongation is confirmed by two ECG readings and with 
prior approval by the Medical Monitor.  After restart of study medication, ECG 
evaluation should occur within 1 to 2 hours of dosing, and future ECG monitoring should 
be continued per the visit schedule for increased safety monitoring. 
In all other study phases, temporarily withheld study medication for QTc prolongation 
may, in some cases, be resumed, using the same regimen, after confirmed QTc 
correction.  However, unless an etiology other than study drug has been implicated, QTc 
prolongation will usually result in permanent study medication discontinuation and study 
withdrawal (see Sections 5.4.1 and 6.4.3.1). 
Additional information for evaluating and managing prolonged QTc Interval is available 
in Appendix O.  
6.4.4 Clinical Laboratory Tests 
Samples for clinical laboratory testing will be collected at the times indicated in the Time 
and Events Schedules (Appendix A).  A complete list of all the analytes is provided in 
Appendix B.  In addition to routine chemistry, hematology and urinalysis, laboratory 
analytes will include: serum cortisol, ACTH, TSH, FT4, prolactin, free and total 
testosterone, coagulation measures (prothrombin time [PT], partial thromboplastin time 
[PTT], INR), triglycerides, lipid panel (total cholesterol, LDL-C, HDL-C, LDL-c:HDL-C 
ratio), fasting insulin for calculation of HOMA-IR, HbA1c, hsCRP, and spot urine for 


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albumin/creatinine ratio to determine microalbuminuria.  Also, in women only: FSH 
estradiol, and urine pregnancy test. Screening safety laboratory tests will also include the 
following:  HIV and antibodies against hepatitis B and C. All scheduled testing will be 
conducted in the fasted state and in the morning unless stated differently in the Time and 
Events Schedules (Appendix A).   
Liver safety monitoring including AST, ALT, total bilirubin, LDH, GGT and AP, will be 
performed throughout the study.  In addition, liver safety tests should be measured 
immediately if a subject develops signs and symptoms suggestive of hepatic dysfunction 
(any of the following: nausea, anorexia, fever, fatigue, right upper quadrant discomfort, 
pruritus, dark urine or acholic stool).  Nausea, anorexia, and fatigue are non-specific 
symptoms and may be caused by hypocortisolemia; however, medical evaluation of 
such symptoms must also include assessment of liver safety tests.   
6.4.4.1 Prevention of Pregnancy 
Regardless of menopausal status, all female participants must have a negative pregnancy 
test at study visits indicated in the Time and Events Schedules (Appendix A).  Urine beta 
human chorionic gonadotropin (βhCG) will be assayed on site; results of the test must be 
available before dosing can begin (levoketoconazole-naïve cohort) or before 
randomization (SONICS-completer cohort). 
Post-menopausal is defined as age greater than 50 with amenorrhea for at least 12 
consecutive months, accompanied by elevated FSH (at least 23 mIU/mL) and low 
estradiol (no more than 40 pg/mL [140 pmol/L]) during the Screening Phase 
(Appendix B).   
Women of child-bearing potential must agree to use an effective form of contraception 
for up to 2 weeks after study completion.  Acceptable methods include the following: 
• Male partner is sterile prior to female subject entry into the study, and 
this male partner is the sole partner for that subject; or  
• Implant of levonorgestrel inserted for at least 1 month prior to study 
medication administration but not beyond the third successive year 
following insertion (must be replaced); or  
• Oral contraceptive (combined or progestogen only) administered for at 
least one monthly cycle prior to study medication administration and 
throughout the study; or  
• Double barrier method: condom or occlusive cap (diaphragm or 
cervical/vault caps) plus spermicidal agent 
(foam/gel/film/cream/suppository); or  
• An intrauterine device (IUD); or  
• Estrogenic vaginal ring; or Percutaneous contraceptive patches; or  
• If medical contraceptives and barrier methods are not feasible for medical 
or religious reasons, an assurance of abstinence will be deemed an 
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Fertile men must agree to use a double-barrier method of contraception (condom plus 
spermicide or diaphragm plus spermicide) or abstinence, if routinely practiced, while 
participating in the study and for 2 weeks after the last dose of study drug OR, the male 
subject or his female partner must be surgically sterile (e.g. vasectomy, tubal ligation) or 
the female partner must be post-menopausal. 
Reports of pregnancies in female subjects (or in female partners of male subjects) will be 
collected after the start of dosing and until the final study visit.  Female subjects found to 
be pregnant will be withdrawn from the study.  
6.4.4.2 Action to be Taken if Pregnancy Occurs 
The Investigator will collect pregnancy information on any female subject or a male 
subject’s partner who becomes pregnant while participating in this study.  The 
Investigator will record pregnancy information on the appropriate form and submit it to 
the Sponsor within 24 hours of learning of the pregnancy.  The subject will also be 
followed to determine the outcome of the pregnancy.  Generally, follow-up will be no 
longer than 6 to 8 weeks following the estimated delivery date.  Premature termination of 
the pregnancy will be reported. 
All pregnancies will be reported by the Investigator and documented per the same 
procedures as SAE.  While pregnancy will not be considered an SAE, any pregnancy 
complication or elective termination of pregnancy for medical reasons will be recorded as 
an AE or SAE, as indicated. 
Spontaneous abortion is always considered an SAE and must be reported as such.  
Furthermore, any SAE accompanying and related to a post-study pregnancy, which is 
considered reasonably related to the investigational product by the Investigator, will be 
reported to the Sponsor.  However, Investigators are not obligated to seek such 
information proactively from former study participants. 
6.4.5 Disease-Related Assessments 
6.4.5.1 24-Hour Urinary Collections for Free Cortisol (UFC) 
24-hour urine collections for determination of UFC are critical to drawing reliable 
inferences from this study.  Subjects should be fully informed prior to initiating 
procedures that they will be asked to collect 24-hour urine samples frequently 
throughout the study, including during work days and possibly holidays. 
Please see the SPM for details on urine collection procedures. Note that, in addition to 
following the lifestyle and dietary restrictions listed in Section 7, subjects should be 
instructed to avoid consuming more than 4 L/day of liquids on the day of urine 
collections. 
Urine will be collected in the containers provided.  Subjects will be asked to provide 
either two or three adequate 24-hour urine collections, collected over sequential days per 
the times indicated in the Time and Events Schedules (Appendix A) prior to the actual 
scheduled visit during the TM phase, as results are needed to determine if dose escalation 
is required, or whether a confirmatory UFC is needed to establish Therapeutic Dose.  If 
subjects immediately roll-over at SONICS M12, the two UFC samples collected for that 


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visit can be used (if within 6 weeks of the baseline visit) and one additional confirmatory 
sample will need to be collected for LOGICS screening (after the informed consent form 
for LOGICS has been signed).  The total volume of urine and urine creatinine excretion 
rates will be measured from the 24-hour collections as markers of collection adequacy, as 
detailed below in this section. Collections judged to be inadequate may be repeated at the 
discretion of the Investigator and/or the Sponsor; the rationale for repeat collections 
should be captured in the CRFs.   
Important: Subjects must continue to be seen in clinic no less than approximately once 
every 2 weeks during the TM Phase and no less than approximately once every 4 weeks 
during Randomized-Withdrawal, even if the need for repeated 24-hour urine collections 
delays progress to a subsequent study phase.  The time spent repeating inadequately 
collected 24-hour urine specimens must be actively managed by the Investigator to 
minimize delays in progressing a subject through the study as per the Time and Events 
Schedules (Appendix A).   
For the levoketoconazole-naïve cohort, 24-hour urine collections for assay of UFC are 
required at Screening and throughout the TM Phase as follows: 
• At Screening and the last visit in the TM Phase (TM7) if applicable, subjects will 
be asked to provide a total of three adequate 24-hour urine collections.   
• During the TM Phase, after progressing to a new dose level, subjects will be 
asked to provide two 24-hour urine specimens to assess the need for further dose 
titration. The first 24-hour urine collection will be on Day 8 (±2 days), relative to 
starting the dose level (i.e. Day 1), and the second collection will be on Day 9 
(±2 days).  Subjects will be asked to transport or, preferably, ship via the provided 
courier service, their urine collections to the clinic, as soon as possible after 
collection ends (ideally on or before Day 10).  Urine volume will be measured at 
the clinic (or by HHC professional) prior to shipping to the central laboratory.  
Aliquots of collected samples will be shipped frozen to the designated central 
laboratory for measurement of UFC as soon as possible after receipt to allow 
rapid turnaround of results to facilitate decision-making. 
 
Section 4.2.2.2.1 includes additional details of the dose titration process and 
determination of the Therapeutic Dose.  As part of this process, an additional 
adequate 24-hour urine collection will be obtained to confirm if a Therapeutic 
Dose has been reached.  As described above three adequate 24-hour urine 
collections will also be obtained routinely just prior to the last visit in the TM 
Phase (TM7).   
For all subjects who enter the Double-blind Randomized Withdrawal Phase and 
Restoration Phase, either 2 or 3 24-hour urine collections are required, depending on the 
visit, as described in Table 9.  For the urine collection between RW5 and RES1, subjects 
should have received the previously achieved Therapeutic Dose of blinded study 
medication for at least 1 week before collections commence and complete and at least 
1 week before the RES1 visit.  For urine collections between RES1 and RES2, urine 
collection should commence at approximately Day 18 of the Restoration Phase. 


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Urine collections will begin after the first morning void (collection Day 1) and will be 
collected over 24 hours until the next morning, including the first void on the morning of 
collection Day 2.  Careful instructions must be provided to the subject on the process 
for proper urine collection and cold-storage of samples over 24 hours.  All supplies 
needed for proper collection and storage of urine will be provided by the Sponsor or 
its laboratory vendor to Investigators for distribution to subjects. 
Determining urine collection adequacy 
The total volume of urine and urine creatinine excretion rate will be measured from 
24-hour collections as markers of the adequacy of collection.   
Total urine volume should be between 400 and 4000 mL/day.  
Expected values for normal 24-hour creatinine excretion rates up to age 70 years are 
provided in Table 4. 
Table 4 
Expected Normal 24-Hour Creatinine Excretion from Adequate Urine 
Collections 
Males 
1. Age 18 to 50:  18.5 mg/kg/day 
2. Age 51 to 70:  15.7 mg/kg/day 
 
Females 
1. Age 18 to 50:  16.5 mg/kg/day 
2. Age 51 to 70:  11. 8 mg/kg/day 
 
In subjects over 70 years of age, creatinine excretion rates should 
be discussed on a case by case basis with the Medical Monitor. 
 
Note that the above ranges were derived from populations of generally healthy 
individuals without kidney dysfunction. Due to the muscle wasting observed in CS and 
dependent on the length of the disease, subjects may have 24-hour urine creatinine 
excretion rates below the lower end of the ranges reported in Table 4 [Petersenn 2013].  
Therefore, creatinine excretion values that are somewhat below the normative value will 
be considered indicative of adequate collection when urine volume is adequate. The 
Medical Monitor will provide guidance as to the adequacy of urine collection.  
Urinary Sample Analysis 
UFC levels from the 24-hour urine collection will be assayed at a central laboratory as 
per validated methodology using high pressure liquid chromatography tandem mass 
spectroscopy (HPLC/MS/MS).   
6.4.5.2 Collection of Late-Night Salivary Samples for Free Cortisol (LNSC) 
Late night salivary samples will be collected by each subject at the times indicated in the 
Time and Events Schedules (Appendix A) for LNSC determination prior to the actual 
scheduled visit.  If subjects immediately roll-over at SONICS M12, one LNSC sample 
collected for that visit can be used (if within 2 weeks of baseline visit) and one additional 
confirmatory sample will need to be collected for LOGICS screening (after the informed 
consent form for LOGICS has been signed). Saliva collections must be done between 


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11 PM and midnight and following the lifestyle and dietary restrictions listed in 
Section 7.  Subjects should not sleep and subsequently awaken within 2 hours before 
collecting the saliva sample.   
For the levoketoconazole-naïve cohort, late night samples from 2 nights are required at 
Screening and throughout the TM Phase as follows: 
• Late night samples from 2 nights, will be collected at Screening within 2 weeks of 
Visit TM0 and at the end of the TM Phase (Visit TM7).  LNSC that is unavailable 
from Screening within 14 days of scheduled dosing at Visit TM0 should be 
recollected prior to dosing at TM0 (Appendix A). 
For all subjects who enter the Double-blind Randomized Withdrawal Phase and 
Restoration Phase, late night salivary samples from 2 nights are required as follows: 
• Late night samples from two nights, will be collected at the beginning (Baseline; 
Visit RW0), at the end (Visit RW5) of the Randomized Withdrawal Phase, and at 
the end of the Restoration Phase (RES2).  
Late-night salivary samples from a single night’s collection will be collected at the times 
indicated in the Time and Events Schedules (Appendix A). All samples will be analyzed 
at a central laboratory.  Details for collection and handling of samples are provided in the 
SPM and laboratory manual. 
6.4.5.3 Dexamethasone Suppression Test (DST) (levoketoconazole-naïve 
cohort) 
An overnight DST (1-mg test as described below) will be performed during Screening if 
not previously performed within 2 months (up to 60 days) prior to the start of Screening 
Phase, to confirm eligibility for participation in the study.  The DST test is not needed at 
screening for subjects currently receiving levoketoconazole at the time of the Screening 
visit.  This test can be completed as a home visit during the Screening Phase.  To be 
considered adequate for this study, the procedure described below must be used.  
Overnight 1-mg DST 
• A 1-mg dose of dexamethasone will be administered orally between 11 PM and 
midnight; 
• A blood sample to measure serum cortisol and another to measure 
dexamethasone must be obtained at approximately 8 AM the next morning; the 
exact time of collection must be recorded in the CRF; 
• Subjects will have nothing to drink or eat, except sips of water, for at least 
10 hours before blood is taken. 
 
NOTE: If an LNSC sample is collected on the same night that dexamethasone is 
administered, the LNSC sample should be taken prior to dexamethasone administration.  
Because of the prolonged biological half-life of dexamethasone, to minimize the duration 
of Screening, UFC and LNSC samples should ideally be collected just prior to dosing 
with dexamethasone (as an example LNSC can be collected at 11:00 pm on the night of 


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the day when the last UFC sample collection was complete and this could be followed by 
dosing with dexamethasone at 11:30 pm). If collecting these samples after administering 
dexamethasone, do not collect LNSC until at least 5 days after dexamethasone is 
administered; do not collect UFC until at least 14 days after dexamethasone is 
administered. 
Medications that induce CYP3A4 activity or otherwise interfere with the assay of cortisol 
may affect DST results.  Example include: barbiturates, corticosteroids, phenytoin, 
rifampin, and tetracyclines.   
6.4.5.4 Morning Cortisol and Adrenocorticotrophic Hormone (ACTH) 
Morning serum cortisol (untimed) and ACTH levels will be measured in all subjects as 
described in the Time and Events Schedules in Appendix A.   
6.4.5.5 Pituitary Magnetic Resonance Imaging (MRI) 
Pituitary MRIs are not limited to subjects with a history of pituitary adenoma (e.g. CD), 
as this study will also assess the effects of levoketoconazole on pituitary size in subjects 
with ectopic ACTH or adrenal CS.  Pituitary MRIs will be obtained for subjects who are 
levoketoconazole-naïve or completed SONICS more than 6 months prior to screening, if 
not previously done within 6 months of TM0 or RW0.  For subjects who have recently 
completed SONICS, the SONICS M12 MRI may be used.  If a pituitary MRI is not 
available, then results of a CT scan may be recorded. 
Pituitary MRIs will also be obtained for all subjects who enter the study at Randomized 
Withdrawal Phase (RW0) [the SONICS visit M12 MRI may be used for subjects who 
completed the SONICS Study within 6 months] and again at Visit RW5.  The Visit RW0 
and RW5 MRI may be performed up to 2 weeks BEFORE the visit.  The results of MRIs 
obtained during the study will be evaluated by a central reader (neuroradiologist) and 
pituitary size determined, including measurement of tumor if one is visible. 
6.4.5.6 Oral Glucose Tolerance Test (pre-diabetic subjects with IFG only) 
All pre-diabetic subjects (and only prediabetic subjects) with Baseline fasting glucose 
concentrations at least 100 mg/dL (5.6 mmol/L) but below 126 mg/dL (7.0 mmol/L) (i.e. 
with IFG) and who are not receiving medications to lower blood glucose (i.e. 
antihyperglycemics) will have an OGTT at the times indicated in the Time and Events 
Schedules (Appendix A).  Subjects with diabetes, as defined in Appendix H will be 
excluded from the OGTT. 
After an overnight fast of at least 12 hours, subjects will be asked to drink 75 g of 
glucose.  Blood samples for the determination of glucose and insulin will be drawn 
before glucose administration and 30, 60, 90, and 120 minutes after administration.   
6.4.5.7 Quality of Life and Psychometric Assessments 
The Cushing QoL questionnaire (Webb 2008) (Appendix L) and the Beck Depression 
Inventory (BDI-II) (Appendix N) instrument will be administered at the times indicated 
in the Time and Events Schedules (Appendix A). 


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6.4.6 Situations Requiring Additional Safety Monitoring 
Additional safety monitoring will be required for the following situations.  This list is not 
intended to be an all-inclusive list of situations that could prompt additional safety 
monitoring. 
6.4.6.1 Dose Titration Levels 750 mg/day or Above 
If titration levels are 750 mg/day or above, subjects are required to return to the clinic or 
be seen at home by a qualified HHC professional for one extra safety evaluation 5 days 
(± 2 days) after each dose level escalation.  Additional safety evaluations will include the 
following assessments: AEs, vital signs, routine safety laboratory assessments (liver 
safety tests), ECGs, and morning serum cortisol levels (see Section 4.2.2.4). 
6.4.6.2 QTc Prolongation 
In the event QTc prolongation occurs (as defined in Section 6.4.3.1), additional safety 
monitoring is required, including medical observation of the subject until the QTc 
interval has returned to a value no more than 500 msec or no more than 60 msec change 
from Baseline.  Additional evaluation of the subject, as described in Section 6.4.3.1 and 
Appendix O, will include the potential requirement for additional ECGs, laboratory 
assessments and PK samples.  Cases of persistent, confirmed QTc prolongation should be 
reported to Chiltern Pharmacovigilance as AESIs (Section 13.7). 
6.4.6.3 Adrenal Insufficiency 
Subjects with suspected adrenal insufficiency should be assessed for signs and symptoms 
of adrenal insufficiency and cortisol levels as described in Section 6.5.3 and Appendix O.  
Should mild adrenal insufficiency be deemed present, study drug should be temporarily 
discontinued.  For moderate or severe symptoms/signs, study drug will be temporarily 
discontinued and rescue glucocorticoids administered as indicated.  In all cases, a PK 
sample should be collected as close to the time of the event as possible.   
Study drug at an appropriately lower dose can be restarted once the medical situation is 
deemed sufficiently resolved by the Investigator.  When adrenal insufficiency is observed 
at DL1, subjects may be provided a lower dose of 150 mg QD (DL0) following 
agreement with the Sponsor.  Subjects may resume the Dose Titration scheme after a 
dose reduction at the discretion of the Investigator and agreement of the Sponsor.  Cases 
of suspected adrenal insufficiency should be reported to Chiltern Pharmacovigilance as 
AESIs (Section 13.7). 
6.4.6.4 Liver Function Test Abnormalities 
Subjects with abnormal liver safety tests as described in Section5.4.1 will be monitored 
more intensively if they meet the criteria described.  Such monitoring consists of 
repeating the usual liver test battery and might include additional evaluations to evaluate 
the etiology of the suspected liver injury.  Guidance regarding temporary dose 
interruption and rechallenge is found in Section 4.2.2.3  Cases of possible drug-induced 
liver injury should be reported to Chiltern Pharmacovigilance as AESIs (Section 13.7).   
The Sponsor will provide suggested diagnostic tests in cases that are reported as AESIs 


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(Appendix O).  In all cases, a PK sample should be collected as close to the time of the 
event as possible.   
6.4.7 Pharmacokinetics 
6.4.7.1 Pharmacokinetics Sample Collection  
Blood samples (1 mL minimum) for the determination of plasma concentrations of 
levoketoconazole during a PK visit will be obtained at the following times relative to 
dosing during the study visit per the Time and Events Schedules (Appendix A). 
During the TM Phase, PK samples should be drawn pre-dose and between 1.5 to 
2.5 hours after dosing (i.e. at estimated Tmax) at TM0 and TM7 and at approximately 
6-8 hours after dosing at one interim visit (TM2-TM6 or an additional safety visit) of the 
subject’s choosing.  The 6-8-hour time point for PK sampling is not optional.  PK 
sampling at TM3, TM4, TM5, and TM6 could alternately be performed during additional 
safety visits required for DL4, DL5, DL6 and DL7 if those dose levels are needed.   
During the Restoration Phase, PK samples should be drawn pre-dose and between 1.5 to 
2.5 hours after dosing only at RES1. 
Subjects will be asked to provide the time of the last dose on the day prior to the PK 
sampling visit and to forego taking study medication on the day of the scheduled visit, so 
that dosing can be done at the clinic.   
Actual dosing and PK sampling times can vary from nominal (i.e. ideal or scheduled) 
times.  The following time deviation windows will be allowed for collection of PK 
samples:  
Sample timepoint 
Allowed window (minutes) 
Predose 
30 minutes 
1.5 to 2.5 hours 
10 minutes 
6 to 8 hours 
30 minutes 
 
For purposes of data entry, the actual dose administered, the actual time of drug 
administration, and the actual times of PK sample collection should be recorded rather 
than nominal times.   
Additional PK sampling 
To explore relationships between certain AEs (AESIs) and plasma exposure to drug, 
additional PK sampling is requested in the following situations: 
If persistent and confirmed QTc prolongation is observed, an additional PK sample 
should be collected as close to the time of the event as possible, ideally within 1 to 
2 hours of dosing (see Section 6.4.3).   


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PK samples should also be collected in association with other AESIs, i.e. liver test 
abnormalities considered possibly related to drug and suspected adrenal insufficiency, as 
close to the time of the event as possible (Section 13.2.2). 
6.4.7.2 Pharmacokinetics Sample Analysis 
Sample analysis will be performed by Alturas Analytics (Moscow, Indiana USA) under 
the direction of Cortendo AB.  Concentrations of levoketoconazole (2S,4R-ketoconazole) 
in plasma will be determined using current validated methodology.  
6.5 Additional Considerations for Risk Management 
6.5.1 Instructions for Subjects 
Subjects will be instructed to always carry a card and/or other identifier (e.g. bracelet or 
pendant) that clearly indicates the potential risk for adrenal insufficiency.  This card will 
include the subject’s information, contact information for the Investigator, and the 
potential need for glucocorticoids in cases of shock, surgery, and other conditions, as 
appropriate.  
Subjects should be regularly apprised of the potential risk for adrenal insufficiency and 
be made aware of the signs and symptoms of this condition.  At any time during the 
study, subjects should contact the clinical site in the event of any emerging clinical signs 
and symptoms suggestive of adrenal insufficiency.  Clear instructions should be provided 
to the subject on how to access the medical staff at the investigational site regardless of 
day or time of day. 
In addition, subjects will also be asked to carry an emergency kit containing 
hydrocortisone or another appropriate glucocorticoid, per local medical practice, that can 
be administered immediately in case of adrenal insufficiency.  
6.5.2 Considerations for the Investigator 
Subjects in the TM Phase will be contacted (method by subject preference) 
approximately 1 week after taking the first dose (DL1) and approximately 1 week after 
each dose adjustment (DL0, DL2, and DL3) to check on subject status and ensure 
compliance with medication administration.  During the TM Phase, subjects will be asked 
to return to the clinic or will be visited by a qualified HHC professional for one extra 
safety evaluation 5 days (± 2 days) after each dose adjustment when the total daily dose is 
750 mg/day or above.  
In the Restoration Phase, subjects will be contacted (method by subject preference) 
weekly between study visits.   
Throughout the study, subjects must be monitored and managed by the Investigator for 
the following conditions associated with CS or its treatment, per prevailing guidelines for 
diagnosis and standards of care: 
• Diabetes and impaired glucose tolerance:  See Appendix H for testing 
recommendations. 


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• Hypertension:  See Appendix I for guidelines for classification of blood pressure 
levels and follow-up recommendations.  
• Hypocortisolemia:  See Appendix K for evaluations of signs and symptoms. 
• Hypomineralocorticoidism:  See Appendix K for evaluations of signs and 
symptoms. 
• Hypogonadism:  See Appendix K for evaluations of changes in sexual function as 
reported by the subject. 
• Acute adrenal crisis:  Acute adrenal crisis is a life-threatening condition that 
often occurs primarily because of mineralocorticoid deficiency (Appendix K).  In 
such cases, the major clinical problem is hypotension (low blood pressure or 
shock).  Adrenal crisis can result in seizures, shock, coma or death.  In patients 
treated for CS, adrenal crisis typically occurs in the setting of acute stress or 
pituitary infarction.  With pituitary infarction, glucocorticoid deficiency can 
predominate.  Note that levoketoconazole per se is not anticipated to incite acute 
adrenal crisis, as mineralocorticoid production is not anticipated to be affected to 
a clinically meaningful extent. 
• Adrenal insufficiency:  See the following section (Section 6.5.3) for assessment of 
signs and symptoms of adrenal insufficiency and Appendix K for evaluation of 
signs and symptoms of adrenal insufficiency. 
6.5.3 Adrenal Insufficiency 
All medical care providers identified by the subject, in addition to the Investigator, 
MUST be given sufficient written instructions about the potential risks of adrenal 
insufficiency associated with the use of cortisol synthesis inhibitors, such as 
levoketoconazole. 
It is well recognized that subjects with a good response to treatment for CS resulting in 
decreased, but not necessarily low, cortisol concentrations may exhibit signs and 
symptoms of adrenal insufficiency (a non-life-threatening condition) that can mimic 
those associated with acute adrenal crisis, which is a life-threatening event warranting 
immediate medical intervention.  Therefore, discrimination between the two conditions 
may not be readily evident by history or physical examination.  Furthermore, subjects 
may have adrenal insufficiency without abnormal cortisol concentrations, if the cortisol 
response is inappropriately low for the degree of physiological stress being experienced. 
Symptoms attributable to adrenal insufficiency may include: nausea, vomiting, 
abdominal pain, anorexia, malaise, fatigue, headache, arthralgias/myalgias, 
gastrointestinal discomfort, dizziness (particularly upon standing), irritability, depression, 
sweating, and fever.  Signs of adrenal insufficiency are few and uncommonly observed, 
but postural hypotension and hypoglycemia can occur.   
Subjects should be assessed for symptoms and objective measures relatable to adrenal 
insufficiency as follows: 
• Random serum cortisol as close to the onset of the event as possible (if possible 
early-morning serum cortisol).  Laboratory evidence of hypoadrenalism (or 


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hypocortisolism) is defined as morning serum cortisol level less than 3 μg/dL.  
Even if serum cortisol and/or 24-hour UFC are within the normal laboratory 
reference range, the possibility of adrenal insufficiency should be considered 
based on other clinical signs and symptoms.  Please see Appendix K for a fuller 
list of clinical signs and symptoms; 
• Random glucose and electrolytes; 
• Lying and standing (i.e. orthostatic or postural) blood pressure measurements and 
pulse to evaluate postural changes; 
• Full review of systems. 
Should mild adrenal insufficiency be deemed confirmed or probable, study medication 
should be temporarily withheld.  For moderate or severe symptoms/signs, study 
medication should be temporarily withheld and rescue corticosteroids administered until 
adrenal insufficiency and its underlying trigger, if one is identified, has abated and the 
subject is stable.  Study medication, potentially administered at a lower dose if the event 
occurs during the TM Phase, may be restarted once the clinical situation allows.  If 
adrenal insufficiency is suspected and the subject is taking the lowest levoketoconazole 
dose of 150 mg/day, the subject might be exhibiting exquisite sensitivity to the cortisol-
lowering effects of levoketoconazole.  In such cases, the subject should be informed of 
the heightened risk of future occurrences of adrenal insufficiency before resuming study 
medication, with consideration given to permanent drug discontinuation. 
All cases of suspected adrenal insufficiency, whether eventually considered to be drug-
related or not, should be reported as AESIs to Chiltern Pharmacovigilance (Section 13.7). 
7 
LIFESTYLE AND DIETARY RESTRICTIONS 
Subjects must follow these lifestyle and dietary restrictions throughout the study. 
• Consumption of grapefruit, lime juice and Seville oranges (aka sour orange, 
bigarade orange, or marmalade orange) and its products should be avoided; 
• Genuine licorice (not the same as licorice-flavored candy) should be avoided or 
consumed in small amounts infrequently;  
• Consumption of excessive alcohol should be avoided (note: there is no known 
safe amount in relation to use of levoketoconazole); 
• Donation of blood or blood products is prohibited during the study. 
Subjects must follow the following lifestyle and dietary restrictions for study-specific 
assessments. 
• During the 24-hour urine collection period, subjects must refrain from the 
following: 
o Drinking more than 1 gallon or 4 liters of fluids 
o Use of medicines or other products containing corticosteroids, whether 
administered topically (e.g. drops, creams), inhaled, or ingested.  


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• On the nights that samples are collected for LNSC, subjects must refrain from 
the following: 
o Within 2 hours prior to the collection: 
 Brushing or flossing teeth or doing anything that could induce 
bleeding of the gums  
 Sleeping and subsequently awakening 
o Within 1 hour prior to the collection: 
 Eating or drinking or chewing anything (including tobacco) 
 Using any facial creams or lotions 
 Smoking cigarettes, pipe, cigar or any other substance. 
 
Information on each subject’s job related working shift and sleep hours will be collected. 
8 
INVESTIGATIONAL PRODUCTS 
8.1 Description of Investigational Product 
Levoketoconazole will be provided as 150-mg immediate release tablets for oral 
administration.  The tablets will be 3/8” round, biconvex, and unmarked with a pink film 
coat and supplied in foil induction sealed High Density Polyethylene (HDPE) bottles. 
Refer to the Pharmacy Manual for details of labeling of the investigational product. 
8.2 Description of Reference Therapy 
An active reference therapy will not be used.  Placebo tablets will be supplied to ensure 
adequate concealment of study treatments during the Randomized Withdrawal Phase and 
Restoration Phase.  
Placebo tablets identical in appearance to levoketoconazole will be administered during 
the Randomized Withdrawal Phase using the same regimen as the Therapeutic Dose of 
levoketoconazole established during the TM Phase (levoketoconazole-naïve cohort) or at 
study entry (SONICS-completer cohort).  During the Restoration Phase, blinded placebo 
to be added onto a levoketoconazole regimen will be started at 1 tablet BID and titrated 
every 2 days in 1 tablet increments per Table 2 until the Therapeutic Dose-equivalent is 
achieved unless the Therapeutic Dose is DL0.  The total final tablet count (active + 
placebo) during Restoration Phase will equal twice the total tablet count of the 
Therapeutic Dose, not to exceed 8 tablets BID. 
8.3 Dosage and Administration 
Levoketoconazole or placebo tablets will be administered BID, approximately every 
12 hours, per the titration scheme described in Section 4.2.2.2.  For the levoketoconazole-
naïve cohort, the total daily dose will be titrated in 150 mg increments from a starting 
dose of 300 mg (dosed as 150 mg BID) up to a maximal daily dose of 1200 mg (dosed as 
600 mg BID) until a Therapeutic Dose is established.  The minimum daily dose is 
150 mg QD for subjects who cannot tolerate 150 mg BID.  For subjects in the SONICS-
completer cohort, the Therapeutic Dose will have been established prior to enrollment in 
this study and confirmed in the screening phase.  For subjects in the levoketoconazole-


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naïve cohort, the Therapeutic Dose will be established by the end of the TM Phase.  The 
Therapeutic Dose will be used as the target dose and dose-regimen during the Restoration 
Phase. 
Subjects will receive an adequate amount of the investigational product at each visit, as 
prepared by the study pharmacist.  Please refer to the Pharmacy Manual for dispensing 
instructions. Although no specific restrictions are made regarding the ingestion of fluids 
or food around the time of dosing, it is believed, via inference from studies with 
ketoconazole, that gastric acidity is needed for absorption of levoketoconazole.  
Therefore, varying the timing of food intake, which affects gastric acidity, in relationship 
to dosing is not recommended, especially during dose titration, as doing so might lead to 
excessive variability in levoketoconazole blood levels and thus a variable response to 
therapy. 
8.3.1 Dose Rationale 
The effects of treating CS with any therapeutic agent is not generally predictable a priori. 
Ketoconazole a commonly used therapeutic agent has variable PK and is titrated to effect 
up to levels as high as 1800 mg daily to control severely ill CS patients.  In most patients 
responsive to ketoconazole, doses average approximately 600 to 800 mg/day with the 
range of 200 to 1800 mg having been utilized to achieve normalization of cortisol levels 
[Nieman 2002, Pozza 2012]. 
Like ketoconazole, levoketoconazole is not expected to be administered at a fixed dose 
but will be titrated to effect in each subject.  Levoketoconazole has been used in clinical 
trials up to a dose of 1200 mg daily. The highest dose of 600 mg BID levoketoconazole 
(1200 mg total daily dose) is used during this study, because some CS subjects may 
require higher levels of cortisol suppression to achieve adequate therapeutic response.  
Doses of levoketoconazole higher than 300 mg BID (600 mg total daily dose and higher) 
will be guided by enhanced tolerability and safety monitoring as described in 
Section 4.2.2.4.  It is expected that titration to the highest dose will be the exception 
rather than the norm, based on prior experience with levoketoconazole in SONICS and 
nonclinical comparisons with ketoconazole.  A detailed description of nonclinical and 
prior clinical data with levoketoconazole and rationale for dose selection is provided in 
the Investigator’s Brochure. 
8.3.2 Dose Titration and Maintenance (TM) Phase (levoketoconazole-naïve 
cohort) 
For levoketoconazole-naïve subjects and subjects who completed the M12 visit of 
SONICS who have not received a stable Therapeutic Dose of levoketoconazole for the 
12 weeks immediately preceding Screening, open-label levoketoconazole will be titrated 
to find an effective and tolerable dose for each subject (i.e. the Therapeutic Dose).   
The total daily dose will be titrated in 150 mg increments from a starting dose of 300 mg 
(dosed as 150 mg BID) up to a maximal daily dose of 1200 mg (dosed as 600 mg BID) 
until a Therapeutic Dose is established (Section 4.2.2.2.2).  Subjects re-establishing the 
Therapeutic Dose via re-titration may begin titration at their current or most recently 
received dose at the discretion of the Investigator.   


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The minimum daily dose is 150 mg QD for subjects who cannot tolerate 150 mg BID.  
For subjects in the levoketoconazole-naïve cohort, the Therapeutic Dose must be 
established by the end of the TM Phase. 
For subjects in the SONICS-completer cohort, the Therapeutic Dose will have been 
established prior to enrollment in this study and will be confirmed at screening, prior to 
randomization.   
8.3.2.1 Dosage Changes During TM Phase 
During the TM Phase (while treatment is open-label), once the Therapeutic Dose is 
achieved, the dose should generally not be further adjusted if the UFC levels are within 
normal limits.  However, the dose may be increased if medically necessary to maintain 
eucortisolemia or decreased to address drug intolerance or AE.  The Therapeutic Dose 
must be stable (i.e. fixed), with normal mUFC established, for at least 4 weeks before a 
subject may be eligible for the Randomized Withdrawal Phase. 
8.3.2.2 Dosage Reductions and Use of Dose Level 0 
Dose reductions are allowed and should be used judiciously to manage certain AEs. The 
following AEs are AESIs for which dose reductions can sometimes be helpful: 
• Suspected or confirmed adrenal insufficiency (see Section 6.5.3); 
• Liver safety test abnormalities (see Section 5.4.2); 
• QTc prolongation (see Section 6.4.6.2).   
Generally, if levoketoconazole is restarted during the TM Phase following an AESI, the 
dose should be reduced to the dose level (i.e. one dose level) lower than that associated 
with the AESI to mitigate the risk of future occurrences of the event (as described in 
Section 4.2.2.3).  Further titration is subsequently allowable if the Investigator, in 
consultation with the Medical Monitor, believes that the risk of AESI recurrence is 
outweighed by the expected benefit of the higher dose, as supported by evidence from 
disease-related measures.   
If a suspected drug-related AESI is associated with the lowest usual dose level (DL1, 
150 mg BID), the subject may receive the lowest possible dose of 150 mg QD (DL0) 
following discussion with the Medical Monitor.  Subjects in the TM Phase may 
subsequently resume the titration scheme if DL0 is not a Therapeutic Dose but a partial 
cortisol response is evident and there was evidence of a better response at DL1.  
Discussion of the benefits and risks of resuming titration with the Medical Monitor is 
required in such cases. 
The 150-mg dose for DL0 should be administered in the evening, except on the day of 
the in-clinic or at-home procedures, when the dose should be administered during the 
visit to allow for post-dosing ECG and PK assessments.  
Subjects who experience an AESI during the Randomized Withdrawal or Restoration 
Phase cannot reduce the dose of study medication, which is blinded.  However, study 
medication may be temporarily withheld and subsequently resumed at the prior dose once 


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the AE resolves, if the Investigator believes that continued use of the study medication 
remains in the subject’s best interest.  
8.3.3 Randomized Withdrawal Phase and Restoration Phase 
8.3.3.1 Blinding 
A randomized, double-blind, placebo-controlled design will be used in the Randomized 
Withdrawal Phase and the Restoration Phase of the study.  The Investigator, study site 
personnel, representatives of the Sponsor and the Contract Research Organization (CRO) 
involved in the monitoring, data management, analysis, and other aspects of the study 
will be blinded to the randomized treatment assignments during the Randomized 
Withdrawal Phase and Restoration Phase.  Some individuals, not involved in the conduct 
of the study, will be unblinded for a planned interim analysis after all subjects have either 
completed the Randomized Withdrawal Phase or discontinued prior to the end of the 
Randomized Withdrawal Phase. The rest of the individuals involved in the study will 
remain blinded at the individual subject level until after the database lock at the end of 
the study, except as described below.  Details on the interim analysis are provided in 
Section 12.6. 
The TM Phase is open-label. Subjects who require early rescue during the Randomized 
Withdrawal Phase may receive open-label levoketoconazole and continue in the study.  
The investigational product and reference therapy are identical in appearance and the 
packaging and labelling will be identical to keep the study blinded during the 
Randomized Withdrawal Phase and the Restoration Phase (including when early rescue is 
needed).    
For the Randomized Withdrawal Phase and the Restoration Phase, treatment-code breaks 
should occur only in exceptional circumstances when knowledge of the actual treatment 
is essential for further management.  Investigators are encouraged to discuss with the 
Clinical Research Organization (CRO) Medical Monitor if they believe that unblinding is 
necessary and, in any case, Investigators or other responsible site personnel must report 
unblinding to the Sponsor via telephone/email as soon as feasible after the event.  If 
unblinding is deemed to be necessary, the Investigator should use the main system for 
emergency unblinding through the interactive randomization system via interactive 
response technology (IRT). 
Treat as indicated.  If unblinding cannot be completed promptly, treatment of the subject 
or other affected person should proceed as if the ingested medication were 
levoketoconazole.   
Investigators are encouraged to maintain the blind except as needed to manage the 
emergency, whether the emergency involves the subject or someone outside of the study 
who was exposed to the study medication (e.g. a child who ingests the study medication).  
Treatment allocation must NOT be disclosed to the subject and/or other study personnel 
including other site personnel, monitors, and Sponsor or CRO staff, nor should there be 
any written disclosure of the code in any of the corresponding source documents.  The 
Investigator must report all treatment-code breaks (with reason) as they occur on the 
corresponding CRF page.  Treatment allocation information after a code break should be 


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held by the designated person at site and by the CRO Global Safety Officer for the study 
or designee.  Unblinding should not necessarily be a reason for study drug 
discontinuation.  Investigators are responsible for promptly notifying the Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) in cases involving a 
treatment-code break. 
For purposes of reporting certain AEs to competent authorities, IRBs/IECs, and certain 
responsible Investigators, the Sponsor will designate personnel who will have access to 
information on unblinded study treatment.  Safety signal evaluation and trend analysis 
will remain the responsibility of the Sponsor, as described in the safety monitoring plan 
and DSMB charter. 
8.3.3.2 Randomization and Treatment Assignment 
At the beginning of the Randomized Withdrawal Phase (Visit RW0) eligible subjects will 
be randomly assigned in a 1:1 ratio to receive either: 
• Group 1: Levoketoconazole tablets in the same regimen as the Therapeutic Dose  
• Group 2: Matching placebo tablets in the same regimen as the Therapeutic Dose.   
The Therapeutic Dose will be used as the target dose and dose-regimen during the 
Restoration Phase. Treatments in this phase will continue to be double-blind.  Subjects 
will continue receiving the same treatment as in the Randomized Withdrawal Phase and 
will receive additional rescue treatment with either: 
• Group 1: Placebo tablets 
• Group 2: Levoketoconazole tablets.  
The starting Restoration Phase dose will be one tablet BID and the dose will be titrated in 
one tablet increments every 2 days until the Therapeutic Dose-equivalent tablet count is 
achieved unless the Therapeutic Dose is DL0. 
8.3.3.3 Early Rescue 
Subjects who require early rescue during the Randomized Withdrawal Phase may receive 
open-label levoketoconazole.  The rapid titration schedule of the Restoration Phase 
should be used to reestablish the Therapeutic Dose of open-label levoketoconazole used 
for the early rescue.  Dose adjustments may be made, as medically indicated, after rapid 
re-titration.  This includes adjustments to dose levels above the previous therapeutic dose 
if required to return subject to eucortisolemia.  During early rescue, the titration will 
increase in 1 tablet increments every 2 days alternating AM and PM per Table 2. 
9 
DRUG SUPPLIES, DISPENSING, STORAGE AND ACCOUNTING 
9.1 Product Storage 
Levoketoconazole and matching placebo tablets should be stored at 15°C to 25°C (59°F 
to 77°F). 


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9.2 Investigational Product Accountability 
The Investigator is responsible for investigational product accountability, reconciliation, 
and record maintenance.  In accordance with all applicable regulatory requirements, the 
Investigator or designated site staff must maintain investigational product accountability 
records throughout the course of the study.  The responsible person(s) will document the 
amount of investigational product received from and returned to Cortendo AB (when 
applicable), the amount supplied and/or administered to and returned by subjects, if 
applicable. 
9.3 Compliance Assessment 
Subjects will be asked to maintain a patient diary to record medication administration, 
urine sample collection, saliva sample collection, concomitant medications, and changes 
in condition.  In addition, subjects should bring all empty medication bottles and unused 
medication with them to all in-clinic visits except for additional safety visits required in 
the TM Phase.  Drug accountability to determine compliance will be performed at all 
other in-clinic visits. Drug accountability will not be performed during visits by HHC 
professional.  
9.4 Treatment of Investigational Product Overdose 
There is no known direct antidote to levoketoconazole once absorbed.  However, if 
levoketoconazole was recently ingested, in addition to maneuvers aimed at removing 
tablets from the stomach, its absorption from the intestines into blood might be reduced 
by ingesting fatty foods/liquids.  
Subjects should be medically managed based on their clinical condition (e.g. monitor and 
treat for hypocortisolism).   
Refer to Section 4.2.2.4 for additional safety monitoring for administration of daily doses 
750 mg/day or above.   
10 CONCOMITANT MEDICATIONS 
10.1 Permitted Medications 
For management of dyslipidemia, pravastatin, fluvastatin, pitavastatin and rosuvastatin 
are the only allowed “statins”.  For subjects for whom lipid reduction therapy is being 
considered, all lipid lowering drugs should be added and stabilized for at least 4 weeks 
prior to TM0 for the levoketoconazole-naïve cohort or RW0 for the SONICS-completer 
cohort, as improvements in lipids are being assessed as an endpoint for levoketoconazole 
treatment in this study. 
For management of hypokalemia, potassium supplements are encouraged.  It is advised 
that maintenance of serum potassium levels within the normal range and above 
4.0 mmol/L may reduce the risk of drug-induced QTc prolongation. 
Most medications used to treat T2DM are allowed.  Metformin is allowed, although its 
levels might be increased by levoketoconazole.  Routine monitoring of glucose, kidney, 


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and liver function is considered sufficient to mitigate any risk of the combination with 
levoketoconazole. 
For managing dyspepsia, over-the-counter liquid and tablet antacids containing e.g. 
aluminum, calcium, or magnesium, are allowed but must be used in moderation and taken 
at least 2 hours after dosing with levoketoconazole.  A list will be provided. 
Most commonly used treatments for osteopenia or osteoporosis—excluding certain 
hormonal treatments—are allowed.  Calcium should be taken at least 2 hours after 
ingesting study medication. 
All medications should be scrutinized during Screening, using Appendix J as a guide and 
with help from the Medical Monitor if needed.  Medication additions or switches after 
Screening should be kept to a minimum and should likewise prompt a check against 
Appendix J, ideally prior to the decision to add or switch, to prevent untoward 
experiences, including loss of efficacy, resulting from drug interactions.  Any questions 
concerning concomitant medications should be addressed with the Medical Monitor 
promptly.  
Blood pressure, diabetes, cholesterol, anti-inflammatory, and CS-specific medications 
will be captured with other medications but will require Investigator specification of the 
medication types. 
10.2 Prohibited Medications 
During the study, subjects are not allowed to take the following medications. A more 
complete list of prohibited medications and medications to be used with caution, 
categorized by primary reason for prohibition or precaution, is found in Appendix J.  The 
Investigator is encouraged to contact the Medical Monitor for any questions. 
• Total daily dose of acetaminophen (paracetamol) above 2 g (increased liver 
toxicity risk); 
• Prescription or over the counter H2 receptor antagonists or proton-pump 
inhibitors or sucralfate (inhibition of drug absorption); 
• Statins other than pravastatin, fluvastatin, pitavastatin and rosuvastatin; 
potentially eligible subjects should be switched to an allowed statin (or other 
allowed therapy) several weeks prior to the Baseline Visit for the TM Phase (Visit 
TM0) whenever feasible to allow equilibration of blood lipids (Note: new lipid 
lowering medications should not be added after the screening period as described 
in Section 10.1); 
• Carbamazepine, fenofibrate (assay interference), carbenoxolone; 
• Genuine licorice (mineralocorticoid effects);  
• Steroidogenesis inhibitors or dopamine agonists (interference with drug effect, 
Appendix J, Table 12 and Table 13); 
• Megestrol acetate or medroxyprogesterone acetate and selected other synthetic 
progestins (see Appendix J, Table 14) [Schindler 2003]; 


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• Any other drug treatments used to lower cortisol in CS that are subject to washout 
(see Section 5.2 and Appendix J, Table 15) are prohibited throughout the study; 
• Weight loss medications (either prescription or over the counter, Appendix J, 
Table 16); 
• Drugs whose systemic exposure is potentially increased significantly by 
concomitant use of levoketoconazole (Appendix J, Table 18); 
• Medications that are strong CYP3A4 inhibitors or CYP3A4 inducers as they may 
interfere with the metabolism of levoketoconazole. As examples, rifampicin, 
rifabutin, isoniazid, nevirapine and phenytoin may significantly reduce 
levoketoconazole concentrations via CYP3A4 induction, and ritonavir may 
increase levoketoconazole concentrations via CYP3A4 inhibition, and are 
therefore prohibited (Appendix J, Table 19); 
• Medications resulting in QTc prolongation as a direct effect or because of 
interaction with levoketoconazole, examples include: cisapride, dofetilide, 
pimozide, quinidine. (Appendix J, Table 20).  However, in selected cases where 
no alternative medications are available, permission from the Medical Monitor 
may be sought; 
• Topical or inhaled corticosteroid preparations (interference with drug effect, 
Appendix J, Table 12);  
• The following herbal medicines: St John’s Wort, echinacea, gingko, goldenseal, 
yohimbe, red rice yeast, danshen, silybum marianum, Asian ginseng, schissandra 
sphenanther, shankhapushi, and Asian herb mixture (Xiao chai hu tang and 
Salboku-to). 
10.3 Medications to be Used with Caution 
• There are some medications that are often considered contraindicated when used 
with ketoconazole, due to an increased risk of AEs (Appendix J, Table 23).  These 
medications should generally be avoided while the subject is participating in the 
study.  However, they may be used in selected cases, particularly when they are 
used prior to study entry and when no alternative medications are available.  Such 
usage should follow consultation with and explicit permission from the Medical 
Monitor.  
• Medications that are weak or moderate CYP3A4 inhibitors or CYP3A4 inducers 
or that are metabolized by cytochrome P450 enzymes (CYPs) and plasma 
concentration that increase in exposure moderately in the presence of 
ketoconazole, potentially resulting in increased drug effect, should be avoided if 
alternative therapy is available or should be used with caution.  In such cases, 
careful monitoring, with possible adjustments in doses, is recommended (see 
Appendix J, Table 21). 


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11 SUBJECT COMPLETION AND WITHDRAWAL 
11.1 Subject Completion 
Subjects who complete the end of the Restoration Phase (Visit RES2) of the study, 
regardless of their response status, will be considered to have completed the study and are 
eligible for inclusion into the OPTICS Study. 
Subjects who receive early “rescue” will also be considered to have completed the study 
and are eligible for inclusion into the OPTICS Study.  
11.2 Subject Withdrawal Procedures 
All premature study withdrawals and their causes must be documented, to include the 
specific reason(s) prompting withdrawal, by the Investigator on the CRF, and, if need be, 
on the AE form.   
If the subject chooses to withdraw or is otherwise withdrawn before completing the 
study, the Investigator should make every attempt to have the subject return to the clinic 
to complete safety and PK assessments as outlined in the Schedule of Events for the TM7 
Visit (if in the Dose Titration and Maintenance Phase), the RW5 Visit (if in the 
Randomized Withdrawal Phase) or the RES2 Visit (if in the Restoration Phase) in 
Appendix A.  All data gathered on the subject prior to termination will be made available 
to the Sponsor.   
12 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
12.1 Populations for Analysis 
Intent-to-Treat Population (ITT): The ITT population will include all subjects who are 
randomized and receive at least one dose of blinded study medication during the 
Randomized Withdrawal Phase.  The ITT population will be used for the primary 
analysis of efficacy and secondary analyses of efficacy and safety.   
Per Protocol (PP) Population:  The PP population will consist of all subjects in the ITT 
population who have no major protocol deviations during the Randomized Withdrawal 
Phase that could affect the primary endpoint. This population will be used in supportive 
analyses of the primary endpoint and secondary efficacy endpoints. 
Levoketoconazole-naïve Population:  The levoketoconazole-naïve population will consist 
of all subjects in the levoketoconazole-naïve cohort (defined in Section 4.1) who receive 
at least one dose of study medication during the Dose Titration and Maintenance Phase.  
This population will be used for supportive evaluations of safety and for exploratory 
efficacy, safety, and PK analyses.   
SONICS-completer Population: The SONICS-completer population will consist of all 
subjects in the SONICS-completer cohort (defined in Section 4.1) who receive at least 
one dose of blinded study medication during the Randomized Withdrawal Phase.  This 
population will be used for supportive evaluations of safety and for exploratory efficacy, 
safety, and PK analyses. Because only a minority of the subjects are anticipated to be in 


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the SONICS-completer cohort, the analyses will be performed only if the size of this 
cohort is at least 30% of the ITT population. 
12.2 Hypothesis 
The primary endpoint for this study is the proportion of subjects with loss of therapeutic 
response to levoketoconazole upon withdrawing to placebo compared with continued 
levoketoconazole treatment.  Loss of response is based on the mean of three 24-hour 
UFC measurements (mUFC) obtained at any visit from second through final randomized-
withdrawal visits (RW1 through RW5 inclusive) when:   
• mUFC is more than 1.5X the ULN of the central laboratory’s reference range 
OR  
• mUFC is more than 40% above the Baseline (RW0) value if the RW0 value 
was 1.0X ULN or greater for SONICS-completer cohort subjects OR  
• an early rescue criterion is met. 
The null hypothesis is that the proportion of subjects with loss of response upon 
withdrawing to placebo compared with continued levoketoconazole, as defined above, is 
not different between levoketoconazole and placebo.  The alternative hypothesis is that 
the two proportions are different, specifically that there is an increased loss of response 
for the placebo arm. 
12.2.1 Sample Size Determination 
For the purpose of sample size estimation, it is assumed that among subjects in the ITT 
population who complete at least the RW4 visit in the Randomized Withdrawal Phase, 
10% will lose therapeutic response in the levoketoconazole arm vs. 75% in the placebo 
arm.  The 10% loss of therapeutic response rate in the levoketoconazole arm is based on 
data from the SONICS study.   
For the analysis of the primary endpoint, subjects in the ITT population who withdraw 
prior to RW4 are considered as losing therapeutic response.  As such, the assumed loss of 
therapeutic response rate in the overall ITT population in each arm depends on the 
withdrawal rate prior to RW4 during the Randomized Withdrawal Phase.  It is expected 
that the withdrawal rate will be no more than 10%, but up to 20% is considered in the 
sample size estimation.  If the withdrawal rate is 10% per arm, a sample size of 46 
subjects (23 per arm) randomized and treated during the Randomized Withdrawal Phase 
corresponds to 42 subjects (21 per arm) completing RW4 and provides approximately 
99% power, using two-sided Fisher’s Exact test, to detect the alternative hypothesis of a 
loss of therapeutic response rate of 17% in the levoketoconazole arm and 78% in the 
placebo arm vs. the null hypothesis of no difference between the two arms.  If the 
withdrawal rate is 20% per arm, a sample size of 54 subjects (27 per arm) randomized 
and treated during the Randomized Withdrawal Phase corresponds to 44 subjects (22 per 
arm) completing RW4 and provides approximately 98% power to detect the alternative 
hypothesis of a loss of therapeutic response rate of 26% in the levoketoconazole arm and 
81% in the placebo arm vs. the null hypothesis of no difference between the two arms.   


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Because enrollment into the Dose Titration and Maintenance Phase will be closed prior to 
the last subject being randomized and treated in the Randomized Withdrawal Phase, the 
actual sample size for the Randomized Withdrawal Phase is not prespecified.  The timing 
of enrollment closure will be based on the rolling 4-week completion rate trend for the 
Dose Titration and Maintenance Phase.  A minimum of 46 subjects (23 per arm) and a 
maximum of 54 subjects (27 per arm) will be targeted to be enrolled into the Randomized 
Withdrawal Phase based on the observed withdrawal rate trend for the phase.   
A minority of randomized subjects are anticipated to be in the SONICS-completer cohort.  
Any subject who withdraws after randomization will not be replaced.  Withdrawn 
subjects will not be re-entered into the study. 
12.3 General Considerations for Data Analysis 
The SAS System, Version 9.2 (or higher), will be used for all analyses, unless otherwise 
specified.  Continuous variables (e.g., age) will be summarized using the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum. 
Categorical variables (e.g., sex, race) will be summarized using the number of 
observations (n) and percentage in each category.  
All data used in analyses and/or collected during the study will be provided in listings. 
12.4 Study Completion, Premature Withdrawal and Missing Data 
Definition of Study Completion 
Study completion for purposes of assessing the primary endpoint is defined as either of 
the following:  
(1) having completed Visits RW0 (Randomized Withdrawal Baseline) and RW5 (i.e. 
final scheduled visit in Randomized Withdrawal Phase) regardless of UFC status OR  
(2) having completed RW0 and having met criteria for use of early rescue treatment with 
open-label levoketoconazole (or another rescue medication) after RW0.   
Definition of Non-completion 
Subjects withdrawn from the study without meeting the definition of study completer 
above will be considered as prematurely withdrawn (i.e. non-completers).  All available 
data for subjects who are study non-completers will be included in all analyses. 
Missing or Inadequate UFC Collections 
At any visits for which three 24-hour urine samples for UFC determination are scheduled 
to be collected, at least two UFC collections must be deemed adequate to be able to 
derive a mUFC value and thus be considered as non-missing.  When more than two 
UFC collections are made only those collections deemed adequate by the Sponsor will be 
included in the calculation of the mUFC. 
Study non-completion, reasons for non-completion, and missing or inadequate collections 
for determination of UFC will be summarized. 
Handling of Missing Data for Analyses of the Primary Endpoint 
The following rules will be applied for determining loss of therapeutic response when 


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some or all mUFC data are missing:   
1. A subject withdraws prematurely during the Randomized Withdrawal Phase (i.e. 
Visit RW5 is not completed nor is the subject in need of early rescue treatment) 
and no post-randomization adequate mUFC determination is available.  In this 
case, the subject will be assumed to have lost therapeutic response; OR 
2. A subject withdraws prematurely during the Randomized Withdrawal Phase after 
RW0 and before RW5, with no early rescue, and at least one post-randomization 
mUFC determination is available.  In this case, if the latest available adequate 
mUFC determination is the one for RW4, all available mUFC determination(s) 
will be used to determine if loss of therapeutic response occurred for that subject, 
but if the latest available mUFC determination is for a visit before RW4, the 
subject will be assumed to have lost therapeutic response; OR 
3. A subject completes the Randomized Withdrawal Phase with one or more missing 
adequate mUFC determinations, with at least one post-randomization adequate 
mUFC determination available.  In this case, if the latest available adequate 
mUFC determination is the one for RW4 or RW5, all available mUFC 
determination(s) will be used to determine if loss of therapeutic response occurred 
for that subject, but if the latest available mUFC determination is for a visit before 
RW4, the subject will be assumed to have lost therapeutic response.  
Supportive analyses of the primary endpoint that require more than one adequate mUFC 
determination during the Randomized Withdrawal Phase to be available will be 
performed.  For the secondary and exploratory efficacy endpoints, at-visit analyses will 
be performed using longitudinal models without imputation as the primary approach; 
where specified; imputations to replace missing values will be considered as supportive.  
Details will be provided in the Statistical Analysis Plan (SAP). 
12.5 Final Analyses 
12.5.1 Definitions of Baseline 
For the purposes of analyzing changes and shifts from Baseline, whether for safety or 
efficacy evaluations, two Baselines will be used, depending on the analysis population 
and the assessment timing.  The levoketoconazole-naïve analysis population has its own 
Baseline at Visit TM0 (including values obtained during Screening that are within 3 
weeks of TM0).  The TM0 Baseline will primarily be used to infer changes and shifts that 
occur during the TM Phase only.  Both the levoketoconazole-naïve and SONICS-
completer analysis populations will use as Baseline Visit RW0, which is applicable to 
assessments that are made during the Randomized Withdrawal Phase and the Restoration 
Phase, such as the analysis of primary efficacy.   
Thus, for most measures, analytical summaries will be created using two Baselines when 
the levoketoconazole-naïve population is involved and one Baseline when only the 
SONICS-completer population is involved or when the analysis is concerned with the 
post-randomization period only (e.g. the primary efficacy analysis).  For some endpoints 
analyzed during the Restoration Phase only, there may be interest in looking at the 
changes and shifts from the start of the Restoration Phase for the subset of subjects who 


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were randomized to placebo for the Randomized Withdrawal Phase and received 
levoketoconazole during the Restoration Phase.  In such analyses, the Baseline of interest 
will be Visit RW5. If the Baseline is not obvious, care will be taken to describe the 
specific Baseline used in the description of the analysis. 
12.5.2 Safety Analyses 
The final analysis of safety will be coincident with the last subject visit following 
completion of the Restoration Phase.   
Safety analyses will be conducted by study phase and/or by time point, as applicable.  
Adverse events will be recorded from the date that informed consent was signed.  
Treatment-emergent adverse events (TEAEs) will be summarized and reported by 
pooled-cohorts and separately by SONICS-completer and levoketoconazole-naïve 
cohorts. 
Interim analyses of safety will be performed and reported on a limited basis to satisfy 
requirements of study oversight, for example to IRB/IEC and Competent Authorities.  
These limited analyses (e.g. common adverse reactions summary) will not be 
accompanied by assessments of potential benefits.  Any unplanned interim efficacy 
analyses will be accompanied by unplanned interim safety analyses. 
An independent DSMB will review all SAEs and AESIs on a rolling basis and assess 
benefits and risk of therapy (unblinded) systematically at approximately 6-month 
intervals.  The timing of the first bi-annual DSMB meeting may be adjusted based on 
subject accrual.  There are no plans to stop the study prior to completion based on these 
reviews, and therefore no stopping rules will be created.  The DSMB will not report its 
findings other than to indicate whether the protocol must be changed for the study to 
continue as planned or otherwise make recommendations designed to ensure subject 
safety and study integrity.  Details of the DSMB procedures will be described in a 
separate charter. 
12.5.2.1 
Extent of Exposure 
Study drug exposure will be summarized as the average daily dose, cumulative dose, and 
total number of days on study drug.  Total number of days on study drug will be 
calculated for each subject as the treatment stop date minus treatment start date plus one 
day.  Drug exposure will be calculated separately for each analysis population 
(Section 12.1). 
Study drug compliance at each study phase and cumulative study drug compliance for the 
study overall will be calculated by dividing the number of study drug tablets used (total 
number dispensed minus total number returned/lost/wasted) by the total number of study 
drug tablets that should have been taken and multiplying the result by 100.  
For subjects in the levoketoconazole-naïve cohort, study medication dose levels will be 
listed by visit and days on study, with the Therapeutic Dose indicated.  All study 
medication interruptions or permanent discontinuations prompted by the Investigator or 
Sponsor will be listed for each subject, along with the medication identity, timing and 
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12.5.2.2 
Adverse Events (AEs) 
All AEs will be coded using MedDRA and graded per the National Cancer Institute 
Common Terminology Criteria for Adverse Events, version 4.03 [NCI CTCAE, 2010].  
The TEAEs will be of primary interest.  The number and proportion of subjects reporting 
the following will be calculated and reported:  any TEAE, drug-related TEAEs, serious 
TEAEs, TEAEs of special interest, severe TEAE, TEAEs leading to discontinuation of 
study drug, and TEAEs leading to withdrawal from the study will be computed.  The 
most common TEAEs (frequency above 5% per treatment group) in pooled 
levoketoconazole and placebo groups will also be reported.   
TEAE summaries will include frequency by treatment group (pooled levoketoconazole), 
levoketoconazole dose (individual dose level) and relative onset time (by visit, by Phase, 
by study days, by days in Phase, etc.), depending on the analysis population.  Additional 
summaries and listings will be created to explore TEAE signals. 
12.5.2.3 
Clinical Laboratory Evaluations 
A laboratory value that is within the central laboratory’s reference range will be 
considered normal.  A laboratory value that is outside the central laboratory’s normal 
range will be considered abnormal.  The number and percentage of subjects with 
abnormal laboratory values will be summarized for each scheduled visit.  Shift tables by 
visit will be constructed.  Differences in continuous laboratory values between Baseline 
and each scheduled assessment will be calculated for each analyte and summarized 
descriptively.   
Liver function tests will be further summarized descriptively using modified eDISH plots 
and other displays.  
Further descriptions of laboratory analyses will be included in the SAP. 
12.5.2.4 
Vital Signs 
Heart rate, SBP and DBP will be measured in triplicate at least 3 minutes apart at each 
visit.  The mean of these measurements will be used as the final value for each visit.  
Changes and shifts from normality from Baseline (RW0) for each measurement at each 
visit will be summarized by treatment group and by dose of levoketoconazole.  In 
addition, values of clinical importance (Table 5) will be identified in the data listings.   


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Table 5 
Vital Sign Values of Clinical Importance 
Vital Sign 
Criteria 
Flag 
Heart Rate (HR) 
below 44 bpm 
Low (L) 
 
44-100 bpm 
Normal  
 
101-120 bpm 
High (H) 
 
above 120 bpm 
Very High (VH) 
 
 
 
Systolic Blood Pressure (SBP) 
below 90 mm Hg 
Low (L) 
 
90-139 mm Hg 
Normal 
 
140-169 mm Hg 
High (H) 
 
170 mm Hg and above 
Very High (VH) 
 
 
 
Diastolic Blood Pressure (DBP) 
below 50 mm Hg  
Low (L) 
 
50-89 mm Hg 
Normal 
 
90-109 mm Hg 
High (H) 
 
110 mm Hg and above 
Very High (VH) 
12.5.2.5 
Electrocardiograms (ECGs) and QTc Intervals 
Summary ECGs, based on the measurement of an ECG over 1 to 5 minutes as described 
in Section 6.4.3 will be used for each evaluation.  Quantitative ECG measurements (PR 
interval, QRS duration, HR, QT interval, QTcB interval, and QTcF interval) and changes 
from Baseline (RW0) will be summarized descriptively by dose, treatment group and 
time point.  ECG results will be available to the Investigator shortly after being obtained 
and all ECGs will be reviewed by a central consulting cardiologist who will provide an 
“over-reading” that will serve as the definitive study value.  While on study treatment, a 
QTc above 500 msec or above 60 msec above Baseline will be an AESI (See 
Section 13.2.2). 
Categorical changes from Baseline and QTc values from each visit will be summarized 
by worst change, by visit, by treatment group and by dose of levoketoconazole. The 
clinically important categories (Table 6) of actual and change values will be tabulated 
and provided as listings.  
QTc intervals will be assessed using paired t-tests of change values and QTc shifts from 
normality will be assessed by McNemar’s test.  All other analyses will be descriptive. 
Table 6 
QTc Interval Values of Clinical Importance 
QTc Interval 
Criteria (msec) 
Change from Baseline 
below 30 
 
30-60 
 
above 60 
 
 
Actual Value 
451-480 
 
481-500 
 
above 500 


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12.5.2.6 
Oral Glucose Tolerance Test (pre-diabetic subjects with IFG) 
For pre-diabetic subjects with IFG at Baseline, the number and percent of subjects after 
each study Phase will be summarized for each of the following categories. 
Pre-test:  
• Normal: glucose level < 100 mg/dL (5.6 mmol/L) 
• Impaired fasting glucose: glucose level ≥ 100 mg/dL (5.6 mmol/L) and 
< 126 mg/dL (7.0 mmol/L); 
Post-test: 
• Normal: 2-hour glucose level below 140 mg/dL; 
• Impaired glucose tolerance (pre-diabetic): glucose level at least 140 mg/dL and no 
more than 200 mg/dL; 
• Provisional diagnosis of diabetes (diabetic): glucose level at least 200 mg/mL. 
Glucose and insulin values during the OGTT will also be summarized by maximum 
value, time to maximum value and AUC, and statistically analyzed with a paired t-test for 
each assessment.  Exploratory analyses of insulin resistance and/or beta cell function will 
be described in the SAP. Changes in OGTT-derived glucose values from Baseline (RW0) 
to RW5 and from Visits RW5 to RES2 will be summarized by treatment group. 
12.5.2.7 
Other Safety Measures 
All other safety laboratory measures (e.g. morning serum cortisol, ACTH, prolactin, 
testosterone, urine albumin:creatinine) will be listed by subject and time point and 
descriptively summarized, including changes from Baseline (RW0) by treatment group 
and dose of levoketoconazole.  
Changes in the size of pituitary tumor (in millimeters of largest diameter and/or by 
estimated volume) from Screening to Baseline (RW0) and RW5 (for the 
levoketoconazole-naïve cohort) and from Baseline (RW0) to RW5 (for the SONICS-
completer cohort) will be summarized descriptively by treatment group.   
12.5.3 Efficacy Analyses 
The ITT population (i.e. pooled cohorts) will be used in the main analyses of the primary 
endpoint and the PP population in supportive analyses.  Handling of missing data for 
primary endpoint analyses is described in Section 12.4.  Exploratory efficacy analyses 
will also include the levoketoconazole-naïve and SONICS-completer populations. 
12.5.3.1 Primary Efficacy Analysis 
Loss of Therapeutic Response 
Mean UFC data obtained at Visit RW0 serves as the Baseline measure defining cortisol 
response.  As an entry requirement, all subjects who are enrolled into the Randomized 


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Withdrawal Phase will have achieved a therapeutic cortisol response (though not 
necessarily a normalized mUFC if a SONICS-completer cohort subject) and will be 
taking an established dose of levoketoconazole, the Therapeutic Dose.  Considerations 
for loss of established cortisol response during the Randomized Withdrawal period makes 
an allowance for the subgroup of SONICS-completer cohort subjects  who do not have a 
normalized mUFC response at RW0. 
Loss of response is assessed based on the mean of three 24-hour UFC measurements 
(mUFC) (at least two measurements from adequate collections) obtained at any visit from 
the second through the final Randomized Withdrawal visits (RW1 through RW5 
inclusive) when: 
• The mUFC is above 1.5X the ULN of the central laboratory’s reference range; 
OR 
• The mUFC is over 40% above the Baseline (RW0) value if the RW0 value is 
above the ULN (i.e. >1.0X ULN) for SONICS-completer cohort subjects; OR 
• An early rescue criterion is met. 
The primary efficacy analysis will determine the significance of the difference in 
proportions of subjects losing response among each of the two blinded treatment groups.     
Statistical significance testing will be conducted using a logistic regression model 
containing fixed effect terms for Randomized Withdrawal treatment group 
(levoketoconazole, placebo) and subject cohort (levoketoconazole-naïve cohort, 
SONICS-completer cohort) and confirmed using a two-sided Fisher’s Exact test. 
12.5.3.2 Secondary Efficacy 
Inferences derived from secondary efficacy analyses will be gated on results from the 
primary efficacy analysis.  Secondary efficacy analyses will be hierarchically structured 
to ensure control of the family-wise type I error rate at the 0.05 level.  Hypothesis tests 
for secondary endpoints will be based on null hypotheses that assume no a priori 
differences between placebo and levoketoconazole treatments.  All secondary endpoints 
will be analyzed using the ITT population (primary analyses) and the PP population 
(supportive analyses, but only if PP population is notably different from ITT population, 
see SAP for details). 
Additional details of the testing procedures not included here, including handling of 
missing data, will be described in a SAP to be finalized prior to breaking the blind. 
UFC and LNSC Analyses 
Changes in UFC and LNSC from Baseline 
Mean UFC will be calculated from adequate 24-hour urine collections only.  At Baseline 
(RW0) and at end of Randomized Withdrawal Phase and of Restoration Phase, where 
three samples are to be collected, the mUFC will be calculated only if there are at least 
two adequate samples.  When the number of adequate samples is less than two at any 
visit, the main secondary analyses will consider the UFC value as missing; sensitivity 


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analyses will use a single adequate urine sample or imputations of missing values.  The 
mUFC from the collections at each visit will be used in the analysis of UFC. 
Mean UFC and LNSC will be summarized by time point using descriptive statistics and 
displayed over time.  Changes from Baseline (RW0) in mUFC and LNSC during the 
Randomized Withdrawal Phase will be analyzed using a repeated measures mixed effects 
model with fixed effect terms for treatment group, subject cohort, time (i.e. visit), and 
treatment-by-time interaction, with Baseline value as a covariate and subject as a random 
effect.  The treatment groups will be compared using least squares mean differences 
between treatment groups and associated 95% CIs for each time point will be derived 
from the model.  These CIs will be regarded as descriptive statistics.  Two-sample t-tests 
will also be performed to compare the two treatment groups for the mean change from 
Baseline to each nominal visit during the Randomized Withdrawal Phase.  
Normalization of UFC during Restoration Phase 
The number and proportion of subjects with normalization of mUFC at RES2 is defined 
as the proportion of subjects with abnormal mUFC at RW5 whose mUFC is at or below 
the ULN of the reference range at RES2.  Normalization of mUFC at RES2 will be 
calculated for each treatment group and presented as shift tables from RW5 to RES2 
using three strata of mUFC status at or below ULN, more than ULN and no more 
than 1.5X ULN, above 1.5X ULN. 
Normalization of UFC at the end of Randomized Withdrawal Phase 
The number and proportion of subjects in the Randomized Withdrawal Phase with mUFC 
normalization (at or below ULN) at the end of Randomized Withdrawal Phase (RW5) 
will be summarized for each treatment group and compared using Fisher’s Exact test 
(with corresponding 95% CIs).  
 
CS Comorbidity Biomarkers 
The changes from Baseline (RW0) and percentage change from Baseline in individual 
biochemical markers of CS comorbidities (fasting glucose, fasting insulin, HOMA-IR, 
HbA1c, total cholesterol, LDL-C, and hsCRP) during the Randomized Withdrawal Phase 
and the Restoration Phase will be summarized by treatment group and time point and 
assessed using two-sample t-test comparison at each visit in the Randomized Withdrawal 
Phase.  In addition, shifts from Baseline (with regards to laboratory normal range) in 
individual biochemical markers of CS comorbidities will be summarized at each 
scheduled visit. 
For CS comorbidities measured at more than one visit after RW0 during the Randomized 
Withdrawal Phase, changes from Baseline during the Randomized Withdrawal Phase will 
also be analyzed using a repeated measures mixed effects model with fixed effect terms 
for treatment group, time (i.e. visit), and treatment-by-time interaction, the concurrent CS 
medical conditions (e.g. diabetes, hypertension) as Baseline covariates and with subject 
as a random effect.  Least squares mean differences between treatment groups and 
associated 95% CIs for each time point will be derived from the model.  These CIs will 
be regarded as descriptive statistics.     


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Cushing’s Syndrome Quality of Life Questionnaire  
QoL (Appendix L) measures and changes from Baseline (RW0) at the end of the 
Randomized Withdrawal Phase and Restoration Phase will be summarized by treatment 
group and time point using descriptive statistics and analyzed using two-sample t-test at 
the end of the Randomized Withdrawal Phase.   
Beck’s Depression Questionnaire 
Changes from Baseline (RW0) for the Beck’s Depression questionnaire (Appendix N) at 
the end of the Randomized Withdrawal Phase and Restoration Phase will be summarized 
by treatment group and time point using descriptive statistics and analyzed using two-
sample t-test at the end of the Randomized Withdrawal Phase. 
Acne, Hirsutism and Peripheral Edema 
Acne, hirsutism (for females only) and peripheral edema scores will be calculated as per 
their respective instrument-derived instructions, provided in Appendix M, and results will 
be summarized at each visit, including changes from Baseline and score shifts from 
Baseline.  Changes from Baseline during the Randomized Withdrawal Phase and 
Restoration Phase will be summarized by treatment group and time point and mean 
changes from Baseline assessed using two-sample t-test at each visit in the Randomized 
Withdrawal Phase. 
12.5.3.3 Exploratory Efficacy 
Medication Changes 
Changes to concomitant medications (focusing on, but not necessarily limited, to anti-
hypertensive, anti-hyperglycemic, anti-cholesterol and anti-inflammatory medications) 
will be listed by subject.  The number and proportion of usage of each medication class at 
Baseline and at all post-Baseline visits by treatment will be displayed.  In addition, the 
number and proportion of subjects with medication changes during the study will be 
summarized by treatment group and time point.  The proportions with dose increases and 
decreases, including new and discontinued medications will be displayed.   
Time to Event Analysis 
The time will be calculated from RW0 to the first time when:  
• The mUFC is above 1.5X the ULN of the central laboratory’s reference range; 
OR 
• The mUFC is over 40% above the Baseline (RW0) value if the RW0 value is 
above the ULN (i.e. >1.0X ULN) for SONICS--completer cohort subjects; OR 
• An early rescue criterion is met. 
Time from RW0 to first loss of therapeutic response will be defined as the time from the 
first dose of blinded study drug (levoketoconazole or placebo) to the time when a subject 
meets one of the criteria above.  Time from RW0 to the need for early rescue medication 
is defined as the time from first dose of blinded study drug (levoketoconazole or placebo) 


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to the time at which the Investigator withdraws study drug in favor of other treatments 
including open-label levoketoconazole.   
Time to first normalization of mUFC beginning from RW5 (subset of subjects with 
mUFC above 1.5X ULN at RW5) will be estimated as the time from the first dose of add-
on study drug (levoketoconazole or placebo) at RW5 to the time when a subject has 
confirmed mUFC no more than ULN (i.e. <=ULN) for the assay reference range.   
Time to first normalization of LNSC beginning from RW5 (subset of subjects with LNSC 
above ULN at RW5) will be estimated as the time from the first dose of add-on study 
drug (levoketoconazole or placebo) at RW5 to the time when a subject has an LNSC 
result no more than the ULN for the assay reference range.   
Each time-to-event endpoint will be analyzed using Kaplan-Meier methods.  Median time 
to each event along with the associated two-sided 95% CI will be presented by treatment 
group.  The time to event distributions will be compared statistically with a two-sided 
log-rank test.  The CI will be regarded as a descriptive statistic. 
Normalization of UFC during Dose Titration and Maintenance Phase 
The number and proportion of subjects meeting the following criteria will be summarized 
by therapeutic dose, along with 95% CI for the proportion: 
• Achieved normalization of mUFC at the end of Dose Titration and 
Maintenance Phase (TM7)  
• Achieved either normalization of mUFC or partial response (at least 50% 
decrease in mUFC) at the end of Dose Titration and Maintenance Phase 
(TM7) 
Normalization of LNSC during Restoration Phase 
The number and proportion of subjects with normalization of LNSC at RES2 will be 
analyzed in the same way as the corresponding UFC analyses described in 
Section 12.5.3.2. 
Serum Cortisol and ACTH 
Serum cortisol and ACTH are primarily considered to be safety endpoints (see 
Section 12.5.2.7). 
Clinical Signs and Symptoms Excluding Acne, Hirsutism and Peripheral Edema 
Individual clinical signs and symptoms, defined in Appendix M, will be summarized by 
treatment (or dose) group at each time point by number and percent of subjects.  For 
signs and symptoms other than acne, hirsutism and edema, each sign and symptom 
present at Baseline (RW0) will be graded on a 0 to 3 severity scale (0=absent, 1=mild, 
2=moderate, 3=severe, and the severities reported at each visit will be added to derive a 
total score.  Individual sign and symptoms severity scores will also be summarized using 


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shift tables at each visit. Total severity score and changes from Baseline of the severity 
total score will be presented by visit.  
Other Exploratory Endpoint Analyses 
Partial loss of response 
Proportions of subjects with partial loss of response (mUFC above normal but no more 
than 1.5X ULN, or LNSC that was normal at Baseline (RW0) and becomes abnormal 
(>ULN) based on each of two LNSC collections obtained on different nights) AND 
clinically significant worsening of signs and symptoms of CS will be compared between 
groups using a two-sided Fisher’s Exact test.  
Descriptions of other exploratory analyses will be provided in the SAP. 
12.5.4 Pharmacokinetics Analysis 
The PK model parameters will include: CL/F, V/F, Ka with associated between subject 
variability where feasible.  Model parameters will be tabulated with associated precision.  
Derived parameters including t½, AUC and Cmax will be reported, if appropriate. 
Because the PK of ketoconazole are reported to change over time, time dependent 
changes in CL/F, AUC, and t½ will be investigated and, if identified, changes will be 
described in the model. Derived parameters will be tabulated with associated summary 
statistics. 
A population modeling-based approach will be used to evaluate PK data as implemented 
in NONMEM® (Version 7 level 2 or higher).  Subjects with at least one adequately 
documented dose and concentration record will be considered for inclusion in the 
population PK evaluation.  All evaluations will be conducted based on a pre-specified 
analysis plan. Standard model building and model evaluation procedures will be 
followed.  Derived parameters will be calculated from the final model.  The model will 
include data derived from the SONICS study. 
12.5.5 Pharmacodynamics Analysis 
The PD model parameters including UFC Imax, levoketoconazole dose producing UFC 
IC50, and associated estimates of between-subject variability will be reported.  Individual 
maximal UFC reductions achieved during the TM Phase will be tabulated and summary 
statistics (mean, median, SD and percent coefficient of variation) will be presented.  
Stochastic simulations of the expected response for the preferred dose regimen will be 
generated to explore the range of UFC reduction. 
A population modeling-based approach will be used to evaluate PD data (UFC) as 
implemented in NONMEM® (Version 7 level 2 or higher).  Subjects included in the 
population analysis with at least one adequately documented dose, PK record and UFC 
record will be considered for inclusion in the population PD evaluation.  All evaluations 
will be conducted based on a pre-specified analysis plan. Standard model building and 
model evaluation procedures will be followed.  Derived parameters such as maximal 
response will be calculated from the final model as appropriate.  The PK-PD models will 
include data from SONICS. 


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12.5.6 Subgroup Analyses 
Subgroup analyses for the primary endpoint and biomarkers of CS comorbidities 
endpoints will be performed for a minimum subgroup size of at least 30% of the ITT 
population.  Details will be presented in the SAP. 
12.5.6.1 Prior Therapy for Cushing’s Syndrome 
Subgroup displays for the primary endpoint and the biomarkers of CS comorbidities 
endpoints will be generated for subjects that enter the study as surgery-naïve versus 
surgery-experienced.  Subgroup analyses by number of prior surgeries, time since last 
surgery, and category of prior medical treatment will also be explored depending on 
subgroup size. 
12.5.6.2 Prior Radiation Therapy 
Subset displays for the primary endpoint and the biomarkers of CS comorbidities 
endpoint will be generated, excluding subjects who previously received radiation therapy.   
12.5.6.3 Hypertensive Subjects 
Subgroup displays for the primary endpoint and the biomarkers of CS comorbidities 
endpoint will be generated for subjects who enter the study while being prescribed 
antihypertensive medications versus not and subjects who enter the study with a Baseline 
SBP above 130 mmHg or DBP 90 mmHg or above regardless of antihypertensive 
medication status versus those with lower blood pressure recordings. 
12.5.6.4 Pre-diabetic/Diabetic Subjects 
Subgroup displays for the primary endpoint and the biomarkers of CS comorbidities 
secondary efficacy endpoint will be performed for subjects who enter the study as pre-
diabetic (Baseline fasting glucose greater or equal to 100 mg/dL (5.6 mmol/L) and less 
than 126 mg/dL (7.0 mmol/L) without concomitant use of antihyperglycemic medication) 
versus those with normal fasting glucose or diabetic (Baseline fasting  glucose 126 
mg/dL or above or lower fasting glucose while being prescribed antihyperglycemic 
medications) versus those without diabetes.  
12.6 Interim Analyses and Data Monitoring 
An interim analysis, also referred to as the End of Randomized Withdrawal Phase 
analysis, will be conducted after all enrolled subjects have either completed the 
Randomized Withdrawal Phase or discontinued prior to the end of the Randomized 
Withdrawal Phase.  The interim analysis will include unblinded efficacy and safety data 
up to the end of the Randomized Withdrawal Phase. Data from the Restoration Phase will 
not be analyzed. Prior to the unblinding for the interim analysis, the data up to the end of 
the Randomized Withdrawal Phase will be cleaned and reviewed in a blinded manner to 
resolve data queries.  Details of the planned interim analysis will be provided in the SAP.  
The SAP will be finalized prior to the unblinding for the interim analysis results.   
Subjects, Investigators, study site personnel, representatives of the Sponsor and CRO 
involved in the monitoring of the study, and representatives of the CRO involved in the 


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data management of the study will remain blinded at the individual subject level until 
after the database lock at the end of the study.  The names of individuals who will be 
unblinded at the individual subject level with respect to the interim analysis activities 
and/or its results will be documented by the statistician who will lead the unblinded team 
that will conduct the interim analysis.   
No changes to the design or conduct of the remainder of the study nor the pre-specified 
analyses in the SAP will be made based on the interim analysis results.  The results from 
the interim analysis for the primary endpoint and the secondary endpoints during the 
Randomized Withdrawal Phase will be considered as final.  There will be no statistical 
adjustments of the results at the final analysis that will be conducted after the study ends.  
Since some of the subjects will still be ongoing in the Restoration Phase at the time of the 
interim analysis, the results of the final analysis on the secondary endpoints during the 
Restoration Phase will be analyzed for potential bias resulting from the timing of the 
interim analysis.  These analyses will be described in the SAP.   
An independent DSMB will review key safety data at regular intervals throughout the 
study, as described in Section 12.5.2.  The DSMB charter will include details on the 
restricted access to and the disclosure of the interim safety results presented to the 
DSMB.  
13 ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) 
The Investigator and study staff are responsible for detecting and recording AEs and 
SAEs during scheduled safety evaluations and whenever such information is brought to 
their attention. This section of the protocol provides definitions and detailed procedures 
to be followed. 
During each visit, the Investigator will question the subject about AEs using an open 
question taking care not to influence the subject’s answers, e.g. "have you noticed any 
change in your health?” 
13.1 Definition of an AE 
An AE is any untoward medical occurrence in a study subject that is temporally 
associated with the use of a medicinal product, regardless of its potential relationship to 
the medicinal product.  An AE, therefore, can be any unfavorable or unintended sign, 
including an abnormal laboratory finding, symptom, or disease (new or exacerbated), 
whether related to the study drug or study conduct or not.   
Examples of an AE include: 
• Exacerbation of a pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• New conditions detected or diagnosed after investigational product administration 
even though it may have been present prior to the start of the study. 
• Signs, symptoms of a drug interaction. 
• Signs, symptoms of a suspected overdose of either investigational product or a 
concurrent medication.  


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• A laboratory abnormality worsening or newly occurring after the start of the study 
(i.e., after Screening) that results in subject withdrawal from the study or medical 
treatment or further follow-up. 
NOTE: Abnormal values that reflect hypercortisolism (UFCs, LNSC and serum cortisol) 
will not be recorded as AEs. AEs may include pre- or post-treatment events that occur 
because of protocol-mandated procedures (i.e., invasive procedures, modification of 
subject’s previous therapeutic regimen). 
13.2 Definition of a SAE 
An SAE is any untoward medical occurrence that, at any dose: 
(a) results in death; 
(b) is life-threatening; 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death if it were more severe. 
(c) requires hospitalization or prolongation of existing hospitalization; 
NOTE:  In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or out -
patient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred, or was necessary, the 
AE should be considered serious. 
(d) results in disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption. 
(e) is a congenital anomaly/birth defect, or 
(f) Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 


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13.2.1 Disease-Related Events 
Although symptoms of CS are quite non-specific, all AEs and their attributions will be 
collected and reviewed.  The reduction in cortisol levels, regardless of therapeutic 
intervention, is known to cause symptoms (e.g., nausea, lethargy, muscle aches), and 
these too will be captured as AEs for evaluation. 
13.2.2 Adverse Events of Special Interest (AESI) 
A serious or non-serious event of scientific and medical concern specific to a Sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor can be appropriate. Such an event might warrant further 
investigation to characterize and understand it. 
AESIs should be reported to the designated safety group as per Section 13.7 
regardless of seriousness or causality.  Upon receipt, these AEs will be captured in the 
safety database, targeted follow-up queries will be sent to sites, and source 
documentation will be sent to the DSMB.  As deemed appropriate, analysis of any 
unscheduled PK samples collected in association with AESIs may be expedited. Once 
uploaded and reconciled in the clinical database, these results will be forwarded to the 
DSMB. 
The AESIs for this study are defined as follows: 
 Persistent QTc prolongation:  Persistent elevation of the QTc interval is 
defined as absolute QTc interval above 500 msec (or above 60 msec above the 
Baseline), with an ECG evaluation on repeat determination continuing to 
demonstrate QTc prolongation in the absence of plausible alternative 
explanations.  For purposes of comparing the prolonged QTc interval to a 
Baseline interval for determining if an AESI has occurred, the Baseline interval 
will be TM0 for events first occurring during the Titration and Maintenance Phase 
and RW0 for events first occurring during the Randomized Withdrawal Phase or 
Restoration Phase. 
 Potential hepatic events:  Signs of liver dysfunction or injury, such as: 
• ALT or AST above 8X ULN; 
• ALT or AST rises to above 5X ULN in less than 4 weeks or persists for over 
2 weeks; 
• ALT or AST above 3X ULN and total bilirubin above 2X ULN or INR above 
1.5 not explained by any other cause such as viral hepatitis; 
• ALT or AST above 3X ULN with new onset of or worsening of fatigue, 
nausea, vomiting, fever, rash or eosinophilia, in the absence of other evident 
cause; 
• Signs and /or symptoms suggestive of hepatic dysfunction (any of the 
following: nausea, anorexia, fever, fatigue, right upper quadrant discomfort, 
pruritus, dark urine or acholic stool) coupled with ALT and/or AST above 
3X ULN and/or AP above 2X ULN, and/or total bilirubin above 2X ULN in 


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the absence of evidence for obstruction or Gilbert syndrome. An ultrasound 
evaluation of the gallbladder and bile duct should be conducted to exclude 
cholestasis as the cause for elevated AP and/or total bilirubin. 
Please see Appendix O for guidance on the assessment of abnormal LFTs. 
 Adrenal insufficiency:  A suspicion or diagnosis of adrenal insufficiency, 
based on the considerations laid out in Section 6.5.3. 
13.3 Time Period, Frequency, and Method of Collecting AEs and SAEs 
As a consistent method of soliciting AEs, the subject should be asked a non-leading 
question such as: "How do you feel?"  
All AEs occurring after obtaining the informed consent until the end of the final visit 
must be reported.  All AEs must be recorded irrespective of whether they are considered 
drug-related. 
At each visit/assessment in the period defined above, AEs will be evaluated by the 
Investigator and recorded. 
Any AEs already documented at a previous assessment and designated as ongoing, 
should be reviewed at subsequent visits as necessary.  If these have resolved, this should 
be documented.  Changes in intensity or frequency of AEs should be recorded as separate 
events (i.e., a new record started). 
The recording of AEs and SAEs are described in Section 13.4 (“Recording of AEs and 
SAEs”). 
13.4 Recording of AEs and SAEs 
All clinical events, including either observed or volunteered problems, complaints or 
symptoms are to be recorded on the Adverse Events page(s) of the CRF.  The need to 
capture this information is not dependent upon whether the clinical event is associated 
with study treatment. Adverse clinical events resulting from concurrent illnesses or 
reactions to concurrent medications are also to be recorded.  To avoid vague, ambiguous, 
or colloquial expressions, the AE should be recorded in standard medical terminology 
rather than the subject’s own words. 
Each adverse clinical event is to be evaluated for duration, intensity, and whether the 
event may be associated with the study drug or other causes.  Start and stop dates, 
relationship to study drug, medical management, and alternative causality of event must 
be recorded in the Adverse Events section of the CRF.  AEs believed to be possibly 
related to study drug must be followed until resolution. 
13.5 Evaluating AEs and SAEs 
13.5.1 Severity Rating 
The severity of AEs and SAEs will be graded per NCI CTCAE, Version 4.0.  
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 


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Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
Grade 3  
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
An AE that is assessed as severe should not be confused with an SAE.  An event is 
defined as ‘serious’ when it meets one of the pre-defined outcomes as described in 
Section 13.2 “Definition of a SAE”. 
13.5.2 Relationship to Study Drug 
For AEs, the relationship to study treatment is to be assessed using the following 
definitions: 
• Not related: The AE is definitely not related to the drug.  This designation should 
be reserved for those events which occur prior to study treatment or for those 
events which cannot be even remotely related to study participation (e.g., injuries 
sustained in an automobile accident that itself was not precipitated by a possibly-
related adverse event). 
• Unlikely: There is no reasonable association between the study treatment and the 
suspected event, and a precipitant of the adverse event other than study treatment 
has been identified (e.g., a therapy used outside of the study or the subject’s 
underlying clinical condition). 
o For purposes of expedited regulatory reporting, unlikely causality will be 
considered as not-related causality.  
• Possibly related:  The suspected event may or may not follow a reasonable 
temporal sequence from study treatment administration but seems to be the type 
of reaction that cannot be dismissed as unlikely.  The event could have been 
produced or mimicked by the subject's clinical state or by other modes of therapy 
concomitantly administered to the subject. 
• Probably related: The suspected event follows a reasonable temporal sequence 
from study treatment administration, abates upon discontinuation of the treatment, 
and cannot be reasonably explained by the known characteristics of the subject's 
clinical state. 
• Definitely related: This designation should be reserved for those events which 
have no uncertainty in their relationship to treatment administration. 
13.6 Follow-Up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject.  Further information on SAEs will be provided to the Sponsor’s designated safety 
group on the subject’s condition within 24 hours as described in Section 13.7. 
New or updated information will also be recorded on the “AE” CRF within 24 hours. 


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13.7 Prompt Reporting of SAEs to Sponsor 
Any SAE reported by a subject who has signed the informed consent whether during the 
study or discovered during follow-up, must be reported by the Investigator to the 
Sponsor’s designated safety group within 24 hours even if the SAE does not appear to 
be drug-related. This should be done by emailing or faxing a copy of the SAE Report 
form plus other related information to Sponsor’s designated safety group.  The SAE may 
be reported by telephone; however, this should be followed up within 24 hours with a 
copy of the SAE Report form.  Additionally, it may be necessary for the designated 
safety group to communicate with the Investigator if additional information is required.   
Regardless of seriousness or causality, AEs designated as AESI (instances of persistent 
QTc prolongation, potential hepatic events, and potential adrenal insufficiency) should be 
reported to the Sponsor’s designated safety group within 24 hours, in the same manner as 
SAEs (see also Section 13.2.2). 
During both business and non-business hours, the email address and telephone number 
listed below should be used to report SAEs and AESIs. 
 Reportable Events Contact Details 
Email: GlobalSAEInbox@Chiltern.com 
24-Hour Call Center Phone: +1 416 568 9804  
An SAE Report form must be completed and forwarded via email to Cortendo’s 
designated safety group using the email address listed above within 24 hours of becoming 
aware of the event.  
All additional follow-up evaluations must be reported to Cortendo’s designated safety 
group.  Such data should be sent to the Sponsor within 24 hours.  All SAEs will be 
followed until the Investigator and Sponsor agree the event is satisfactorily resolved. 
The Sponsor will be responsible for completing the safety report and for notifying the 
relevant authorities of any SAE as outlined in the International Conference on 
Harmonization (ICH) Guidelines and per local regulatory requirements.  The Investigator 
and Cortendo’s designated safety group will also ensure that the appropriate IRBs/ IECs 
are notified of the SAE. 


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Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, et al. 
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Steen RE, Kapelrud H, Haug E, Frey H. In vivo and in vitro inhibition by ketoconazole of 
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APPENDIX A 
TIME AND EVENTS SCHEDULES 
Refer to the Section 6 (Study Assessments and Procedures) and the Study Procedures Manual for more specific 
details on the assessments. 
Table 7 
Time and Events Schedule for Screening Procedures 
 
Screening Phase1 
Assessments 
Subjects who completed SONICS 
within the previous 6 months and 
currently receiving levoketoconazole2,3 
Levoketoconazole naïve subjects and 
subjects who completed SONICS > 6 
months prior to study entry 
Informed Consent 
X4 
X 
Eligibility (Inclusion/Exclusion Criteria) 
X 
X 
Medical history and demography 
X 
X 
Prior/concomitant medication 5 
X 
X 
Physical exam & assessment of 
appearance 
 
X 
Cushing’s Signs & Symptoms Form 
 
X 
Vital signs (BP and HR in triplicate and 
temperature) 
 
X 
Weight/height/BMI/body habitus 
 
X 
HIV / Hepatitis B and C screens 
 
X 
ECG – Local ECG machine 
 
(X) 6 
ECG – Spaulding7 
 
X 
Late night salivary cortisol (2 nights)8 
X9 
X 
TSH / FT4 and Prolactin  
 
X 
Pituitary MRI  
 
X if not within 6 months of TM0 or RW0 
FSH and estradiol (women only) 
 
X 
Urine βHCG, females 
 
X 
Routine clinical laboratory tests 
(chemistry, hematology, urinalysis) 
 
X 
Fasting glucose and insulin measurements 
 
X 
INR/PT/PTT 
 
X 
HbA1c 
 
X 
                                               
1 Screening procedures to be performed following informed consent; Screening Phase for levoketoconazole-naive cohort may last up 
to approximately 13 weeks to allow prior medication washout before entering the TM Phase (Table 8); Subjects confirmed as 
eligible for the SONICS-completer cohort will proceed directly to Visit RW0; The Screening Phase, which will rely on data 
collected during SONICS, will not begin before Visit M12 of SONICS and will end once eligibility is confirmed (the time from 
confirmation of eligibility and RW0 should be no more than 11 (+3) days); the minimum time requirement is confirmation of the 
Therapeutic Dose as dictated by tolerability and UFC results). (see Table 9).  
2 If there is a time gap between completion of Screening and TM0 or RW0 for subjects currently receiving levoketoconazole, then 
open-label levoketoconazole should be continued between Screening and TM0 or RW0 to maintain the Therapeutic Dose. If rolling 
over from SONICS, subjects will be dispensed LOGICS medication starting at the screening visit.  If entering from EAP, subjects 
will stay on open-label levoketoconazole dispensed from EAP until the Baseline visit.   
3 For subjects who have completed SONICS more than 6 months prior to the Screening Phase and have not been on a stable 
Therapeutic Dose throughout the previous 12-week period, Screening Procedures will mimic those for the levoketoconazole-naïve 
subjects to confirm eligibility for the current study.   
4 Informed consent for subjects who completed SONICS is administered at or prior to the Screening visit prior to randomization or 
performance of any study procedures for this protocol.  
5 Blood pressure, diabetes, cholesterol, anti-inflammatory, and CS-specific medications will be captured separately from other 
medications. 
6 Local machine to be used only when Spaulding device is non-operational. Local ECGs must be transmitted to Spaulding for central 
reading via printout.  
7 Spaulding ECGs will be obtained over a minimum of 1 minute up to a maximum of 5 minutes at Screening.  
8 Ideally, UFC and LNSC samples should be collected before DST. If collecting UFC and LNSC samples after administering 
dexamethasone, do not collect the LNSC until at least 5 days after dexamethasone is administered; do not start collection of the 
UFCs until at least 14 days after dexamethasone is administered (see Section 6.4.5.3). 
9 Subjects rolling over from SONICS at the M12 visit (and after signing the informed consent form for LOGICS) will need one 
additional LNSC collection for LOGICS screening (total of 2 collections).  
 


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Screening Phase1 
Assessments 
Subjects who completed SONICS 
within the previous 6 months and 
currently receiving levoketoconazole2,3 
Levoketoconazole naïve subjects and 
subjects who completed SONICS > 6 
months prior to study entry 
OGTT10 
 
X 
Dexamethasone Suppression Test (DST)11 
 
X if not done within previous 60 days 12 
ACTH 
 
X 
Fasting lipid measurements, triglycerides 
 
X 
Spot urine for albumin/creatinine ratio 
 
X 
Dispense study medication/diary 
X13 
X14 
Testosterone, free/total 
 
X 
Adverse Event assessment15 
X 
X 
24-h UFC/free cortisol/creatinine/ urinary 
volume (3 collections)  
X16 
X 
                                               
10 OGTT should only be performed in subjects with IFG (i.e. fasting glucose ≥ 100 mg/dL (5.6 mmol/L) and < 126 mg/dL (7.0 
mmol/L)) who do not have diabetes and who are not receiving medications to lower blood glucose (i.e. antihyperglycemics). 
11 DST is not needed at screening for subjects currently receiving levoketoconazole at screening.  
12 This procedure will necessitate a second visit that can be performed at home by a qualified HHC professional.  
13 If rolling over from SONICS, subjects will return SONICS medications and will be dispensed LOGICS medication starting at the 
screening visit.  If entering from EAP, subjects will stay on open-label levoketoconazole dispensed from EAP until the Baseline visit.  
14 Only the study diary should be dispensed at Screening (and not study medication) for levoketoconazole-naïve subjects and subjects 
currently receiving levoketoconazole via an EAP but who completed SONICS greater than 6 months ago. 
15 AEs at Screening will only include AEs reported after ICF signing.  AEs reported in SONICS protocol and present at Screening will 
be recorded as medical history.  
16 Subjects who completed SONICS at M12 visit (and after the informed consent form for LOGICS is signed) will need one additional 
UFC collected at Screening (total of 3 UFC collections needed).   
NOTE: The UFC samples should not be collected within 2 weeks (approximately 14 days) after administering DST.   


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Table 8 
Time and Events Schedule for Dose Titration and Maintenance Phase (levoketoconazole-naïve Cohort) 
Assessments 
Dose Titration and Maintenance (TM) Phase 1 
 
BL 
Visit interval 14 days (± 3) 
Additional 
safety visit 
(in office)2  
Additional 
safety visit 
(HHC)2 
TM03  
TM1 
TM2 
TM3 
TM4 
TM5 
TM6 
TM74 
Prior/concomitant medication5  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer Study drug/patient study diary review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug accountability/dispensation of drug and study diary 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical exam & assessment of appearance 
(X) 
 
 
X 
 
X 
 
X 
 
 
Cushing’s Signs & Symptoms Form 
(X) 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs (BP and HR in triplicate and temperature) 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/height/BMI/body habitus 
(X) 
 
 
 
X 
 
 
X 
 
 
Abdominal Girth (in triplicate) 
X 
 
 
 
X 
 
 
X 
 
 
ECG – Local ECG machine6  
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 
ECG – Spaulding7  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Late night salivary cortisol (1 night)8 
 
X 
X 
X 
X 
X 
X 
 
 
 
Late night salivary cortisol (2 nights)8 
  (X)8  
 
 
 
 
 
 
X 
 
 
TSH / FT4 and Prolactin  
(X)9  
 
 
 
 
 
 
X 
 
 
Urine βHCG, females 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Routine clinical laboratory tests (chemistry, hematology, coagulation, 
urinalysis) 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting glucose and insulin measurements 
(X) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
 
 
 
 
 
 
X 
 
 
                                               
1 The approximate usual interval between dose-titration visits will be 14 days (±3 days) [including reporting time for UFC levels and safety laboratory assessments]. 
2 One extra safety evaluation 5 (±2) days after each dose escalation to 750 mg/day or above during the TM phase to include: AEs, vital signs, routine safety, laboratory assessments (including liver safety 
tests), ECGs, morning serum cortisol.  PK sampling at TM3, TM4, TM5, and TM6 could alternately be performed during additional safety visit required for DL4, DL5, DL6 and DL7 if required.  
Additional safety visit can occur anytime bases on dose escalations to 750 mg/day or above.  Safety visit can be performed at home by a qualified HHC professional. 
3 TM0 serves as Baseline for the TM Phase.  Screening procedures completed within 3 weeks of TM0 (within 2 weeks for LNSC, QTc interval and liver safety tests; and within 6 weeks for UFCs) will 
be used as the TM0 or Baseline value.  If other Screening procedures were completed more than 3 weeks prior to TM0, then they will be repeated at TM0, except for pituitary MRI, which may be 
completed up to 6 months prior to TM0 or RW0 and UFCs which may be completed up to 6 weeks prior to TM0.  All blood samples, except for post-dose PK samples, should be obtained prior to 
administering the first dose of levoketoconazole.   
4 TM7 procedures will also be completed by subjects who prematurely withdraw from the study during the TM Phase. 
5 Blood pressure, diabetes, cholesterol, anti-inflammatory, and CS-specific medications will be captured with other medications but will require specification of these medication types.  
6 Local machine to be used only when Spaulding device is non-operational. Local ECGs must be transmitted to Spaulding for central reading via printout.  
7 Spaulding ECGs will be obtained over a minimum of 1 minute up to a maximum of 5 minutes and within approximately 1-2 h after drug administration at each visit.  
8 LNSC collections should be collected before each visit.  LNSC collections during Screening to provide the Baseline measurements should be collected within 14 days prior to dosing at TM0.   
9 TSH/FT4 and prolactin to be measured if not done at Screening. 
 


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Assessments 
Dose Titration and Maintenance (TM) Phase 1 
 
BL 
Visit interval 14 days (± 3) 
Additional 
safety visit 
(in office)2  
Additional 
safety visit 
(HHC)2 
TM03  
TM1 
TM2 
TM3 
TM4 
TM5 
TM6 
TM74 
OGTT (pre-diabetic subjects with IFG only) 10  
   
 
 
 
 
X 
 
X 
 
 
Serum cortisol (morning) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACTH 
(X) 
 
 
X 
 
X 
 
X 
 
 
Fasting lipid measurements, triglycerides 
(X) 
 
 
 
X 
 
 
X 
 
 
hsCRP 
X 
 
 
 
X 
 
 
X 
 
 
Spot urine for albumin/creatinine ratio (only if abnormal at Screening) 
(X) 
 
 
X 
 
 
X 
X 
 
 
Testosterone, free/total 
(X) 
 
 
X 
 
X 
 
X 
 
 
Safety contact11 
X 
(X) 
(X) 
 
 
 
 
 
 
 
Adverse Event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cushing QoL questionnaire 
X 
 
 
 
 
 
 
X 
 
 
BDI-II instrument 
X 
 
 
 
 
 
 
X 
 
 
24-h UFC/creatinine/ urinary volume (3 collections)12 
(X) 
 
 
 
 
 
 
X 
 
 
24-h UFC/creatinine/ urinary volume (2 to 3 collections)13  
 
X 
X 
X 
X 
X 
X 
 
 
 
Pharmacokinetic sampling 14  
X 
 
(X) 
(X) 
(X) 
(X) 
(X) 
X 
(X) 
(X) 
 
 
                                               
10 Levoketoconazole-naïve cohort subjects with IFG should have OGTT prior to RW0 if still escalating at TM5 after the Therapeutic Dose has been established in TM Phase (i.e. at TM7). 
11 Contact (method by subject preference) approximately 1 week after first dose and each dose adjustment up to DL3.  
12 Prior to the final open-label visit (TM7), three complete 24-hour urine specimens will again be obtained (NOTE: collections should be collected prior to the visit and need not be repeated if the final 
open-label visit coincides with the initial establishment of UFC normalization) to confirm maintenance of UFC normalization prior to randomization, denoting UFC-eligibility for the Randomized 
Withdrawal Phase. UFC results must be received before next TM visit in order to determine the need to escalate dose.   
13 First 24-hour urine collection will be ~Day 8 (±2 days) and the second collection will be ~Day 9 (±2 days) after start of each dose level.  24-hour UFC collections should occur prior to and not at the 
visit and results must be received before next TM visit.  If UFC ≤ULN, there will be an additional 24-hour urine collection to confirm UFC results. 
14 During the TM Phase, PK samples should be drawn pre-dose, at 1.5-2.5 hours after dosing at TM0 and TM7 and at approximately 6-8 hours after dosing at one interim visit (TM2-TM6 or an 
additional safety visit) of the subject’s choosing.  The subject should forgo taking study medication on the day of the scheduled visit, so that dosing can be done at the clinic or by HHC professional. The 
6-8-hour time point for PK sampling is non-optional.  In case of AESI, a PK sample should be obtained as close to the time of the event as possible.   


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Table 9 
Study Time and Events Schedule for Randomized Withdrawal Phase and Restoration Phase (Both Cohorts) 
Assessments 
Randomized Withdrawal Phase 1 
Restoration Phase 
BL 
D10 
D20 
D30 
D40 
D58 
Visit interval 28 days (± 5) 
RW0 2 
RW1 
RW2 
RW3 
RW4 
RW5 3 
RES1 
RES2 4 
Concomitant medication 5 
X 
X 
X 
X 
X 
X 
X 
X 
Administer study drug/patient diary review and dispensation 
X 
X 
X 
X 
X 
X 
X 
(X) 6 
Drug accountability/dispensation of drug7 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam & assessment of appearance 
X 
 
 
X 
 
X 
 
X 
Cushing’s Signs & Symptoms Form 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP and HR in triplicate and temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/height/BMI/body habitus 
X 
 
 
X 
 
X 
 
X 
Abdominal Girth (in triplicate) 
X 
 
 
 
 
X 
 
X 
ECG – Local ECG machine 8 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
ECG – Spaulding 9 
X 
X 
X 
X 
X 
X 
X 
X 
Safety contact (between visits)10 
 
 
 
 
 
 
weekly 
                                               
1 Visits RW1, RW2 and RW4 are required but are optionally at-home visits for which assessments may be made by a qualified HHC professional appointed by the Sponsor and agreed to with the 
Investigator and subject.  For RW1, RW2 and RW4, the visit can be up to 2 days before D10, D20 and D40, respectively.  For RW3 and RW5, the visit can be up to 4 days before D30 and D58, 
respectively. 
2 RW0 serves as the Baseline Visit for the primary efficacy endpoint for all subjects.  The procedures done at Visits TM7 (for levoketoconazole-naïve cohort), at Screening (for subjects who have exited 
SONICS more than 6 months prior to the Screening Phase and have been on a stable Therapeutic Dose throughout the previous 12-week period), or at SONICS Visit M12 (for subjects who completed 
SONICS) need not be repeated at RW0 unless a dose change was required at Visit TM7; however, the findings/assessments from those procedures will be entered into the clinical database at Visit 
RW0 for subjects continuing into the Randomized Withdrawal Phase, and Eligibility must be confirmed for all subjects at RW0 to include confirmation of continuous therapy with a Therapeutic Dose 
of levoketoconazole for the requisite time period prior to RW0.  RW0 should be scheduled to occur no earlier than 14 weeks and no later than ~19 weeks after TM0, depending on duration until 
reaching a Therapeutic Dose. At least 4 weeks should elapse between reaching the Therapeutic Dose and RW0 to ensure tolerability and stability (continued effectiveness) of the Therapeutic Dose.  
Randomization (RW0) may occur concurrently with the final TM Phase visit or no more than 11 (+3) days later unless a dose change was required at Visit TM7. 
3 Subjects who require early rescue with open-label levoketoconazole will undergo RW5 procedures immediately prior to administration of open-label rescue medication (except ECG to be done 1-2 
hours after administration of rescue medication).  Subjects who complete all Randomized Withdrawal visits will undergo RW5 procedures immediately prior to administration of blinded Restoration 
Phase study medication (except ECG to be done 1-2 hours after administration of rescue medication).  As this is open-label treatment, titration beyond the previously established Therapeutic Dose is 
permitted if medically necessary.  The visit interval between RW5 and RES1 is 28 (+5) days 
4 RES2 procedures will also be performed by subjects who prematurely withdraw from the study during Restoration Phase. 
5 Blood pressure, diabetes, cholesterol, anti-inflammatory, and CS-specific medications will be captured as specific categories on the eCRF. 
6 Accountability check only. Drug administration will not occur in conjunction with this study at RES2. 
7 Drug accountability and dispensation only to be completed when visits are performed in-clinic and not applicable to HHC visits.  No dispensation of drug to occur at RW1, RW2, RW4 and RES2. All 
drug-dispensation visits including any unscheduled visit for distribution of drug should be recorded in the IRT. 
8 Local ECG machine to be used only when Spaulding device is non-operational. Local ECGs must be transmitted to Spaulding for central reading via printout.  
9 Spaulding ECGs will be obtained over a minimum of 1 minute up to a maximum of 5 minutes at Screening and within approximately 1 – 2 h after drug administration at each visit. 
10 Weekly safety contact during Restoration Phase (between RW5 and RES2) —method according to preference—to be made between visits to inquire regarding adverse events, subject status and to 
ensure compliance with study medication. 
 


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Assessments 
Randomized Withdrawal Phase 1 
Restoration Phase 
BL 
D10 
D20 
D30 
D40 
D58 
Visit interval 28 days (± 5) 
RW0 2 
RW1 
RW2 
RW3 
RW4 
RW5 3 
RES1 
RES2 4 
Late night salivary cortisol (1 night) 11 
 
X 
X 
X 
X 
 
X 
 
Late night salivary cortisol (2 nights)11 
X 
 
 
 
 
X 
 
X 
TSH / FT4 and Prolactin 12 
X 
 
 
 
 
X 
 
X 
Pituitary MRI13 
X 
 
 
 
 
X 
 
 
Urine βHCG, females 
X 
X 
X 
X 
X 
X 
X 
X 
Routine clinical laboratory tests (chemistry, hematology, 
coagulation, urinalysis) 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting glucose and insulin measurements 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
 
 
 
 
X 
 
X 
OGTT (pre-diabetic subjects with IFG only) 
   (X) 14 
 
 
 
 
X 
 
X 
Serum cortisol (morning) 
X 
X 
X 
X 
X 
X 
X 
X 
ACTH 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid measurements, triglycerides 
X 
 
 
 
 
X 
 
X 
hsCRP 
X 
 
 
 
 
X 
 
X 
Spot urine for albumin/creatinine ratio (only if abnormal at 
Screening) 
X 
 
 
 
 
X 
 
X 
Testosterone, free/total 
X 
 
 
 
 
X 
 
X 
Adverse Event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Cushing QoL questionnaire 
X 
 
 
 
 
X 
 
X 
BDI-II instrument 
X 
 
 
 
 
X 
 
X 
24-h UFC/creatinine/ urinary volume (3 or 4 collections)15 
X 
 
 
 
 
X 
 
X16 
24-h UFC/creatinine/ urinary volume (2 collections)15 
 
 
 
 
 
 
X16 
 
24-h UFC/creatinine/ urinary volume (2 to 3 collections) 15,17 
 
X 
X 
X 
X 
 
 
 
                                               
11 LNSC collections must be collected before the visit.  A second night’s collection should be done if LNSC is being used to establish the need for early rescue therapy during Randomized Withdrawal 
Phase. 
12 TSH/FT4 to be measured at TM7 Visit during the TM Phase.  If subjects reach their maximum dose before the TM7 visit during the TM Phase, they will have TSH/FT4 measured at Visit RW0 of the 
Randomized Withdrawal Phase. 
13 SONICS-completer cohort subjects will have Pituitary MRI done as part of SONICS Visit M12.  The Visit RW0 and RW5 MRI may be performed up to 2 weeks BEFORE the visit. 
14 For those who completed SONICS and are pre-diabetic with IFG at the SONICS baseline should have OGTT done to become the Baseline value for current study.  Levoketoconazole-naïve subjects 
should have the test completed during the screening phase and prior to RW0 after the Therapeutic Dose has been established in the TM Phase (i.e. at TM7). 
15 24-hour UFC collections should occur prior to the visit.  
16 For the urine collection between RW5 and RES1, subjects should have received the previously achieved Therapeutic dose of blinded study medication for at least 1 week before collections commence 
and complete and at least 1 week before the RES1 visit.  For urine collections between RES1 and RES2, urine collection should commence at approximately Day 18 of the Restoration Phase. 
17 First 24-hour urine collection will be ~Day 8 (±2 days) and the second collection will be ~Day 9 (±2 days) after the clinic visit.  A third UFC collection should be done if UFC is being used to 
establish the need for early rescue therapy during the Randomized Withdrawal Phase.  
 


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Assessments 
Randomized Withdrawal Phase 1 
Restoration Phase 
BL 
D10 
D20 
D30 
D40 
D58 
Visit interval 28 days (± 5) 
RW0 2 
RW1 
RW2 
RW3 
RW4 
RW5 3 
RES1 
RES2 4 
Pharmacokinetic sampling 18 
 
 
 
 
 
 
X 
 
 
                                               
18 During the Restoration Phase, PK samples should be drawn pre-dose and between 1.5 to 2.5 hours after dosing only at RES1. In case of AESI, a PK sample should be obtained as close to the time of 
the event as possible. 
 


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APPENDIX B 
LABORATORY ANALYTES 
Laboratory studies to be collected as per Time and Events Schedules (Appendix A). 
 
Disease-related Assessments 
Urinary free cortisol, total creatinine and total volume from 24-hour urine collections 
Salivary cortisol 
Serum cortisol 
Plasma ACTH 
Dexamethasone 
 
CS Cardiovascular Co-Morbidity Biomarkers 
 
Fasting glucose 
Fasting insulin 
Hemoglobin A1c [HbA1c] 
 
High-sensitivity C-reactive protein [hsCRP] 
Fasting lipids and triglycerides: including total cholesterol, high density lipoprotein cholesterol 
[HDL-C], and low density lipoprotein-cholesterol [LDL-C] 
 
Routine Clinical Laboratory Tests 
 
Hematology 
Platelet Count  
RBC Indices: 
Automated WBC Differential: 
RBC Count 
MCV 
Neutrophils 
WBC Count (absolute)  
MCH 
Lymphocytes 
 
MCHC 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
 
Clinical Chemistry 
Blood Urea Nitrogen 
Liver Safety Tests 
Creatinine 
AST (SGOT) 
Sodium 
ALT (SGPT) 
Potassium 
GGT 
Chloride 
Alkaline phosphatase 
Total CO2 
Total and direct bilirubin 
Calcium, Magnesium, Phosphate 
Coagulation tests (INR/PT/PTT) 
Uric Acid 
LDH 
Albumin 
 
Total Protein 
 
 


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Urinalysis 
Specific gravity 
pH, glucose, protein, blood and ketones by dipstick 
Microscopic examination (if blood or protein is > trace positive by dipstick) 
Other analytes/measures 
HIV 
Hepatitis B and C antibodies  
Free and total testosterone (both men and women) 
Estradiol and FSH (women only) 
Pregnancy test (urine βHCG, all women regardless of childbearing potential) 
Spot urine for albumin/creatinine ratio—if normal at Baseline, no further testing is required 
throughout the study 
TSH/free T4, Prolactin 
OGTT (pre-diabetic subjects with IFG only)   
 


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APPENDIX C 
STUDY MANAGEMENT AND MATERIALS 
Study Documentation 
The Investigator is required to prepare and maintain adequate and accurate case histories 
(i.e., source documents and/or Medical Record Supplement) designed to record all 
observations and other data pertinent to the study for each study participant.  This 
includes accurate documentation of accountability of study medications.  The medical 
records must contain adequate information to allow for verification of subject identity 
throughout the study.   
Electronic CRFs (eCRFs) will be completed for each subject who is enrolled in the study. 
Subject numbers will be assigned systematically immediately following the execution of 
written informed consent.  A subject Screening/enrollment log, noting reasons for screen 
failure where applicable, will be maintained for all subjects who are consented. 
All information recorded on the CRFs for this study must be consistent with the subject’s 
source documentation (i.e., source documents and/or Medical Record Supplement).  The 
source documents may include the hospital and/or the physician’s chart, X-rays, or 
laboratory test documentation.   
The CRFs for each subject will be periodically checked against the subject’s source 
documents at the study site by the site monitor.  Instances of missing or unclear data will 
be discussed with appropriate site personnel for resolution.  A quality assurance audit will 
be performed on the database. 
Archiving of Study Documentation 
The Investigator shall retain records for two (2) years following the date a marketing 
application is approved for the indication pertaining to this clinical study; or, if the drug 
is planned to be terminated or if a regulatory application is not planned to be progressed, 
until two (2) years after the investigation is discontinued and the FDA or a competent 
regulatory authority is notified. 
The Sponsor will inform the Investigator, in writing, as to when these documents no 
longer need to be maintained. 
Monitoring and Quality Assurance 
During the study, a monitor will make routine site visits to review protocol compliance, 
compare CRFs with individual subject’s original source documents, assess drug 
accountability and ensure that the study is being conducted per pertinent regulatory 
requirements.  The review of the subjects’ original medical records will be performed in a 
manner to ensure that subject confidentiality is maintained. 


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APPENDIX D 
ADMINSTRATION AND REGULATORY POLICIES 
Ethical Conduct of Study 
The Investigator(s) should conduct the study in accordance with this protocol, the 
Declaration of Helsinki and ICH GCP guidelines and FDA regulations.  The 
Investigator(s) and the Sponsor will sign the protocol and study contract, to confirm 
agreement.  The Investigator(s) will not implement any amendment (deviation or changes 
of the protocol) without agreement by the Sponsor and IRB/IEC approval, except where 
necessary to eliminate immediate hazard(s) to study subjects, or when change(s) involve 
only logistical or administrative aspects of the study. 
Records that may reveal the identities of subjects must be well protected, with 
consideration given to confidentiality and the right to privacy of subjects. 
Informed Consent 
Each subject or his/her parent/legal representative must be provided with a statement that 
the investigation involves research and that the IRB/IEC has approved solicitation of 
subjects to participate; a fair explanation of the procedures to be followed and their 
purposes, including identification of any procedures that are experimental; a description 
in lay language of any possible side effects; a description of any attendant discomforts 
and risks reasonably to be expected; a description of any benefits reasonably to be 
expected; a disclosure of any appropriate alternative procedures that might be 
advantageous for the subject; an offer to answer any inquiries concerning the procedures, 
and instruction that the person is free to withdraw consent and discontinue participation 
in the project or activity at any time without prejudice to the subject.  Payment to research 
subjects for participation in the study is considered a benefit.  All information concerning 
payment, including the schedule of payments, must be set forth in the informed consent, 
including a disclosure that the Investigator is being paid to perform the stated research. 
A subject (or the subject’s legally authorized representative) must give written consent to 
participate in the study.  This consent must be dated and retained by the Principal 
Investigator as part of the study records.  A copy shall be given to the person signing the 
form.  The informed consent process must be documented in the subject’s source 
documents. 
The Investigator agrees that the Sponsor, its employees or agents will have the right from 
time to time during this study to audit and review pertinent medical records relating to 
this clinical trial.  A statement will be obtained from each subject participating in the 
study permitting the release of his/her medical records as necessary for inspection by 
authorized personnel of the Sponsor, FDA, other Competent Authorities and the staff 
managing the clinical study.  
The release of medical records and review of their contents will comply with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) and applicable data 
protection regulations in the countries concerned. 
Institutional Review/Ethical Review 
The protocol and informed consent form for this study must be approved by an IRB/IEC.  
A copy of the Letter of Approval from the Board/Committee, which contains specific 


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identification of the documents approved, must be received by the Sponsor prior to 
shipment of drug supplies to the Principal Investigator. 
All changes to the protocol, as well as a change of Principal Investigator, must also be 
approved by the Board/Committee and documentation of this approval provided to the 
study monitor.  Records of the IRB/IEC’s review and approval of all documents 
pertaining to the study must be kept on file by the Principal Investigator and are subject 
to FDA/Competent Authority inspection at any time.  IRB/IEC re-approval is required 
each year or per local regulations.  The Principal Investigator is to notify the study 
monitor, in writing, of the approval to continue the study.   
Clinical Monitoring/Record Keeping 
There shall be no alterations in the protocol design without the written consent and 
approval of the Sponsor and the approval of the IRB/IEC, except in the case that subjects 
are at immediate risk without immediate implementation of such alterations.  In such 
situation, the site should notify the Sponsor and IRB/IEC of the deviation as soon as 
possible, and should seek the written consent and approval of the Sponsor and the 
approval of the IRB/IEC. 
All results of this trial must be recorded on eCRFs.  Each subject who has been enrolled 
must have a completed eCRF.  Reasons for termination must be stated in the early 
termination section.  Study subjects are not to be identified by name on eCRFs, but rather 
by coded identifiers and subject initials.   
The study monitor will verify the accuracy of the data by reviewing pertinent source 
documents such as office records or hospital charts of the subjects. 
Study records include eCRFs, signed FDA Form 1572, original reports of test results, and 
signed informed consent forms.  IRB/IEC approval letters and other documents 
pertaining to the conduct of the study are to be kept on file by the Investigator.   If the 
study files are assigned to someone else or removed to another location, the Investigator 
is to notify the study monitor or Sponsor in writing of the change.  All study records are 
subject to FDA or Competent Authority inspection at any time. 
The Investigator shall retain records for a period as defined elsewhere (see Appendix C, 
Study Management and Materials).   
All information supplied to the Investigator by the Sponsor before, during, and after the 
study is confidential.  Such information is to be used solely in connection with the 
clinical study.  The study protocol, IB, and any other pertinent study-related materials or 
records provided are to be maintained in a confidential manner, reviewed carefully with 
attention to admonitions and returned to the Sponsor upon request.  No part of these 
materials may be reproduced or transmitted in any form without prior written permission 
from the Sponsor. 


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APPENDIX E 
PUBLICATION POLICY 
All data generated from this study are the property of Cortendo and shall be held in strict 
confidence along with all information furnished by Cortendo.  Independent analyses 
and/or publication of these data by an Investigator or any member of his/her staff is not 
permitted without prior written consent of Cortendo.   
Any formal presentation or publication of data from this trial will be considered as a joint 
publication by the Investigator(s) and appropriate Cortendo personnel.  Authorships will 
be determined chiefly by merit, with rights of final authorship decisions to be held by 
Cortendo, unless superseded by an agreement stipulating otherwise.  Factors determining 
merit will include active participation in study design and conduct, as well as interest and 
ability to participate meaningfully in analyzing or interpreting, writing or presenting 
study results.  The venue(s) selected for publication will be determined jointly by the 
publication authors.  The first publication will be based on data from all study centers and 
analyzed as stipulated in the protocol and SAP.  Investigators participating in multicenter 
studies agree not to present data gathered from one study center or a subset of centers 
before the first full publication, unless formally agreed by Cortendo in advance.  Written 
permission to Investigators to publish subset or secondary results will be contingent on 
prior review by Cortendo of the proposed methodology and analytical plan.  Any 
Investigator-led publication or presentation will provide for nondisclosure of Cortendo 
confidential or proprietary information.  In all cases, parties planning to publish data 
agree to submit all draft manuscripts or abstracts to Cortendo and other relevant parties at 
least 60 days prior to publication submission.  This will enable involved parties to protect 
proprietary information and to provide comments to authors.   
Further details on the publication process may be provided in individual contractual 
agreements signed by the Investigators and Cortendo. 


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APPENDIX F 
PROTOCOL AMENDMENT(S) 
Each protocol amendment will be a stand-alone document.  All revisions dictated by the 
amendments will be made in the protocol proper.  A list of changes from the previous 
version will be provided.  Each time a protocol is amended, a new amended version date 
will be added to the cover page. 


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APPENDIX G 
CONDITIONS ASSOCIATED WITH PSEUDO-
CUSHING’S SYNDROME 
 
Reference:  Nieman 2008. 48-hour, 2 mg dexamethasone suppression test may be 
necessary to exclude pseudo-Cushing’s disease.  
Some clinical features of CS may be present: 
• Pregnancy 
• Depression and other psychiatric conditions 
• Alcohol dependence 
• Morbid obesity 
• Poorly controlled diabetes mellitus 
• Polycystic Ovary Disease (PCOD) 
 
Unlikely to have any clinical features of CS 
• Physical stress (hospitalization, surgery, pain) 
• Malnutrition, anorexia nervosa 
• Glucocorticoid resistance 
• Intense chronic exercise 
• Hypothalamic amenorrhea 
• Cortisol-binding globulin (CBG) excess (increased serum but not urine cortisol) 
 


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APPENDIX H 
CRITERIA FOR DIAGNOSES OF PREDIABETES AND 
DIABETES  
Reference: American Diabetes Association. Classification and diagnosis of diabetes. 
Sec. 2. In Standards of Medical Care in Diabetes—2016. Diabetes Care 
2016;39(Suppl. 1):S13–S22. 
The American Diabetes Association (ADA) standards for the diagnosis of prediabetes 
consider three different categories of prediabetes, based on measures of fasting glucose, 
HbA1c, or 2-hour postprandial glucose during a 75-gram oral glucose tolerance test 
(OGTT). For purposes of this study, however, the diagnosis of prediabetes will be limited 
to a single prediabetes category of impaired fasting glucose (IFG), as follows: 
Prediabetes is defined by a fasting glucose of ≥ 100 mg/dL (5.6 mmol/L) and 
< 126 mg/dL (7.0 mmol/L) (after no caloric intake for ≥ 8 hours and in the absence of 
antihyperglycemic medications).   
ADA criteria for the diagnosis of diabetes will be used as follows. 
Diabetes Is Diagnosed by One of the Following Criteria: 
• A fasting glucose of ≥ 126 mg/dL (7.0 mmol/L) after no caloric intake for ≥ 8 hours 
  
 
 
 
OR 
• A random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) associated with classic 
diabetes symptoms:  increased urination, increased thirst and unexplained weight loss   
OR 
• 2-hour post-glucose load plasma glucose ≥ 200 mg/dL (11.1 mmol/L) following oral 
ingestion of a 75-gram anhydrous glucose solution in water.  NOTE: Oral glucose 
tolerance testing is not necessary if the subject has a fasting glucose level of 
≥ 126 mg/dL. 
OR 
• HbA1C ≥ 6.5% (48 mmol/mol). The test should be performed in a laboratory using a 
method that is National Glycohemoglobin Standardization Program (NGSP) certified 
and standardized to the Diabetes Control and Complications Trial (DCCT) assay. 
NOTE: In the absence of unequivocal hyperglycemia, results indicating diabetes should 
be confirmed by repeat testing using any of the above measures. 


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APPENDIX I 
GUIDELINES FOR HYPERTENSION 
Reference:  The Seventh Report of the Joint National Committee on Prevention, 
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), 2004 
Table 10 
Blood Pressure Classification (for Adults Over 18 Years of Age) 
Blood Pressure Classification 
SBP (mmHg) 
DBP (mmHg) 
Normal 
< 120 
and < 80 
Pre-hypertension 
120-139 
or 80-89 
Stage 1 hypertension 
140-159 
or 90-99 
Stage 2 hypertension 
≥ 160 
or ≥ 100 
 
Table 11 
Recommendations for Follow-up Based on Initial Blood Pressure 
Measurements for Adults without Acute End Organ Damage 
Initial Blood Pressure (mmHg)a 
Follow-up Recommendedb 
Normal 
Recheck in 2 years 
Pre-hypertension 
Recheck in 1 yearc 
Stage 1 hypertension 
Confirm within 2 months c 
Stage 2 hypertension 
Evaluate or refer to source of care within 1 month.  
For those with higher pressures (e.g. > 
180/110 mmHg), evaluate and treat immediately 
or within 1 week depending on clinical situation 
and complications. 
a. If systolic and diastolic categories are different, follow recommendations for shorter time follow-up (e.g. 
160/86 mmHg should be evaluated or referred to source of care within 1 month) 
b. Modify the scheduling of follow-up according to reliable information about past BP measurements, other 
cardiovascular risk factors, or target organ disease 
c. Provide advice about lifestyle modifications. 
 


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APPENDIX J 
CONCOMITANT MEDICATIONS PROHIBITED OR 
TO BE USED ONLY WITH PRIOR PERMISSION 
 
Table 12 through Table 20 provide examples of drugs that are PROHIBITED for 
concomitant use in COR-2017-01. Table 21 through Table 23 provide examples of drugs 
that REQUIRE PERMISSION from the study Medical Monitor prior to concomitant 
use.  
Some drugs have been categorized into multiple drug-interaction categories (e.g. 
dexamethasone is both a systemic corticosteroid and a strong CYP3A4 inducer). Where 
drugs are categorized into more than one category, the most restrictive category should 
hold precedent.   
Although an attempt was made to provide a comprehensive list of relevant medications 
that are believed to present a potential risk of clinically significant drug interaction with 
levoketoconazole, the lists intentionally omit some medications that should not be used 
concomitantly with levoketoconazole, since concomitant use is not expected (e.g. some 
chemotherapeutic agents), and the lists probably omit others unintentionally. 
Furthermore, these lists will evolve as new drugs come to market and more is learned 
about the pharmacology of levoketoconazole and other medications. Therefore, they 
should be regarded as a minimum set of excluded and precautioned concomitant 
medications rather than as a comprehensive set. 
 


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Prohibited concomitant medications 
 
Table 12 
Steroidogenesis Inhibitors and Systemic Corticosteroids  
Interferes with study drug assessment; must be avoided or washed out prior to Baseline 
Assessments, including UFCs and LNSCs 
Steroidogenesis 
Inhibitors: 
Systemic corticosteroids include any corticosteroid intended to 
act systemically, alone or in combination with other drugs, 
examples include: 
Metyrapone 
Betamethasone, Budesonide, Cortisone, Deflazacort,  
Ketoconazole 
Dexamethasone (except for DST), Hydrocortisone,  
Etomidate 
Methylprednisolone, Prednisolone, Prednisone,  
Mitotane 
Triamcinolone 
Trilostane 
 
 
Table 13 
Dopamine Agonists  
Interferes with study drug assessment; must be avoided or washed out prior to Baseline 
Visit 
Apomorphine 
Pergolide 
Bromocriptine  
Piribedil 
Cabergoline (8 weeks’ washout) 
Pramipexole 
Ciladopa 
Propylnorapomorphine 
Dihydroergotamine/ergotamine 
Quinagolide 
Dihydrexidine 
Ropinirole 
Dinapsoline 
Rotigotine 
Doxanthrine 
Roxindole 
Epicriptine 
Sumanirole 
Etilevodopa (alone or with inhibitors of dopamine metabolism) 
Levodopa (alone or with inhibitors of dopamine metabolism) 
Lisuride 
Melevodopa (alone or with inhibitors of dopamine metabolism) 


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Table 14 
Synthetic Progestins that Bind with Moderate to High Affinity1 to 
Glucocorticoid Receptor (GR) or Mineralocorticoid Receptor (MR)  
Interferes with study drug assessment and/or influences underlying signs/symptoms of 
disease; must be avoided or washed out 
Medroxyprogesterone acetate 
Megestrol acetate 
Micronized progesterone 
Segesterone (nesterone) acetate 
Drospirenone 
Gestodene 
 
Table 15 
Somatostatin Analogs  
Interferes with study drug assessment and/or influences underlying signs/symptoms of 
disease; must be avoided 
Octreotide (all forms) 
Lanreotide (all forms) 
Pasireotide (all forms) 
 
Table 16 
Weight Loss Medications  
Interferes with endpoints assessment; must be avoided or washed out 
Amfepramone 
Diethylpropion 
Orlistat 
Benzphetamine 
Ephedrine 
Phendimetrazine 
Bupropion/naltrexone 
Etilamfetamine 
Phentermine 
 
Fenfluramine 
 
Cathine 
Lorcaserin 
Rimonabant 
Clobenzorex 
Mazindol 
Sibutramine 
Dexfenfluramine 
Mefenorex 
Topiramate 
 
Table 17 
Drugs Predicted to Interfere with Levoketoconazole Absorption  
Must be avoided; use an allowed substitute or wash out 
Histamine H2 receptor antagonists: 
cimetidine, famotidine, nizatidine, ranitidine, 
Sucralfate 
Proton-pump inhibitors: dexlansoprazole, esomeprazole, 
lansoprazole, omeprazole, pantoprazole, rabeprazole 
 
 
                                               
1 The listed drugs have been reported to bind with at least 50% relative binding affinity to GR or MR as 
compared with the natural ligand (set as 100%). Africander D. Et al. Steroids 76:636-652, 2011. 


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Note on Drug-drug Interactions via CYP3A4 
Levoketoconazole is a substrate and potent inhibitor of CYP3A4. Therefore, the 
following drug interactions may occur when levoketoconazole is co-administered with 
other drugs that interact with CYP3A4.  
• Levoketoconazole may decrease the elimination of drugs metabolized by 
CYP3A4, thereby increasing their plasma concentrations. Increased exposure 
to these drugs may cause an increase or prolongation of their therapeutic 
and/or adverse effects. Concomitant use with levoketoconazole is 
prohibited for drugs known to present a risk of serious side effects with 
increased exposure (Table 18). 
• For other drugs that are metabolized by CYP3A4, monitoring of plasma 
concentrations is advised when possible. Clinical signs and symptoms 
associated with these drugs should be monitored, with dosage adjusted as 
needed. 
• Drugs that may significantly decrease or increase the plasma concentrations of 
levoketoconazole by induction or inhibition of CYP3A4 or by altering 
absorption are prohibited (Table 19). 
The following drug interaction checker may be useful (see “Interaction View” tab). 
However, this checker will not supersede the protocol excluded medications lists nor the 
judgment of the Medical Monitor or delegate: 
https://mor.nlm.nih.gov/RxNav/search?searchBy=String&searchTerm=ketoconazole 
 
Table 18 
Drugs Whose Systemic Exposure is Predicted to be Significantly 
Increased by Levoketoconazole via CYP3A4 Inhibition  
Must be avoided or washed out 
Systemic exposure to these drugs is potentially increased significantly by the 
addition of levoketoconazole; must be avoided 
Alprazolam, midazolam, triazolam 
HMG-CoA reductase inhibitors: 
atorvastatin, lovastatin, simvastatin, (NOT 
pravastatin, fluvastatin, pitavastatin and 
rosuvastatin)  
Cisapride 
Dofetilide  
Eplerenone  
Ergot alkaloids  
(ergotamine, dihydroergotamine)  
Pimozide 
Quinidine 
Nisoldipine 
 


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Table 19 
Drugs That Are Predicted to Reduce (Top) or Increase Significantly 
(Bottom) the Plasma Concentration of Levoketoconazole via CYP3A4 
Induction or Inhibition, Respectively and Are Prohibited 
Must be avoided or washed out 
Strong CYP3A4 Inducers 
Avasimibe 
Oxcarbazepine 
Carbamazepine 
Phenobarbital 
Enzalutamide 
Phenylbutazone 
Efavirenz 
Phenytoin 
Fosphenytoin 
Pioglitazone 
Griseofulvin 
Rifabutin 
Isoniazid 
Rifampicin 
Modafinil  
Rifampin 
Nafcillin 
Rifapentine 
Nelfinavir  
St John's wort 
Nevirapine 
Sulfinpyrazone 
Strong CYP3A4 Inhibitors 
Atazanavir 
Indinavir 
Suboxone 
Boceprevir 
Iopinavir 
Telaprevir 
Ceritinib 
Itraconazole 
Telithromycin 
Clarithromycin 
Mibefradil 
Telaprevir 
Cobicistat & coformulations 
Nefazodone 
Telithromycin  
Conivaptan 
Ombitasvir-combinations 
 
Darunavir 
Posaconazole  
 
Idelalisib 
Saquinavir 
 
 


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Table 20 
Drugs that can Cause QTc Prolongation  
Must be avoided. Permission prior to use is required unless no suitable alternative is 
available after the Baseline Visit 
Alfuzosin 
Eliglustat  
Perphenazine 
Amiodarone 
Erithromycin 
Pimozide 
Anagrelide 
Fingolimod 
Pipamperone 
Arsenic 
Flecainide 
Procainamide 
Artemether 
Fluconazole 
Propafenone  
Asenapine 
Granisetron 
Propofol 
Astemizole 
Haloperidol 
Quetiapine 
Atomoxetine 
Hydrocodone ER 
Quinine 
Azithromycin 
Ibutilide 
Ranolazine 
Bedaquiline 
Iloperidone 
Risperdone 
Buprenorphine 
Imipramine 
Solifenacin 
Chloroquine 
Isradipine 
Sotalol 
Cilostazol 
Levofloxacin 
Sulpiride 
Ciprofloxacin 
Lopinavir 
Tetrabenazine 
Citalopram 
Lumefantrine 
Thioridazine 
Clomipramine 
Methadone 
Tiapride 
Desipramine 
Mirabegron 
Tizanidine 
Dolasetron 
Mirtazapine 
Tolterodine 
Disopyramide 
Moexipril/HCTZ 
Toremifene  
Domperidone 
Moxifloxacin 
Trimipramine 
Donepezil 
Norfloxacin 
Tropisetron 
Dosulepin 
Nortriptyline 
Vardenafil 
Doxepin 
Ofloxacin 
Venlafaxine 
Dronedarone 
Ondansetron  
Ziprasidone 
Droperidol 
Paliperidone 
Zuclopenthixol 
 
 
 


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Medications that require prior permission to be used 
concomitantly with study drug 
 
Table 21  Drugs Whose Systemic Exposure is Predicted to be Increased 
Moderately by Levoketoconazole 
Systemic exposure to these drugs is predicted to be increased by levoketoconazole: 
Substitute if possible and discuss with Medical Monitor prior to use. Careful monitoring 
is recommended, with possible adjustment in doses. 
 
Alfentanil, fentanyl, sufentanil 
Docetaxel, paclitaxel 
Amlodipine, felodipine, nicardipine, nifedipine 
Rifabutin 
Bosentan 
Sildenafil 
Buspirone 
Sirolimus  
Busulfan 
Tacrolimus 
Cariprazine 
Telithromycin 
Coumarin oral anticoagulants 
Trimetrexate 
Cyclosporine 
Verapamil 
Digoxin 
Vinca alkaloids  
 
Table 22 
Topical or Inhaled Steroids  
Interferes with study drug assessment. Should be avoided; to be used only with prior 
permission 
Inhaled corticosteroids: 
Flunisolide 
Beclomethasone 
Fluticasone furoate 
Betamethasone dipropionate 
Mometasone 
Budesonide 
Prednisolone 
Ciclesonide 
Tixocortol 
Dexamethasone 
Triamcinolone 
Topical/inhaled corticosteroids:    Fluticasone propionate 
Topical corticosteroids: 
 
Amcinonide 
Halcinonide 
Clobetasol propionate 
Halobetasol propionate 
Esocimetasone 
Halometasone 
Diflorasone diacetate 
Hydrocortisone butyrate 
Fluocinolone acetonide 
Hydrocortisone valerate 
Fluocinonide 
Mometasone furoate 
Flurandrenolide 
Traimcinolone acetonide 
 


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Table 23 
Other Medications Contraindicated or Relatively Contraindicated with 
Ketoconazole  
Increased risk of AEs; to be used only with prior permission 
Afatinib 
Ergoloid Mesylates 
Nimodipine 
Alitretinoin 
Ergonovine 
Olaparib 
Almotriptan 
Escitalopram  
Oxycodone 
Amodiaquine 
Estazolam 
Palbociclib 
Aprepitant 
Eszopiclone 
Pazopanib 
Aripiprazole 
Everolimus 
Red Yeast Rice 
Artesunate 
Fesoterodine 
Reboxetine 
Avanafil 
Flibanserin 
Rivaroxaban 
Axitinib 
Grazoprevir 
Saccharomyces boulardii 
Barnidipine 
Ibrutinib 
Salmeterol 
Brexpiprazole 
Pendetide 
Silodosin 
Blonanserin 
Irinotecan 
Simeprevir 
Bosutinib* 
Isavuconazonium Sulfate 
Sonidegib 
Cabozantinib 
Ivabradine 
Suvorexant 
Cobimetinib 
Lapatinib 
Tamsulosin 
Crizotinib 
Lercanidipine 
Tegafur 
Cyclosporine 
Levomilnacipran 
Ticagrelor 
Dabrafenib 
Lomitapide 
Tolvaptan 
Dapoxetine 
Lurasidone 
Trabectedin 
Edoxaban 
Macitentan 
Udenafil 
Elbasvir 
Methylergonovine 
Ulipristal 
Eletriptan 
Mirodenafil 
Vorapaxar 
 
Naloxegol  
 
*Examples of contraindicated tyrosine kinase inhibitors (TKIs) are shown; all approved TKIs are also 
contraindicated for purposes of the study. 


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APPENDIX K 
SIGNS AND SYMPTOMS OF CONDITIONS FOR RISK 
MANAGEMENT PURPOSES 
Disease 
Symptoms 
Signs 
Laboratory values 
Adrenal Insufficiency 
Fatigue/Tiredness/Malaise 
Weakness 
Anorexia 
Nausea 
Vomiting 
Constipation 
Abdominal pain 
Diarrhea 
Headache 
Salt carving 
Arthralgias/Myalgias 
Dizziness (esp. on standing) 
Less common: 
Irritability 
Depression 
Sweating 
Fever 
Weight loss 
Hypotension 
Hyperpigmentation 
Less common: 
Hypoglycemia 
 
Serum cortisol level < 
3 μg/dL 
Inadequate cortisol 
response to ACTH 
stimulation 
Hypoglycemia 
Moderate to high ACTH 
(assuming primary 
adrenal insufficiency) 
Hypocortisolemia 
 
Fatigue 
Muscle weakness 
Loss of appetite 
Weight loss 
Nausea, vomiting 
Dizziness, esp. on standing 
Irritability 
Depression 
Sweating  
Joint aches and pains 
Low blood pressure 
Symptomatic 
Orthostatic 
hypotension 
Reduction in weight 
 
Reduced serum and 
salivary cortisol levels 
Hypoglycemia 
 
Hypomineralocorticoidism 
 
Muscle weakness 
Fatigue 
Fainting 
Salt craving 
Irritability 
Low blood pressure 
Severe orthostatic 
hypotension 
 
Hyperkalemia 
Hyponatremia 
 
 
Hypogonadism 
Erectile dysfunction 
Reduction in beard and body 
hair 
Enlarged breasts (in men) 
Fatigue 
Reduced libido 
Hot flashes 
Difficulty concentrating 
Gynecomastia 
Reduced body hair 
Osteoporosis 
 
Reduced testosterone 
levels (AE in males, 
beneficial in women) 
 
 


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APPENDIX L 
QUALITY OF LIFE QUESTIONNAIRE 
CUSHING’S SYNDROME QUALITY OF LIFE 
QUESTIONNAIRE 
(CushingQoL) 
 
The following sentences refer to what you may think or feel about your Cushing’s 
syndrome. Your answers will help us to know how you feel and how much your 
illness has interfered in your usual activities in the past 4 weeks. 
 
Below each sentence you will find several response choices. Please read each 
sentence carefully. After reading each sentence, check the box next to the 
answer that best describes what you think is happening to you. 
 
There are NO right or wrong answers. We are simply interested in what is 
happening to you because of your Cushing’s syndrome. 
 
1.  I have trouble sleeping (I wake up during the night; it takes me a long 
time to get to sleep, etc.). 
□ Always 
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
2.  I have pain that keeps me from leading a normal life. 
□ Always 
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
3.  My wounds take a long time to heal. 
□ Always 
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
 


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4.  I bruise easily. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
5.  I am more irritable, I have sudden mood swings and angry 
outbursts. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
6.  I have less self-confidence; I feel more insecure. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
7.  I’m worried about the changes in my physical appearance due to my 
illness. 
□ Very much  
□ Quite a bit  
□ Somewhat  
□ Very little  
□ Not at all 
 
8.  I feel less like going out or seeing relatives or friends. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 


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9.  I have had to give up my social or leisure activities due to my illness. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
10. My illness affects my everyday activities such as working or studying. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
11. It’s difficult for me to remember things. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
12. I’m worried about my health in the future. 
□ Very much  
□ Quite a bit  
□ Somewhat  
□ Very little  
□ Not at all 
 
 


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CONFIDENTIAL
 
APPENDIX M 
ASSESSMENT OF CLINICAL SIGNS AND 
SYMPTOMS OF CUSHING’S SYNDROME 
Visit 
                        Date 
 
 
 
       DD          MMM           YYYY  
SUBJECT NUMBER: 
         SUBJECT INITIALS:  
 
To be completed by the Investigator or qualified trained HHC professional 
The severity of specific signs and symptoms will be rated at each visit by the Investigator 
on a categorical 4-point scale:  
1. Moon facies:  
 
None   
Mild 
 
Moderate 
 
Severe 
2. Facial plethora:   
None   
Mild 
 
Moderate 
 
Severe 
3. Striae: 
 
 
None   
Mild 
 
Moderate 
 
Severe 
4. Bruising: 
 
None   
Mild 
 
Moderate 
 
Severe 
5. Supraclavicular fat:  
None   
Mild 
 
Moderate 
 
Severe 
6. Menstrual abnormalities (females only):  
 
A. Irregular menstruation: 
 
None 
 
Mild 
 
Moderate 
 
Severe 
Definition: A disorder characterized by irregular cycle or duration of menses. 
Mild - Intermittent menses with skipped menses for no more than 1 to 3 months 
Moderate – Intermittent menses with skipped menses for more than 4 to 6 months 
Severe - Persistent amenorrhea for more than 6 months 
B. Dysmenorrhea:  
None 
 
Mild 
 
Moderate 
 
Severe 
Definition: A disorder characterized by abnormally painful abdominal cramps during 
menses. 
Mild - Mild symptoms; intervention not indicated 
Moderate – Moderate symptoms; limiting instrumental ADL 
Severe - Severe symptoms; limiting self-care ADL 
 
 
 
7. Acne 
 
Grading System for Acne:  
Acne assessments will be performed using the Global Acne Grading System described by 
Doshi  et al. 1997.  A total of six locations will be evaluated.  
 
Forehead 
 
 
Left Cheek 
 
 
Chin 
 
Right Cheek 
 
 
Nose 
 
 
 
Chest and Upper Back 
 
 
 
 
 


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 153 of 162     
 
CONFIDENTIAL
 
Grading Scale: 
 
0 = No Lesions 
1 = ≥ one comedone 
2 = ≥ one papule 
3 = ≥ one pustule 
4 = ≥ one nodule 
 
 
 
 
Evaluate each of the six locations identified above and assign a grade.  Record the grading 
within the eCRF, which will calculate the Local and Global Scores.   
 
 
 
 
8. Hirsutism (females only) 
Hirsutism will be evaluated using the rating system described by Hatch 1981. The degree of 
hairiness present will be evaluated for nine body areas: 
 
 
Upper Lip 
 
Abdominal 
 
Thigh 
 
 
Chin 
 
 
Pubic 
 
 
Back 
 
 
Chest  
 
Arm 
 
 
Buttocks 
 
Location 
Grade (0-4)  
Forehead (I) 
 
Right Cheek (II) 
 
Left Cheek (III) 
 
Nose (IV) 
 
Chin (V) 
 
Chest and Upper 
Back (VI) 
 


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 154 of 162     
 
CONFIDENTIAL
 
Grading Scale: [NOTE: Use grade 0 for no hirsutism] 
 
Evaluate each of the nine locations identified above and assign a grade.  Record the grading 
within the eCRF.  
 
 
9. Peripheral edema  
Edema will be assessed according to the method established by Brodovicz 2009. Three 
anatomical areas will be evaluated:  
 
• 
Lower calf at 7 cm proximal to the midpoint of the medial malleolus 
• 
Behind the medial malleolus 
• 
Dorsum of the foot 
 
Each location will be individually evaluated.  Using two fingers or thumb, press the 
skin firmly in the area to be evaluated and start the stopwatch or watch (second 
hand) immediately after release of pressure until completion of rebound to pre-
pressure appearance.   
 
Evaluate each of the three locations identified above and assign a grade.  Record the grading 
within the eCRF.   
Body Area  
Rating (0-4) 
Upper Lip 
 
Chin 
 
Chest 
 
Abdominal 
 
Pubic 
 
Arm 
 
Thigh 
 
Back 
 
Buttocks 
 


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 155 of 162     
 
CONFIDENTIAL
 
 
Grading Scale: [NOTE: Use grade 0 for no edema] 
 
 
 
 
Name of Assessor (PI or designated site personnel) or qualified trained HHC professional 
completing assessment:  
(Printed)_______________________________ 
 
Signature of Assessor (PI or designated site personnel) or qualified trained HHC 
professional completing assessment:  
 
______________________________________ 
 
Date__________________________________ 
 
Body Area 
Rating (1-4) 
Time to Rebound 
(sec) 
Lower calf at 7 
cm proximal to 
the midpoint of 
the medial 
malleolus 
 
 
Behind the medial 
malleolus 
 
 
Dorsum of the 
foot 
 
 


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 156 of 162     
 
CONFIDENTIAL
 
APPENDIX N 
BECK DEPRESSION INVENTORY (BDI-II)  
 


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 157 of 162     
 
CONFIDENTIAL
 
 


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 158 of 162     
 
CONFIDENTIAL
 
APPENDIX O 
ADDITIONAL INFORMATION ON ADVERSE EVENT 
OF SPECIAL INTEREST (QTC INTERVAL, 
INSTRUCTIONS FOR LIVER FUNCTION TEST 
ANORMALITIES FOLLOW-UP AND ADRENAL 
INSUFFICIENCY) 
Additional information for evaluation and management of prolonged QTc Interval 
 
 


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 159 of 162     
 
CONFIDENTIAL
 
Instructions for Liver Function Test Abnormalities Follow-up 
If a patient experiences a potential hepatic event, the following information will be 
requested. 
1. Pertinent details of the patient’s medical history (inclusive of alcohol use, 
recreational drug use, special diets, non-alcoholic steatohepatitis, and prior 
elevations in liver function tests), with start/end dates were known. 
2. Details of any recent or current use of acetaminophen/paracetamol (including 
cold/allergy medications containing acetaminophen/paracetamol) with start/stop 
dates and doses. 
3. Concomitant medications (including herbal and non-prescription medications, and 
dietary supplements), with start/stop dates and doses. 
4. Potentially confounding factors for the event. 
5. Details of any symptoms present around the time of the event such as: 
Fatigue 
Nausea 
Vomiting 
Rash/pruritus 
Eosinophilia 
Dark urine 
Acholic stool 
Fever 
Right upper quadrant pain/tenderness 
6. Information regarding liver specialist consultation. 
7. Results of any liver function tests performed to date (including baseline and 
repeat testing). 
8. All INR, PT and PTT readings (including baseline). 
9. Imaging procedures. 
10. Any other tests performed (liver panel below can be ordered from central 
laboratory).  


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 160 of 162     
 
CONFIDENTIAL
 
HEPATITIS A ANTIBODY, IgM (Focus) 
HEPATITIS B CORE IGM AB (Centaur) 
Hepatitis B Virus DNA Quant PCR (Panel) 
Hepatitis D Antibody, Total 
Hepatitis E Ab IgM 
Cytomegalovirus IgM Antibody 
Epstein-Barr Viral Capsid Antigen IgM Antibody (Focus) 
Acetaminophen Adduct 
Actin (Smooth Muscle) Antibody 
ANA screen with reflex 
ANA screen with reflex to titer and pattern (Panel)-Bioplex 
Immunoglobulin G (IgG) 
Liver Kidney Microsome-1 Antibody 
Ammonia 
11. Dechallenge and rechallenge results. 
 


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 161 of 162     
 
CONFIDENTIAL
 
 
 
 
 
Recommended LFT Management Guidance 
 
 
 
ALT or AST > 3 x ULN AND 
Total Bilirubin > 2 x ULN 
or INR > 1.5 
ALT or AST  
> 5 x ULN within < 4 weeks 
or persists > 2 weeks 
 
ALT or AST > 8 x ULN 
Temporarily interrupt study medication, 
obtain PK sample 
Safety Follow Up (performed as soon as possible) 
 
• Liver-directed medical history and physical exam 
• Hepatitis screen 
• Abdominal ultrasound (liver and biliary tree) 
• Collect liver chemistry panel 
Continue follow up LFT monitoring every 3-4 
days until resolution or return to baseline status 
Liver function test elevation persists  
> 4 weeks off drug or worsens 
Yes 
No 
Discontinue study 
and continue 
safety follow-up 
Resume study drug at 
original or lower dose 
level and recheck within 4 
days and at 7-10 days 
Discontinue study 
and continue 
safety follow-up 
ALT or AST > 3 x ULN 
or AP > 2 x ULN 
or Total Bilirubin > 2 x ULN  
with  
signs or symptoms of liver 
dysfunction 
ALT or AST increase 
with rechallenge 
Yes 
No 
Continue per protocol 


Cortendo AB 
Protocol COR-2017-01 
 
Amendment 4 
23 September 2019 
Page 162 of 162     
 
CONFIDENTIAL
 
Recommended for Management of Adrenal Insufficiency 
 

SAP_001.pdf: 
COVANCE INC. CONFIDENTIAL 
 
 
 
 
CLINICAL STUDY PROTOCOL 
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 
 
Statistical Analysis Plan 
 
Cortendo AB*  
COR-2017-01 (LOGICS) 
 
 
Covance Study ID: 39204 
Document Version: Amendment 2 
Document Date: August 13, 2020 
 
 
 
 
 
 
Covance Inc. CDCS 
Clinical Development Commercialization Services 
*Cortendo AB is a subsidiary of Strongbridge Biopharma plc. 
 
 
 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 2 of 87 
 
 
 
 
Table of Contents 
TABLE OF TABLES ...................................................................................... 5 
Approvals.................................................................................................... 6 
Reviewers ................................................................................................... 7 
Version History ............................................................................................ 8 
Glossary of Abbreviations ............................................................................. 11 
1. 
Source Documents .............................................................................. 13 
2. 
Protocol Details ................................................................................... 14 
2.1 
Study Objectives ............................................................................. 14 
2.2 
Overall Study Design ....................................................................... 15 
2.3 
Sample Size and Power .................................................................... 18 
3. 
Study Endpoints .................................................................................. 19 
3.1 
Primary Efficacy Endpoint ................................................................. 19 
3.2 
Secondary Efficacy and Safety Endpoints ............................................ 20 
3.3 
Exploratory Efficacy and Safety Endpoints ........................................... 21 
3.4 
Pharmacokinetic/Pharmacodynamic Endpoints ..................................... 22 
4. 
Analysis Populations ............................................................................ 23 
4.1 
Intent-to-Treat (ITT) Population ........................................................ 23 
4.2 
Per-Protocol (PP) Population .............................................................. 23 
4.2.1 
Major Protocol Deviations Leading to Exclusion from PP Population Analysis ... 23 
4.3 
Levoketoconazole-naïve(L-N) Population ............................................. 24 
4.4 
SONICS-completer Population ........................................................... 24 
4.5 
Safety Population ............................................................................ 24 
5. 
Data Handling..................................................................................... 25 
5.1 
Baseline, First Dose Date, and Last Dose Date ..................................... 25 
5.2 
Study Day and Relative Day .............................................................. 27 
5.3 
Time Points and Visit Windows .......................................................... 27 
5.4 
Urinary Free Cortisol – Determination of Adequacy and Calculation of Mean
 
29 
5.5 
Early Rescue Criteria – Programmed Verification of Quantitative Criteria .. 31 
5.6 
Late Night Salivary Cortisol – Calculation of Means ............................... 31 
5.7 
Blood Pressure, Heart Rate, and Abdominal Girth – Calculation of Means .. 32 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 3 of 87 
 
 
 
 
5.8 
Cushing’s Syndrome Quality of Life and Beck Depression Inventory (BDI) II 
– Calculation of Total Scores ..................................................................... 32 
5.9 
Acne, Hirsutism, Peripheral Edema, and Other Clinical Signs and Symptoms 
of Cushing’s Syndrome – Calculation of Total Scores ..................................... 33 
5.10 Handling of Dropouts, Missing Data, and Outliers ................................. 35 
6. 
Statistical Methods .............................................................................. 38 
6.1 
General Principles ............................................................................ 38 
6.2 
Subject Disposition .......................................................................... 42 
6.3 
Protocol Deviations .......................................................................... 43 
6.4 
Demographics and Other Background Characteristics ............................ 44 
6.4.1 
Demographics and Baseline Characteristics ................................................ 44 
6.4.2 
Medical History, Surgical History, and Prior Radiotherapy ............................. 45 
6.4.3 
Prior and Concomitant Medications ............................................................ 45 
6.5 
Study Drug Exposure and Compliance ................................................ 46 
6.6 
Efficacy ......................................................................................... 48 
6.6.1 
Primary Efficacy Analysis ......................................................................... 48 
6.6.2 
Secondary Efficacy Analyses ..................................................................... 49 
6.6.2.1 
UFC and LNSC Analyses ..................................................................... 50 
6.6.2.2 
CS Comorbidity Biomarkers................................................................ 52 
6.6.2.3 
Cushing’s Syndrome Quality of Life Questionnaire ................................. 53 
6.6.2.4 
BDI-II ............................................................................................. 53 
6.6.2.5 
Acne, Hirsutism and Peripheral Edema ................................................ 53 
6.6.3 
Sensitivity Analyses ................................................................................ 53 
6.6.4 
Additional Subgroup Analyses ................................................................... 55 
6.6.4.1 
Prior Surgery for Cushing’s Syndrome ................................................. 55 
6.6.4.2 
Prior Radiotherapy ............................................................................ 55 
6.6.4.3 
Hypertensive Subjects ....................................................................... 55 
6.6.4.4 
Pre-diabetic/Diabetic Subjects ............................................................ 55 
6.6.4.5 
Region............................................................................................. 56 
6.6.4.6 
Sex ................................................................................................. 56 
6.6.4.7 
Age ................................................................................................. 56 
6.6.5 
Exploratory Analyses ............................................................................... 56 
6.6.6 
Pharmacokinetics Analysis ....................................................................... 61 
6.6.7 
Pharmacodynamics Analysis ..................................................................... 61 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 4 of 87 
 
 
 
 
6.7 
Safety ........................................................................................... 61 
6.7.1 
Adverse Events ....................................................................................... 62 
6.7.2 
Laboratory Evaluations ............................................................................ 65 
6.7.3 
Oral Glucose Tolerance Test (for Pre-diabetic Subjects) ............................... 69 
6.7.4 
Vital Signs ............................................................................................. 71 
6.7.5 
Electrocardiograms ................................................................................. 73 
6.7.6 
Pituitary Magnetic Resonance Imaging ....................................................... 74 
6.7.7 
Subgroup Analyses for Safety ................................................................... 75 
6.8 
Interim Analysis .............................................................................. 76 
7. 
Changes from Planned Analyses in the Protocol ........................................ 78 
8. 
References ......................................................................................... 79 
9. 
APPENDIX 1 Safety Laboratory and Vital Signs Tests – Identifying Worst 
Values ....................................................................................................... 80 
10. 
APPENDIX 2 Laboratory Tests – Precision Levels....................................... 83 
11. 
APPENDIX 3 SAS STAT Procedure Details ................................................ 85 
 
 
 
 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 5 of 87 
 
 
 
 
TABLE OF TABLES 
Table 1 
Cohort Determination .................................................................... 15 
Table 2 
Study Treatment Schema ............................................................... 17 
Table 3 
RW Phase and RES Phase – Visit Windows for by-visit Analysis of Efficacy 
and Safety ................................................................................................ 28 
Table 4 
General Principles for the Presentation of Results in Tables, Figures, and 
Listings 
38 
Table 5 
The Severity of AEs and SAEs per NCI CTCAE, Version 4.03 ................. 62 
Table 6 
Laboratory Test PCS Criteria ........................................................... 67 
Table 7 
Vital Sign Clinical Importance Criteria............................................... 71 
Table 8 
Blood Pressure Classification (Adults Over 18 Years of Age) ................. 72 
Table 9 
Vital Sign PCS Criteria ................................................................... 72 
Table 10 
QTcF Interval Clinical Importance Criteria ...................................... 74 
Table 11 
Electrocardiogram (ECG) PCS Criteria ............................................ 74 
 
TABLE OF FIGURES 
Figure 1 
Study Design Schematics ............................................................ 16 
 
 
 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 6 of 87 
 
 
 
 
Approvals  
The undersigned agree that all required reviews of this document are complete and 
approve this Statistical Analysis Plan as final.  Programming of the tables, figures 
and listings based upon the specifications within this document can proceed. 
Approved by: 
Covance Lead Statistician 
 
 
 
 
Signature 
 
 
Date 
 
 
 
Shahnaz Hawkins, Sr. Principal Biostatistician, Covance Inc. 
Covance Management Approval: 
 
 
 
 
Signature 
 
Date 
 
 
Dan Pericak, Director, Biostatistics, Covance Inc. 
 Cortendo AB Approval: 
 
 
 
 
Signature 
 
 
Date 
 
 
 
Robbie Huang, Associate Director, Biostatistics and Statistical Programming,  
Strongbridge Biopharma plc on behalf of Cortendo AB 
 
 
 
 
Signature 
 
Date 
 
 
Fredric Cohen, Chief Medical Officer, Strongbridge Biopharma plc on behalf of 
Cortendo AB 
 
 
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 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 7 of 87 
 
 
 
 
Reviewers 
The following reviews of the Statistical Analysis Plan were conducted by Covance: 
 
 
 
Name and Title  
 Role 
Version Last 
Reviewed 
Company/ 
Organization 
Dan Pericak, Director, 
Biostatistics 
Senior Statistical and 
QC Review 
Draft 3, 
Version 0.1  
Covance 
Richard McNally, Statistical 
Fellow, Statistical Analysis 
Research Center 
Senior Statistical and 
General Review 
Draft 3, 
Version 0.1 
(comments 
from sponsor) 
Covance 
Dan Pericak, Director, 
Biostatistics 
Senior Statistical and 
QC Review, Updates 
as per the sponsor 
comments 
Draft 3, 
Version 0.1 
(comments 
from sponsor) 
Covance 
Dan Pericak, Director, 
Biostatistics 
Senior Statistical and 
QC Review, Updates 
as per the sponsor 
comments 
Draft 4, 
Version 0.1 
(comments 
from sponsor) 
Covance 
Margaret, Connolly, Sr. 
Principal Biostatistician 
Senior Statistical and 
QC Review, Updates 
as per the sponsor 
comments 
Draft 5, 
Version 0.1 
(comments 
from sponsor) 
Covance 
Margaret, Connolly, Sr. 
Principal Biostatistician 
Senior Statistical and 
QC Review, Updates 
as per the sponsor 
comments 
Draft 6, 
Version 0.1 
(comments 
from sponsor) 
Covance 
Mark Evangelista, 
Biostatistician II 
Peer Statistical and QC 
Review, Updates as 
per the sponsor 
comments 
SAP 
Amendment 
version 1 
Covance 
Margaret, Connolly, Sr. 
Principal Biostatistician 
Senior Statistical and 
QC Review, Updates 
as per the sponsor 
comments 
SAP 
Amendment 
version 1 
Covance 
Dan Pericak, Director, 
Biostatistics 
Senior Statistical and 
QC Review 
SAP 
Amendment 
version 2 
Covance 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 8 of 87 
 
 
 
 
Version History  
Version # 
Description of Changes 
Version Date 
1 
Initial version 
12 November 
2019 
Amendment 1 
1. Updates to Glossary of Abbreviations 
2. Section 5.10 - Revision to the paragraph on the 
handling of missing data for the analysis of secondary 
efficacy endpoints by visit in the RW Phase and RES 
Phase to delete the reference to imputation to replace 
missing values. 
3. Section 6.3 – Added text regarding subjects affected 
by COVID-19 related study disruption and protocol 
deviations arising from COVID-19 illness and/or public 
health control measures. 
4. Section 6.4.1 - Updated the variables to be presented 
for demographic, baseline, and disease characteristics. 
5. Sections 6.6.1 and 6.6.2 - Added details regarding 
subgroup analyses for the primary and secondary 
efficacy endpoints. 
6. Section 6.6.2 - Clarified that End of RW Phase time 
point is the main time point of interest for secondary 
efficacy analyses assessed by visit during the RW Phase. 
7. Section 6.6.2 - Elevation of the normalization of mUFC 
at the end of the RW Phase to the first among the 6 sets 
of secondary efficacy endpoints. 
8. Section 6.6.2 - Deletion of statistical tests to compare 
the two treatment groups with respect to their mean 
percent changes from RW Baseline in the secondary 
efficacy endpoints by visit. 
9. Section 6.6.2.1 - Revision to the definition of the 
normalization of mUFC at the end of RW Phase, using the 
last non-missing post-baseline mUFC result during the 
RW phase (before discontinuing or early rescue), instead 
of mUFC value at RW5 (or RW4 if RW5 value is missing). 
10. Section 6.6.3 - Deletion of a sensitivity analysis on 
the secondary efficacy endpoints of change from RW 
Baseline in mUFC and biomarkers for CS comorbidities in 
the RW Phase that was supposed to exclude data 
collected after early rescue for subjects randomized to 
placebo, since there are no such data as the RW Phase 
concludes once subjects are early rescued.  
11. Section 6.6.3 - Added sensitivity analyses to describe 
the handling of potential impact of Coronavirus 2019 on 
the SAP.  
22 June 2020 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 9 of 87 
 
 
 
 
Version # 
Description of Changes 
Version Date 
12. Section 6.6.5 - Expansion of the analysis of the 
exploratory endpoint normalization of mUFC at the end 
of TM Phase to also include normalization of mUFC at any 
time during the TM Phase 
13. Sections 6.7.2, 6.7.4, and 6.7.5 - Added analysis of 
laboratory parameters, vital signs, and ECGs based on 
PCS criteria 
14. Section 6.7.3 - Deletion of insulin from the OGTT 
analyses, because the blood samples for OGTT have not 
been analyzed for this parameter by the central 
laboratory; hence, insulin-related analysis cannot be 
performed.   
15. Section 6.7.6 – This section has been expanded to 
provide more details on the data from the MRI central 
reads that will be summarized. 
16. Section 6.8 – The reference to a top line analysis has 
been deleted, since all analyses, both top line and non-
top line, will be included in the interim analysis study 
report. 
17. Section 7 - New text added to describe changes from 
planned analyses in the protocol. Previously, this section 
stated that there were no changes from the planned 
analyses. 
18. There were also minor edits and updates for 
accuracy and completeness. 
Amendment 2 
1. Section 5.3 Table 3 – Added clarification for End of RW 
Phase analysis visit window in Table 3. 
2. Section 5.4 – Various updates added to clarify how 
samples were taken for the S-C cohort, the differences in 
sample date for the first two samples versus the third 
confirmatory sample, and how different samples should 
be grouped together for mUFC calculation. 
3. Section 5.6 – Various updates added to clarify how 
different samples were collected and how samples 
mapped to different visit should be analyzed. 
4. Section 5.9 – Add clarification for missing grade for 
irregular menstruation. 
5. Section 6.1 Table 4 – Added clarification of using 
Satterthwaite method in 2-sample t-test. 
6. Section 6.6.2.1 – Added clarification on definition of 
mUFC normalization at the end of RW Phase; updated 
“Changes in mUFC and LNSC from RW Baseline” section 
with the addition of Wilcoxon rand sun test. 
13 August 
2020 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 10 of 87 
 
 
 
 
Version # 
Description of Changes 
Version Date 
7. Section 6.6.2.2 – Added definition for HOMA-IR, as 
well as exclusions for related analysis. 
8. Section 6.6.2.2 – Removed LDL, Total Cholesterol, and 
hsCRP from the repeated measures mixed effect model 
section as these parameters were only measured at 
Baseline (RW0) and RW5, therefore the model doesn’t 
apply. 
9. Section 6.6.5 – Updated analysis on medication 
changes. 
10. Section 6.6.5 HOMA%B Analysis – Corrected an error 
and clarified exclusions for related analysis. 
11. Section 6.7.2 Table 6 – Corrected errors in PCS 
criteria - SI unit. 
12. Section 6.7.3 – Clarified that time to maximum 
glucose is calculated from the time of glucose 
administration 
13. Section 6.7.5 – Clarified that QTcF results and time 
elapsed relative to study drug/PK draw will be 
summarized and listed, and rejected ECG readings will 
not be excluded from listings. 
 
 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 11 of 87 
 
 
 
 
Glossary of Abbreviations 
Abbreviation 
Term 
ACTH 
Adrenocorticotrophic Hormone 
ASCVD 
Atherosclerotic Cardiovascular Disease 
AICC 
Corrected Akaike Information Criterion    
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
AP 
Alkaline Phosphatase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Concentration Time Curve 
BID 
Twice Daily 
BDI 
Beck Depression Inventory 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CD 
Cushing’s Disease 
CL/F 
Clearance 
Cmax 
Peak Concentration 
COVID-19 
Coronavirus Disease 2019 
CS 
Cushing’s Syndrome 
DBP 
Diastolic Blood Pressure 
DSMB 
Data Safety and Monitoring Board 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
eDISH 
Evaluation of Drug-induced Serious Hepatotoxicity 
GGT 
Gamma-glutamyl Transferase  
FPI 
Fasting Plasma Insulin 
FPG 
Fasting Plasma Glucose 
HbA1c 
Hemoglobin A1c 
HDL-C 
High-Density Lipoprotein-Cholesterol 
HOMA-IR 
Homeostatic Model Assessment-Insulin Resistance  
HOMA-%B 
Homeostatic Model Assessment-Beta Cell Function 
HR 
Heart Rate 
HRQoL 
Health-related Quality of Life 
hsCRP 
High Sensitivity C-reactive Protein 
IC50 
Levoketoconazole Concentration Producing Half Maximal UFC 
Suppression 
ICH 
International Conference on Harmonization 
Imax 
Maximal Suppression of UFC 
ITT 
Intent-to-Treat 
IFG 
Impaired Fasting Glucose 
Ka 
Absorption Rate Constant 
kg 
Kilogram 
KM 
Kaplan-Meier 
L 
Liter 
LDH 
Lactate Dehydrogenase 
LDL-C  
Low-Density Lipoprotein-Cholesterol 
LFT 
Liver Function Tests 
LLN 
Lower Limit of Normal 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
COVANCE INC. CONFIDENTIAL 
ST-AD-008 version 04                                                                                                              Page 12 of 87 
 
 
 
 
L-N 
Levoketoconazole-naïve 
LNSC 
Late Night Salivary Cortisol 
Max 
Maximum 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA  
Medical Dictionary for Regulatory Activities  
mg 
Milligram 
Min 
Minimum 
mL 
Millilitre 
MRI 
Magnetic Resonance Imaging 
mUFC 
Mean Urinary Free Cortisol 
n 
Number of subjects/observations 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
OGTT 
Oral Glucose Tolerance Test 
PD 
Pharmacodynamic 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PT 
Preferred Term 
QoL 
Quality of Life 
RBC 
Red Blood Cell 
RES  
Restoration (Phase)  
RW  
Randomized Withdrawal (Phase)  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
S-C 
SONICS-completer 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
International System of Units 
SOC 
System Organ Class 
TFLs 
Tables, Figures, and Listings 
TM 
Dose Titration and Maintenance (Phase) 
TSH 
Thyroid-stimulating Hormone 
t½ 
Half-life 
UFC 
Urinary Free Cortisol 
ULN 
Upper Limit of Normal 
US 
United States 
V/F 
Volume of Distribution 
WBC 
White Blood Cell  
WHO 
World Health Organization 
 
 
 


 Statistical Analysis Plan  
Sponsor Name: Cortendo AB 
Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
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ST-AD-008 version 04                                                                                                              Page 13 of 87 
 
 
 
 
1. Source Documents 
The Statistical Analysis Plan (SAP) was written based on the following documentation: 
The planned statistical methodologies described in this SAP are in accordance with the 
principles outlined in the International Conference on Harmonization (ICH) E9. 
 
 
Document 
Date 
Version 
Protocol 
17 April 2017 
Original 
Protocol Amendment 1 
06 July 2017 
Amendment # 1 
Protocol Amendment 2 
21 June 2018 
Amendment # 2 
Protocol Amendment 3 
14 December 2018 
Amendment # 3 
Protocol Amendment 4 
23 September 2019 Amendment # 4 
Coronavirus Disease 2019 
(COVID-19) Annex 
14 April 2020 
Version 1.0 
Electronic Case Report Form 
(eCRF) 
29 January 2020 
Version 8.0 


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ST-AD-008 version 04                                                                                                              Page 14 of 87 
 
 
 
 
2. Protocol Details 
2.1 Study Objectives 
The objectives of Study COR-2017-02 (also referred to as LOGICS) are: 
• 
Primary: 
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. 
• 
Secondary: 
1. To compare the effects of levoketoconazole with placebo on cortisol status 
(inferred from mean urinary free cortisol [mUFC] and/or late night salivary 
cortisol [LNSC]) during the Randomized Withdrawal (RW) Phase and the 
subsequent Restoration (RES) Phase; 
2. To compare the effects of levoketoconazole with placebo on changes in 
biomarkers of Cushing’s Syndrome (CS) comorbidities (fasting glucose, 
fasting insulin, homeostatic model assessment-insulin resistance [HOMA-
IR], hemoglobin A1c [HbA1c], total cholesterol, low-density lipoprotein-
cholesterol [LDL-C], and high-sensitivity C-reactive protein [hsCRP]); 
3. To compare the effects of levoketoconazole with placebo on changes in 
health-related quality of life (QoL) and symptoms of depression; 
4. To compare the effects of levoketoconazole with placebo on changes in acne, 
hirsutism and peripheral edema; 
5. To assess the safety and tolerability of levoketoconazole; 
6. To evaluate the population pharmacokinetics (PK) of levoketoconazole in 
subjects with CS. 
NOTE: Secondary Objectives 5 and 6 are not subject to hypothesis tests.   
• 
Exploratory: 
1. To assess changes in anti-diabetic, anti-cholesterol, anti-hypertensive, and 
chronic anti-inflammatory therapies; 
2. To describe the effects and durations of levoketoconazole action with 
respect to cortisol status and clinical signs and symptoms of CS other than 
acne, hirsutism and peripheral edema; 
3. To describe the dose-response relationship of levoketoconazole with 
respect to safety and tolerability; 


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4. To describe the effects of levoketoconazole on glucose tolerance among 
subjects with impaired fasting glucose (IFG). 
2.2 Overall Study Design 
The study is a double-blind, placebo-controlled, randomized withdrawal and 
restoration (or as needed early rescue) study in subjects with endogenous CS 
previously treated with single-arm, open-label levoketoconazole that will assess 
efficacy, safety, tolerability, and PK of levoketoconazole. 
Around 45 sites in North America, Europe and the Middle East will enroll up to 
approximately 54 subjects into the RW Phase of the study. 
Two populations (cohorts) will be eligible for participation in the study.  One cohort is 
based on previous participation in the COR-2012-01 (aka SONICS) trial and usage of 
a stable Therapeutic Dose of levoketoconazole in the 12-week timeframe prior to 
screening.  This cohort will represent a minority of randomized subjects.  The second 
cohort includes subjects completely naïve to levoketoconazole (the largest proportion 
of randomized subjects) and those who previously participated in SONICS but were 
not on a stable Therapeutic Dose in the 12-week timeframe prior to screening (also a 
minority of randomized subjects).  The cohort determination will be collected in the 
clinical database and will not be derived. 
Table 1 
Cohort Determination 
Cohort 1: 
Levoketoconazole-naïve 
(1) Subjects who did not participate in the prior clinical study of 
levoketoconazole (COR-2012-01 aka SONICS); or 
(2) Subjects who completed Visit Month 12 (M12) of SONICS 
(final scheduled visit prior to safety follow-up) but who have not 
been treated with a Therapeutic Dose of levoketoconazole 
throughout the 12-week period immediately prior to Screening in 
the current study. 
Cohort 2: 
SONICS-completer 
(1) Subjects who have completed all visits in the SONICS study 
through M12 (final scheduled visit prior to safety follow-up) at 
any time prior to the current study and who have been treated 
with a Therapeutic Dose of levoketoconazole throughout the 12-
week period immediately prior to Screening. 
Total duration of the study will depend on the cohort. 
Cohort 1: Subjects in the levoketoconazole-naïve (L-N) cohort will be enrolled for up 
to approximately 51 weeks due to the Screening and Dose Titration and Maintenance 
(TM) phases of the study. 


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Cohort 2: Subjects in the SONICS-completer (S-C) cohort who have established a 
Therapeutic Dose level of levoketoconazole and will be enrolled for less time (up to 21 
weeks). 
The overall study design is presented in Figure 1 below. 
Figure 1 Study Design Schematics 
 
TM Phase: After confirmation of eligibility, subjects in the L-N cohort (including 
subjects who completed SONICS but require re-titration) will enter the TM Phase.  The 
first dose of open-label therapy for this phase will be at the TM0 visit.  Subjects who 
did not complete Visit M12 of SONICS will always begin titration at Dose Level 1 (150 
mg BID).  Subjects who have completed Visit M12 in SONICS and have not been 
treated with a Therapeutic Dose of levoketoconazole throughout the 12-week period 
immediately prior to Screening must also re-establish a Therapeutic Dose and remain 
in the TM Phase for a full 14-week period, regardless of the duration needed to 
establish their Therapeutic Dose for this study (i.e. even if it takes less than 14 weeks). 


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Sponsor Protocol ID: COR-2017-01 
 
Covance Study ID: 39204 
 
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The RW Phase and RES Phase of the study will be the same for both cohorts.  All 
subjects have established their own Therapeutic Dose level prior to the start of the 
double-blind RW Phase. 
• 
RW Phase: The subjects will be randomized on a double-blind basis to either 
continue levoketoconazole at the Therapeutic Dose level or receive matched 
placebo. 
• 
RES Phase: Subjects who complete the RW Phase and do not meet any of the 
early rescue criteria will enter the double-blind RES Phase.  The 
levoketoconazole Therapeutic Dose level is maintained for those subjects 
randomized to levoketoconazole and is restored for those subjects randomized 
to placebo.  Those who have been randomized to levoketoconazole will receive 
matched placebo, while those who have been randomized to placebo will 
receive levoketoconazole additionally. 
 
The treatment schema for the study is presented in the table below. 
   
Table 2 
Study Treatment Schema 
Open-label 
levoketoconazole 
Therapeutic Dose established from TM Phase for subjects in the L-N 
cohort, or from SONICS study for S-C cohort 
Randomization 
(RW0) 
Blinded 
Randomized 
Withdrawal 
Phase 
Levoketoconazole at 
Therapeutic Dose 
Placebo at equivalent tablet count to 
Therapeutic Dose 
Blinded 
Restoration 
Phase 
Placebo added as 1 tablet 
twice daily (BID) at RW5 then 
add 1 tablet every 2 days, 
alternating AM and PM, until 
the total tablet count is double 
the count at RW0 
Levoketoconazole added as 1 tablet 
BID at RW5 then add 1 tablet every 
2 days, alternating AM and PM, until 
the total tablet count is double the 
count at RW0 
 
Subjects who meet any of the early rescue criteria during the RW Phase and are 
rescued with open-label levoketoconazole may continue in the RES Phase, except that 
therapy will be administered as open-label therapy.  Subjects who meet any of the 
early rescue criteria during the RW Phase, but are not rescued with open-label 
levoketoconazole, will be discontinued from the study.  For the purposes of defining 
study completion, however, subjects who complete RW0 and met any of the early 
rescue criteria during the RW Phase are considered as study completers (see Section 
5.10). 


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2.3 Sample Size and Power 
For the purpose of sample size estimation, it is assumed that among subjects in the 
intent-to-treat (ITT) population who complete at least the RW4 visit in the RW Phase, 
10% will lose therapeutic response in the levoketoconazole arm versus 75% in the 
placebo arm.  The 10% loss of therapeutic response rate in the levoketoconazole arm 
is based on data from the SONICS study. 
For the analysis of the primary endpoint, subjects in the ITT population who withdraw 
prior to RW4 are considered as losing therapeutic response.  As such, the assumed 
loss of therapeutic response rate in the overall ITT population in each arm depends 
on the withdrawal rate prior to RW4 during the RW Phase.  It is expected that the 
withdrawal rate will be no more than 10%, but up to 20% is considered in the sample 
size estimation.  If the withdrawal rate is 10% per arm, a sample size of 46 subjects 
(23 per arm) randomized and treated during the RW Phase corresponds to 42 subjects 
(21 per arm) completing RW4 and provides approximately 99% power, using two-
sided Fisher’s Exact test, to detect the alternative hypothesis of a loss of therapeutic 
response rate of 17% in the levoketoconazole arm and 78% in the placebo arm versus 
the null hypothesis of no difference between the two arms.  If the withdrawal rate is 
20% per arm, a sample size of 54 subjects (27 per arm) randomized and treated 
during the RW Phase corresponds to 44 subjects (22 per arm) completing RW4 and 
provides approximately 98% power to detect the alternative hypothesis of a loss of 
therapeutic response rate of 26% in the levoketoconazole arm and 81% in the placebo 
arm versus the null hypothesis of no difference between the two arms. 
Because enrollment into the TM Phase will be closed prior to the last subject being 
randomized and treated in the RW Phase, the actual sample size for the RW Phase is 
not prespecified.  The timing of enrollment closure will be based on the rolling 4-week 
completion rate trend for the TM Phase.  A minimum of 46 subjects (23 per arm) and 
a maximum of 54 subjects (27 per arm) will be targeted to be enrolled into the RW 
Phase based on the observed withdrawal rate trend for the phase. 
A minority of randomized subjects are anticipated to be in the S-C cohort.  Any subject 
who withdraws after randomization will not be replaced.  Withdrawn subjects will not 
be re-entered into the study. 
 
 


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3. Study Endpoints 
3.1 Primary Efficacy Endpoint 
Loss of Therapeutic Response 
The primary efficacy endpoint is 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 the mean of three 24-hour UFC measurements (mUFC) obtained at any visit from 
second through final randomized-withdrawal visits (RW1 through RW5 inclusive) 
when: 
• 
mUFC is above 1.5X the upper limit of normal (ULN) of the central laboratory’s 
reference range OR  
• 
mUFC is more than 40% above the Baseline (RW0) value, if the Baseline value 
is above the ULN (i.e. > 1.0X ULN)1 OR  
• 
an early rescue criterion is met. 
Early Rescue Criteria 
Early rescue during the RW Phase must be considered when a subject demonstrates 
one or more of the following criteria at any time after randomization: 
1. Relapse of hypercortisolemia (i.e. loss of therapeutic response). Defined as: 
• 
mUFC from three urine collections that is above 1.5X ULN  
OR  
• 
mUFC from three urine collections that increases by 40% or more above 
the Baseline (RW0) value and when the Baseline value is above 1X ULN, 
for the S-C cohort only.  
2. Partial loss of cortisol response. Defined as:  
• 
mUFC from three urine collections that increases from Baseline (RW0) to 
greater than 1X ULN but no more than 1.5X ULN  
OR  
• 
LNSC that was normal at Baseline (RW0; both values ≤ULN) and 
becomes abnormal (>ULN) based on each of two LNSC collections  
obtained on different nights  
 
1 This category applies only to subjects who have completed SONICS, who may have a Therapeutic Dose established with mUFC 
above the ULN of the reference range.  Levoketoconazole-naïve cohort must have mUFC at or below the ULN at RW0 to qualify for 
randomization. 


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         AND 
In addition to one of the above partial-loss criteria, the subject must 
exhibit clinically significant worsening of signs and symptoms of CS, as 
determined by: 
• 
Clinically significant deterioration in disease-related signs or  
symptoms (using the signs and symptoms validated instrument  
and/or physical examination). 
         OR  
• 
Relevant deterioration in one or more disease-related biomarkers 
(protocol Section 4.3.1, Table 3). 
3. In the absence of loss or partial loss of cortisol response as defined above, 
clinically significant deterioration in disease-related signs or symptoms (using the 
signs and symptoms validated instrument and/or physical examination) AND 
clinically relevant deteriorations in two or more disease-related biomarkers (see 
protocol Section 4.3.1, Table 3). 
Early rescue that occurs without meeting one of the three pre-defined categories 
above will not be considered a loss of response for the purposes of the primary 
endpoint. 
3.2 Secondary Efficacy and Safety Endpoints 
• 
Changes from Baseline (RW0) in mUFC and LNSC at all post-baseline visits with 
these assessments through the final study visit (RES2)—applies to Secondary 
Objective 1; 
• 
Proportion of subjects with normalization of mUFC at RES2—applies to 
Secondary Objective 1; 
• 
Proportion of subjects with normalization of mUFC at the end of RW Phase 
(RW5) -applies to Secondary Objective 1; 
• 
Changes from Baseline (RW0) in biomarkers of CS comorbidities at all post-
baseline visits with these measurements through the final study visit (RES2)—
applies to Secondary Objective 2; 
• 
Changes from Baseline (RW0) in health-related QoL and symptoms of 
depression at all post-baseline visits with these assessments through the final 
study visit (RES2)—applies to Secondary Objective 3; 
• 
Changes from Baseline (RW0) in acne, hirsutism and peripheral edema at all 
post-baseline visits with these assessments through the final study visit 
(RES2)—applies to Secondary Objective 4; 


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• 
Incidence and severity of adverse events (AEs), particularly adverse events of 
special interest (AESIs) during levoketoconazole open-label therapy in the TM 
Phase (L-N cohort) and during blinded therapy in the RW Phase and RES 
Phase (both cohorts)—applies to Secondary Objective 5. 
3.3 Exploratory Efficacy and Safety Endpoints 
• 
Frequency of usage and changes from Baseline (RW0) in frequency of usage of 
anti-diabetic, 
anti-cholesterol, 
anti-hypertensive, 
and 
chronic 
anti-
inflammatory therapies at all post-baseline visits; changes in corresponding 
biomarkers accounting for changes in medication usage will also be explored—
applies to Exploratory Objective 1; 
• 
Time from RW0 to first time of loss of response, when:  
   (1)  mUFC is above 1.5X the ULN of the central laboratory’s reference 
range, OR  
   (2)  mUFC is more than 40% above the RW0 value, if the RW0 value is 
above the ULN (i.e. >1.0X ULN)2, OR  
   (3)  an early rescue criterion is met—applies to Exploratory Objective 2; 
• 
Time to first normalization of mUFC beginning from RW5 (subset with mUFC 
above 1.5X ULN at RW5)—applies to Exploratory Objective 2; 
• 
Time to first normalization of LNSC beginning from RW5 (subset with LNSC 
above ULN at RW5) —applies to Exploratory Objective 2; 
• 
Proportion of subjects with normalization of mUFC at the end of TM Phase 
(TM7) - applies to Exploratory Objective 2; 
• 
Proportion of patients with either normalization of mUFC or partial response 
(at least 50% decrease in mUFC) at the end of TM Phase (TM7) - applies to 
Exploratory Objective 2; 
• 
Proportion of subjects with normalization of LNSC at RES2—applies to 
Exploratory Objective 2; 
• 
Changes from Baseline (RW0) in serum cortisol and adrenocorticotrophic 
hormone (ACTH) at all post-baseline visits with these assessments through 
the final study visit (RES2)—applies to Exploratory Objective 2; 
• 
Changes from Baseline (RW0) in clinical signs and symptoms of CS excluding 
acne, hirsutism and peripheral edema at all post-baseline visits with these 
 
2 This category applies only to subjects who have completed SONICS, who may have a Therapeutic Dose established with UFC above 
the ULN of the reference range.  Levoketoconazole-naïve cohort must have UFC at or below the ULN at RW0 to qualify for randomization. 


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assessments through the final study visit (RES2)—applies to Exploratory 
Objective 2; 
• 
Frequency and severity of common AEs and laboratory abnormalities in relation 
to dose of study drug administered at the time of the reported AE or laboratory 
abnormality—applies to Exploratory Objective 3; 
• 
Shifts from normality and concentration changes from Baseline (RW0) in serum 
transaminases, alkaline phosphatase (AP), and total bilirubin at all post-
baseline visits in relation to dose of study drug administered at the time of the 
shift or change—applies to Exploratory Objective 3; 
• 
Durations and changes in durations from Baseline (RW0) of the QT interval 
corrected for heart rate (QTc interval) in relation to dose of study drug 
administered proximal to the measurement—applies to Exploratory Objective 
3. 
• 
Change from Baseline (RW0) in observed and derived glucose and insulin 
parameters during oral glucose tolerance test (OGTT) in the subset of subjects 
with IFG—applies to Exploratory Objective 4. 
3.4 Pharmacokinetic/Pharmacodynamic Endpoints 
• 
Estimates of the following PK parameters: clearance (CL/F), volume of 
distribution (V/F), absorption rate constant (Ka), with associated between-
subject variability where feasible. These parameters will be used to calculate 
half-life (t½), area under the concentration time curve (AUC) and peak 
concentration (Cmax), if feasible—applies to Secondary Objective 6; 
• 
Estimates 
of 
the 
following 
pharmacodynamic 
(PD) 
parameters: 
levoketoconazole concentration producing half maximal UFC suppression 
(IC50), maximal suppression of UFC (Imax) and associated estimates of 
between-subject variability, if feasible. UFC concentrations in relation to dose 
and plasma exposure will be explored—applies to Secondary Objective 6. 
 
 


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4. Analysis Populations 
4.1  Intent-to-Treat (ITT) Population  
The ITT population will include all subjects who are randomized and receive at least 
one dose of blinded study drug during the RW Phase.  The ITT population will be used 
for the primary analysis of efficacy and secondary analyses of efficacy and safety.  For 
efficacy, subjects will be analyzed by their randomized treatment assignment.  For 
safety, subjects will be analyzed by the actual study drug they receive. 
The ITT population for levoketoconazole in the RES Phase will include all subjects who 
receive at least one dose of levoketoconazole during the RES Phase.  It will be referred 
to as the RES ITT population and will be used for the analysis of efficacy and safety 
during the RES Phase. 
4.2  Per-Protocol (PP) Population 
The PP population will consist of all subjects in the ITT population who have no major 
protocol deviations during the RW Phase that could affect the primary endpoint.  This 
population will be used in supportive analyses of the primary endpoint.  Selective 
secondary efficacy endpoints will also be analyzed using PP population if PP population 
< 90% of the ITT population. 
A protocol deviation is defined as any change, divergence, or departure from the study 
design or procedures defined in the study protocol.  Major protocol deviations are a 
subset of protocol deviations and may significantly impact the correctness, accuracy, 
and/or reliability of the study data or may significantly affect a subject’s rights, safety, 
or well-being. 
4.2.1 
Major Protocol Deviations Leading to Exclusion from PP 
Population Analysis 
All major (also known as important) protocol deviations occurring during the RW Phase 
of the study will be reviewed and approved by the Sponsor prior to the lock of the 
database containing data through the end of the RW Phase and prior to treatment 
unblinding.  Of these major protocol deviations, those that will lead to exclusion of 
subjects from the PP population will be identified by the Sponsor prior to the first 
database lock that will occur after the last subject completes the RW Phase. 
The list of categories of protocol deviations during the RW Phase that may be 
considered major by the Sponsor, subject to review of the actual deviations that occur, 
are provided in a separate document called the Study Specific Protocol Deviation List 
dated August 06, 2019. 


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4.3 Levoketoconazole-naïve(L-N) Population 
The L-N population will consist of all subjects in the L-N cohort who receive at least 
one dose of study drug during the TM Phase.  This population will be used for 
supportive evaluations of safety and for exploratory efficacy, safety, and PK analyses. 
4.4  SONICS-completer Population 
The S-C population will consist of all subjects in the S-C cohort who receive at least 
one dose of blinded study drug during the RW Phase.  This population will be used in 
summaries of disposition, demographics and baseline characteristics, and prior 
medications by subject cohort.  Because the size of this cohort is n=5, which is < 30% 
of the minimum expected ITT population size, there will be no additional efficacy, 
safety, and PK analyses for this population except for those explicitly specified in 
Sections 6.6.1 and 6.6.2.1 (for the primary efficacy endpoint and Set 1 of the 
secondary efficacy endpoints). 
4.5  Safety Population 
The Safety population will be determined based on study phase and the study overall.  
Subjects will be analyzed by the actual study drug they receive. 
The Safety population for the study overall (i.e. all phases combined), referred to 
simply as the Safety population, will include all subjects who receive at least one dose 
of study drug during any of the 3 study phases. 
The Safety population for levoketoconazole for the TM Phase will include all subjects 
who receive at least one dose of levoketoconazole during the TM Phase.  This is the 
same as the L-N population defined in Section 4.3 and will be referred to as such. 
The Safety population for the RW Phase will include all subjects who receive at least 
one dose of blinded study drug during the RW Phase.  This is the same as the ITT 
population defined in Section 4.1 and will be referred to as such. 
The Safety population for levoketoconazole for the RES Phase will include all subjects 
who receive at least one dose of levoketoconazole during the RES Phase.  This is the 
same as the RES ITT population defined in Section 4.1 and will be referred to as such. 
The Safety population for levoketoconazole for the RW Phase and RES Phase 
combined, will include all subjects who receive at least one dose of levoketoconazole 
during the RW Phase or the RES Phase. 
The ITT population is the main Safety population of interest.  All safety endpoints will 
be analyzed on this Safety population.  The other definitions of Safety populations will 
be used for supportive evaluations of safety. 
 


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5. Data Handling 
5.1 Baseline, First Dose Date, and Last Dose Date 
There are three phases of interest in the study, as listed below.  The phase of main 
interest is the RW Phase, with the RES Phase and the TM Phase of secondary interest.  
For some endpoints, the combined RW Phase and RES Phase are of interest.  Baseline 
visit, Baseline value, first dose date, and last dose date are defined for each study 
phase, or combination thereof, as stated below. 
• 
TM Phase (applicable to the L-N cohort only): 
o Baseline visit is the TM0 visit. 
o Baseline value is the pre-dose value at the TM0 visit; if this value is 
missing or post-dose, then the last non-missing value prior to the TM0 
visit, if there is any, will be used as the Baseline value. 
o First dose date (and the start of the study phase) is the TM0 visit date, 
as recorded in the TM0 Visit Date eCRF. 
o Last dose date is the day before the RW0 visit date (i.e. RW0 visit date 
– 1 day) for subjects who continue on to the RW Phase, or the date of 
last dose recorded in the eCRF for those subjects who discontinue 
otherwise. 
o End of the study phase is the last dose date for subjects who continue 
on to the RW Phase.  It is either the last dose date or the date of study 
discontinuation, whichever is later, for those subjects who discontinue 
prior to the RW Phase. 
• 
RW Phase: 
o Baseline visit is the RW0 visit. 
o Baseline value is the pre-dose value at the RW0 visit; if this value is 
missing or post-dose, then the last non-missing value prior to the RW0 
visit, if there is any, will be used as the Baseline value. 
o First dose date (and the start of the study phase) is the RW0 visit date, 
as recorded in the RW0 Visit Date eCRF. 
o Last dose date is the RW5 visit date, as recorded in the RW5 Visit Date 
eCRF, minus 1 day for subjects who continue on to the RES Phase, or the 
date of last dose recorded in the eCRF for those subjects who discontinue 
otherwise.  This last dose date is also considered as the end of the RW 
Phase.  The subjects who continue on to the RES Phase include not only 


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the subjects who complete all visits in the RW Phase but also the early 
rescue subjects who receive open-label levoketoconazole as early rescue 
treatment. 
o End of the study phase is the RW5 visit date, prior to the first dose in the 
RES Phase for subjects who continue on to the RES Phase.  It is either 
the last dose date or the date of study discontinuation, whichever is later, 
for those subjects who discontinue prior to the RES Phase. 
• 
RES Phase: 
o Baseline visit is the RW5 visit. 
o Baseline value is the pre-dose value at the RW5 visit; if this value is 
missing or post-dose, then the last non-missing value prior to the RW5 
visit will be used as the Baseline value. 
o First dose date (and the start of the study phase) is the RW5 visit date. 
o Last dose date is the date of last dose recorded in the eCRF.  If this date 
is missing for a subject who completes the RES Phase, then the RES2 
date will be used instead.  
o End of the study phase is either the last dose date or the date of study 
completion (for subjects who complete the RES Phase) or study 
discontinuation (for subjects who discontinue during the RES Phase), 
whichever is later. 
• 
RW Phase and RES Phase Combined: 
o Baseline visit, Baseline value, and First dose date are the same as the 
ones for the RW Phase above. 
o Last dose date and end of the study phase are the same as the ones for 
the RW Phase for subjects who discontinue prior to the RES Phase and 
are the same as the ones for the RES Phase for subjects who continue 
on to the RES Phase. 
• 
All Phases Combined (applicable to the L-N cohort only): 
o Baseline visit, Baseline value, and First dose date are the same as the 
ones for the TM Phase above. 
o Last dose date and end of the study phase are the same as the ones for 
the TM Phase for subjects who discontinue prior to the RW Phase, the 
same as the ones for the RW Phase for subjects who discontinue prior to 
the RES Phase, and the same as the ones for the  RES Phase for subjects 
who continue on to the RES Phase. 


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As there are 3 Baselines defined above, they will be designated as TM Baseline, RW 
Baseline, and RES Baseline.  RW Baseline is the Baseline of main interest.  Changes 
from Baseline will be calculated relative to the TM Baseline for the TM Phase, relative 
to the RW Baseline for the RW Phase, relative to the RES Baseline for the RES Phase, 
and relative to the RW Baseline for the RW Phase and RES Phase, combined. 
5.2 Study Day and Relative Day 
Study day is calculated within each study phase based on the first dose date within 
the study phase. 
• 
If the date of assessment is before the date of first dose, then Study Day = 
Date of assessment – First dose date; 
• 
If the date of assessment is on or after the first dose date, then Study Day = 
Date of assessment – First dose date + 1 day;  
• 
If the first dose was never given in a study phase, then the Study day will be 
missing. 
Relative day is calculated in an analogous manner to Study day, based on the date of 
interest (e.g. AE onset date) and the date of reference (e.g. date of first dose). 
Day 1 within a study phase is defined as the day of first dose of study drug for that 
study phase.  The day prior to Day 1 is Day -1.  As the study days are relative to a 
study phase, they will be designated as TM Day x, RW Day x, and RES Day x. 
5.3 Time Points and Visit Windows 
Efficacy and safety endpoints for the TM Phase will not be analyzed by visit, because 
the L-N cohort who completed SONICS but require re-titration may begin dose 
titration at their current or more recently received dose of levoketoconazole, which 
may be higher than Dose Level 1 (300 mg/day).  As such, each TM visit will have 
subjects at differing dose levels, which would make inferences of efficacy and safety 
results by visit during this phase untenable.  With the exception of AEs which will be 
analyzed for incidence rates during the entire phase, safety endpoints will be analyzed 
by: 1) the worst results (for shift or threshold analyses only), 2) the last non-missing 
results, and 3) the non-missing results at the highest dose received during the TM 
Phase.  Efficacy endpoints will be analyzed by: 1) the last non-missing results and 2) 
the non-missing results at the highest dose received during the TM Phase. 
For the RW Phase and RES Phase, Table 3 below presents the visit windows that will 
be used for the by-visit analysis of efficacy and safety.  It also presents the visit 
window that will be used for the End of RW Phase time point analysis of efficacy and 
safety. 


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ST-AD-008 version 04                                                                                                              Page 28 of 87 
 
 
 
 
Table 3 
RW Phase and RES Phase – Visit Windows for by-visit Analysis 
of Efficacy and Safety  
1Study Days are relative to RW Day 1 (= RW0 visit date) 
2Study Days are relative to RES Day 1 (=RW5 visit date)  
3Data from assessments performed after RES Day 70 will not be considered in any by-visit analysis of efficacy and 
safety but will be included in the data listings. 
For all populations, multiple visits within the same window will be dealt with as follows: 
• 
If both scheduled and unscheduled visits fall within the same visit window, then 
the scheduled visit will be used for analysis, except for by-visit safety endpoints 
(e.g. laboratory evaluations) when they are analyzed with respect to normal 
ranges (e.g. shift tables) or prespecified thresholds; the worst results among 
all scheduled and unscheduled visits within the same visit window will then be 
used instead.  For vital signs (specifically blood pressure and heart rate) and 
electrocardiogram (ECG) intervals (specifically QT, QTcF, QTcB, PR, and QRS), 
the worst result for a subject in a study phase or visit window is defined as the 
maximum value for that subject in that study phase or visit window.  For the 
safety laboratory tests, the worst result for a subject in a study phase or visit 
window can be the maximum or minimum value, depending on the laboratory 
test.  Refer to Appendix 1 for details on the identification of the worst results 
for safety laboratory tests.  If multiple scheduled visits occur within a single 
visit window, then the visit closest to the target day of the visit window will be 
used in the analysis.  If there is a tie, then the later scheduled visit will be used 
in the analysis.   
Nominal Visit/Time 
Point 
Target Study Day 
(range) 
Study Day Analysis Visit Window 
Range 
RW1/D10 
10 (8 to 10)1 
RW Days 2 to 151 
RW2/D20 
20 (18 to 20)1 
RW Days 16 to 251 
RW3/D30 
30 (26 to 30)1 
RW Days 26 to 351 
RW4/D40 
40 (38 to 40)1 
RW Days 36 to 451 
RW5/D58 
58 (54 to 58)1 
RW Days 461 to RES Day 12 (or the end of 
the RW Phase [see Section 5.2]) for 
subjects who do not enter the RES Phase) 
End of RW Phase 
 No specific target day 
(range) specified, so long 
as it is during the RW 
Phase. 
No specific study day analysis visit 
window range specified, so long as it is 
during the RW Phase.  The non-missing 
result from the last analysis visit window 
in the RW Phase for a subject will be used 
for the End of RW Phase time point. 
Note: This time point is the main analysis 
time point of interest for secondary 
efficacy endpoints that are assessed 
during the RW Phase. 
RES1 
28+/-5 days after RW5 
RES Days 2 to 422 
RES2 
28+/-5 days after RES1 RES Days 43 to 702,3 


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ST-AD-008 version 04                                                                                                              Page 29 of 87 
 
 
 
 
• 
If multiple unscheduled visits occur within a single visit window (with no 
scheduled visit within the window), then the unscheduled visit closest to the 
target day of the visit window will be used in the analysis.  If there is a tie, then 
the later unscheduled visit will be used in the analysis. 
A blinded review of the analysis visit assignments for the RW Phase based on the 
analysis visit window ranges above will be performed by the Contract Research 
Organization (CRO) Lead Statistician (and confirmed by the Sponsor Lead Statistician)  
prior to the first database lock of all data through the end of the RW Phase, which will 
occur after the last subject completes the RW Phase.  A blinded review of analysis visit 
assignments for the RES Phase based on the analysis visit windows above will be 
performed by the CRO Lead Statistician (and confirmed by the Sponsor Lead 
Statistician) prior to the final database lock after the end of the study.  The reviews 
will check for illogical analysis visit assignments.  The blinded listing that will be 
produced for the review will list the following data: subject id, parameter or endpoint, 
visit name and number in the database, whether the visit is scheduled or unscheduled, 
visit date (and time, if applicable), study day, and assigned analysis visit.  The 
following parameters/endpoints will be included in the blinded listing for review: 
Primary and secondary efficacy endpoints, liver function tests (LFTs), ECGs, and vital 
signs. Only visits with non-missing data for the parameter or endpoint will be included 
in the listing.  Any change to the analysis visit window ranges specified in this SAP as 
a result of the blinded review(s) will be documented in a SAP amendment prior to 
database lock and (in the case of the blinded reviews during the dry runs) prior to 
treatment unblinding. 
5.4 Urinary Free Cortisol – Determination of Adequacy and Calculation 
of Mean 
24-hour urine samples will be collected for determination of UFC during the 3 study 
phases.  Depending on the visit, 2 or 3 samples will be collected over sequential days 
per the study days indicated in Appendix A (Time and Events Schedules) of the 
protocol, prior to the actual scheduled visit.  At the Screening, TM0, TM7, RW0, RW5, 
and RES2 visits, 3 samples will be collected over sequential days prior to the visit.  For 
subjects in the S-C cohort for which their first 2 samples for the Screening visit are 
from their Month 12 visit in SONICS, their third sample will be collected just prior to 
their first visit in LOGICS.  At the TM1 to TM6 visits, 2 samples will be collected over 
sequential days prior to the visit.  If the mUFC from the first 2 samples is ≤ ULN, a 
third sample will be collected as a confirmatory sample as soon as possible following 
the visit to confirm UFC normalization.  At the RW1 to RW4 visits, 2 samples will be 
collected over sequential days prior to the visit.  A third sample will be collected as a 
confirmatory sample as soon as possible following the visit if UFC is being used to 
establish the need for early rescue therapy during the RW Phase.  At the RES1 visit, 


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2 samples will be collected over sequential days prior to the visit.  In general, the first 
2 samples will be on consecutive days, but the third sample may be several days after 
the second sample.  This includes the case of subjects in the S-C cohort and their 
samples corresponding to the Screening visit.  This also includes the case of any 
subject where the third sample for a visit is a confirmatory sample (i.e. either to 
confirm UFC normalization or the need for early rescue therapy).   
For the analyses of the primary efficacy endpoint and other UFC-related endpoints, 
only UFC values from adequate urine collections will be included.  The urine creatinine 
excretion rate will be measured from the 24-hour urine samples as a marker of the 
adequacy of the urine collections. 
A urine sample for UFC is considered to be adequate for analysis purposes if its 
corresponding urine creatinine excretion is ≥ 4.5 mg/kg/day for females and ≥ 6.2 
mg/kg/day for males.  The thresholds of 4.5 mg/kg/day for females and 6.2 
mg/kg/day for males were based on the mean minus (2 x SD) of all urine creatinine 
excretion values in the SONICS study by sex, which meant that approximately 2.5% 
of the urine creatinine excretion values from SONICS were < 4.5 mg/kg/day for 
females and < 6.2 mg/kg/day for males.  It is anticipated that LOGICS will have about 
the same overall means by sex and, therefore, using these thresholds will result in 
excluding about 2.5% of all samples from analyses. 
At each visit, the mUFC corresponding to that visit will be calculated using all UFC 
values: 1) from adequate 24-hour urine collections and 2) with urine sample start 
dates within the analysis window for that visit.  The mUFC for a subject at a visit will 
be calculated only if there are at least two UFCs that meet these two requirements; 
otherwise, mUFC will be considered as missing for that subject at that visit. For the 
purpose of determining loss of therapeutic response for the primary endpoint when a 
subject was not early rescued, mUFC must be based on three adequate samples.  In 
the case of subjects in the S-C cohort and their samples corresponding to the 
Screening visit, the first 2 samples may be recorded at one visit (e.g. Screening) and 
the third sample at another visit (e.g. RW0).  In the case of any subject where a third 
sample is collected as a confirmatory sample, the third sample may be recorded at a 
different CRF visit than the first 2 samples, because it will be collected following the 
visit instead of prior to the visit.  In these cases, the third sample will be included in 
the calculation of the mUFC for that visit, so long as it was an adequate sample.  
Additional 24-hour urine samples for UFC other than those specified in Appendix A of 
the protocol will not be included in the calculation of the mUFC for a visit. 
To ensure that samples for UFC that are included in the calculation of a mUFC for a 
subject are always samples corresponding to the same visit, blinded reviews of the 
urine collections included in the calculation of the mUFCs will be conducted in 
conjunction with the blinded review of the analysis visit assignments, described in 


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Section 5.3.  The blinded listing will list only the following data: subject id, visit name 
and number in the database, whether the visit is scheduled or unscheduled, urine 
collection start and stop dates and times, study day start and stop, whether the 
sample is adequate or not based on the Sponsor’s determination, assigned analysis 
visit, and a flag variable that indicates if the UFC (not provided in the listing) 
corresponding to the sample is used in the calculation of mUFC.  Only urine collections 
with non-missing UFC will be included in the listing. 
Sensitivity analyses that allow for the use of a single adequate urine sample that is 
within the analysis visit window to calculate mUFC for that visit or the imputation of a 
missing mUFC due to all missing or inadequate samples for that visit in the RW Phase 
will be performed Section 6.6.3.  Sensitivity analyses where UFC values from all urine 
samples, regardless of adequacy, will be used to calculate mUFC will also be performed 
(see Section 6.6.3). 
5.5 Early Rescue Criteria – Programmed Verification of Quantitative 
Criteria 
The study Medical Monitor is to be informed by the site when early rescue for a subject 
in the RW Phase is deemed necessary by the Investigator.  Prior to the site’s initiation 
of early rescue therapy, the Medical Monitor is supposed to review the relevant data 
to confirm that the subject meets the early rescue criteria as defined in Section 3.1 of 
this SAP and Table 3 in Protocol Section 4.3.1. 
The early rescue criteria met by a subject are recorded in the Early Rescue Study 
Completion eCRF.  For the quantitative element(s) that is (are) marked in this eCRF 
as having met by the subject, a blinded programmed verification using the electronic 
laboratory data will be performed prior to the first database lock that will occur after 
the last subject completes the RW Phase.  If the programmed results do not confirm 
that the quantitative element(s) is (are) met for one or more early rescue subjects, a 
sensitivity analysis of the primary efficacy endpoint will be performed with the 
subject(s) excluded from the analysis (see Section 6.6.3). 
5.6 Late Night Salivary Cortisol – Calculation of Means 
Salivary samples will be collected between 11 PM and midnight for the determination 
of LNSC during the 3 study phases.  Depending on the visit, 1 or 2 samples will be 
collected prior to the actual scheduled visit.  At the Screening, TM0, TM7, RW0, RW5, 
and RES2 visits, 2 samples will be collected over sequential days.  For subjects in the 
S-C cohort for which the first sample for the Screening visit is from their Month 12 
visit in SONICS, their second sample will be collected just prior to their first visit in 
LOGICS; therefore, there may be a gap of several days between the 2 samples. At 


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the TM1 to TM6 and RES1 visits, 1 sample will be collected.  At the RW1 to RW4 visits, 
1 sample will also be collected, and a second sample may be collected as soon as 
possible following the visit if LNSC is being used to establish the need for early rescue 
therapy during the RW Phase.  As such, there may be a gap of several days between 
the 2 samples. 
For the analysis of LNSC at a visit, only adequate sample(s), defined as those collected 
between 10 PM and midnight (i.e., a 1-hour allowance earlier), and with collection 
date(s) within the analysis window for that visit will be included.  If there are 2 such 
samples, the mean LNSC will be calculated and used in the analysis.  In the case of 
subjects in the S-C cohort and their samples corresponding to the Screening visit, the 
first samples may be recorded at one visit (e.g. Screening) and the second sample at 
another visit (e.g. RW0).  In the case of any subject where a second sample is 
collected to establish the need for early rescue therapy, the second sample may be 
recorded at a different CRF visit than the first sample, because it will be collected 
following the visit instead of prior to the visit.  In these cases, the second sample will 
be included in the calculation of the mean LNSC for that visit, so long as it is adequate 
and within the same analysis visit window. 
5.7 Blood Pressure, Heart Rate, and Abdominal Girth – Calculation of 
Means 
Blood pressure, heart rate, and abdominal girth are measured in triplicate at each 
visit.  The mean of the measurements will be used as the result for each visit.  The 
mean of the measurements will be calculated only if there are at least 2 
measurements. 
5.8 Cushing’s Syndrome Quality of Life and Beck Depression Inventory 
(BDI) II – Calculation of Total Scores 
The CS QoL questionnaire is a general questionnaire of 12 items that assesses subject 
health-related quality of life.  Answers to QoL are based on Likert scales with five 
response categories, rated on a scale of 1-5, where ‘1’ corresponds to ‘Always’ or 
‘Very much’ and ‘5’ to ‘Never’ or ‘Not at all’.  The lower the score, the lower the health-
related quality of life (HRQoL).  The total score for QoL is the sum of all the item 
responses and can range from 12 (worst score) to 60 points (best score).  A 
standardized total score on a scale from 0 (worst HRQoL) to 100 (best HRQoL) will be 
calculated with the following formula: 
         Standardized total score = 
 
100
min
max
min ×
−
−
TotalScore


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where ‘min’ is the minimum (min=12 if all 12 item responses are non-missing), and 
‘max’ is the maximum possible score (max=60 if all 12 item responses are non-
missing). 
If more than 3 items have a missing response, then the total score will be considered 
missing for that visit.  The standardized total score can be calculated (as above) if the 
number of unanswered items does not exceed 3 (25% of the questions).  In this case, 
the standardized total score will have min = the number of item responses that are 
non-missing and max = 5 x the number of items responses that are non-missing. 
The BDI-II inventory comprises 21 questions, with a score from 0 to 3.  Scores for 
each question are summed to create a total score.  A total score between 0 and 13 
indicates minimal depression, 14 to 19 mild depression, 20 to 28 moderate 
depression, and 29 to 63 severe depression.  Scoring information for the 21 questions 
is in Appendix N of the protocol.  If one question has a missing score, then the missing 
score will be imputed as the average of the non-missing scores for that question in 
the ITT population.  If there are more than 25% of the questions (i.e. 6 or more 
questions out of 21) with a missing score at a given visit, then the total score will be 
set to missing. 
5.9 Acne, Hirsutism, Peripheral Edema, and Other Clinical Signs and 
Symptoms of Cushing’s Syndrome – Calculation of Total Scores 
Acne Global Score 
Each type of lesion is graded with a value depending on the severity: 0 - No Lesions, 
1 - Greater than or equal to one comedone, 2 - Greater than or equal to one papule, 
3 - Greater than or equal to one pustule, 4 - Greater than or equal to one nodule.  
Factor is dependent on the location of the lesion: 2 – Forehead, 2- Right Cheek, 2- 
Left Cheek, 1 – Nose, 1 – Chin and 3 - Chest and Upper Back. 
The score for each area (Local score) is calculated using the formula: 
Local score = Factor × Grade (0-4) 
The global score is the sum of local scores as follows: 
Global score = Sum (all local scores) 
The global score can range from 0 to 44. If one area has a missing local score, then 
the missing local score will be imputed as the average of the non-missing local scores 
for that area in the ITT population.  If there are more than 25% of the areas (i.e. 2 or 
more areas out of 6) with a missing local score at a given visit, then the global score 
will be set to missing. 
Hirsutism Total Score (for females only) 


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Hirsutism will be assessed for females only.  The total score is the sum of all the scores 
obtained in each of the 9 locations.  Total score can vary between 0 and 36.  A high 
score means that the hirsutism is more visible.  If one location has a missing score, 
then the missing score will be imputed as the average of the non-missing scores for 
that location in the ITT population.  If there are more than 25% of the locations (i.e. 
3 or more locations out of 9) with a missing location score at a given visit, then the 
total score will be set to missing. 
Peripheral Edema Total Score 
The total score is the sum of all the scores obtained in each of the 3 locations.  Total 
score can range between 0 and 12.  A high score means that the edema is more 
pronounced.  If one or more locations has a missing score, then the total score will be 
set to missing. 
Total Score for the Other Clinical Signs and Symptoms of Cushing’s 
Syndrome 
The other clinical signs and symptoms, defined in Appendix M of the protocol, are 
moon facies, facial plethora, striae, bruising, supraclavicular fat, irregular 
menstruation (females only), and dysmenorrhea (females only).  Each symptom, if 
present, is graded as Mild (=1), Moderate (=2), or Severe (=3).  If not present, the 
symptom is graded as None (=0).  If the grade is missing for irregular menstruation 
or dysmenorrhea for a female subject who is post-menopausal or surgically sterile, 
the missing grade will be set to 0. Total severity score (or simply, total score) is the 
sum of the severities for each sign or symptom assessed.  Since only 5 of the 7 signs 
and symptoms apply to males, their total score is divided by 5 and then multiplied by 
7 to standardize it to the same scale as the total score for females.  The total score 
can range from 0 (none) to 21 (worst).  If more than 25% of the individual signs and 
symptoms (i.e. 2 or more signs and symptoms out of 5 for males and out of 7 for 
females) have missing scores at a given visit for a subject, then the total score will be 
set to missing.  If 4 of 5 signs and symptoms for males and 6 of 7 signs and symptoms 
for females are actually assessed, the total score will be standardized by dividing it by 
the number of non-missing signs and symptoms and then multiplying by 7. 


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5.10  Handling of Dropouts, Missing Data, and Outliers 
Definition of Study Completion 
Study completion for purposes of assessing the primary endpoint is defined as either 
of the following: 
1. having completed Visits RW0 (RW Baseline) and RW5 (i.e. final scheduled visit 
in RW Phase) regardless of UFC status, OR,  
2. having completed RW0 and having met at least one of the three criteria for 
use of early rescue treatment with open-label levoketoconazole (or another 
rescue medication) after RW0. 
Definition of Non-completion 
Subjects withdrawn from the study without meeting the definition of study completer 
above will be considered as prematurely withdrawn (i.e. non-completers). 
Missing or Inadequate UFC Collections 
Refer to Section 5.4 for the handling of missing or inadequate UFC collections. 
Handling of Missing Data for the Analysis of the Primary Endpoint 
The following rules will be applied for determining loss of therapeutic response when 
some or all mUFC data are missing: 
1. A subject withdraws prematurely during the RW Phase (i.e. Visit RW5 is not 
completed nor is the subject in need of early rescue treatment) and there is no 
post-randomization data available for determination of adequate mUFC.  In this 
case, the subject will be assumed to have lost therapeutic response; OR 
2. A subject withdraws prematurely during the RW Phase after RW0 and before 
RW5, with no early rescue, and at least one post-randomization mUFC 
determination is available.  In this case, if the latest available adequate mUFC 
determination is the one for RW4, all available mUFC determination(s) will be 
used to determine if loss of therapeutic response occurred for that subject, but 
if the latest available mUFC determination is for a visit before RW4, the subject 
will be assumed to have lost therapeutic response; OR 
3. A subject completes the RW Phase with one or more missing adequate mUFC 
determinations, with at least one post-randomization adequate mUFC 
determination available.  In this case, if the latest available adequate mUFC 
determination is the one for RW4 or RW5, all available mUFC determination(s) 
will be used to determine if loss of therapeutic response occurred for that 
subject, but if the latest available mUFC determination is for a visit before RW4, 
the subject will be assumed to have lost therapeutic response.  


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Sensitivity analysis of the primary endpoint that requires at least two RW visits, rather 
than one, with adequate mUFC determination during the RW Phase to be available in 
#2 and #3 above will be performed (see Section 6.6.3).    
Handling of Missing Data for the Analysis of Secondary Efficacy Endpoints by 
Visit in the RW Phase and RES Phase 
For the secondary and exploratory efficacy endpoints assessed at multiple visits, at-
visit analyses will be performed using by-visit univariate methods (for the RW and 
RES Phases) and longitudinal models (for the RW Phase) without imputation.  For the 
RW Phase, in addition to the by-visit analysis, analysis of the secondary endpoints will 
be performed at the End of RW Phase time point (see Table 3), where the last non-
missing value during the RW Phase will be used as the End of RW Phase value, if there 
is no non-missing value at RW5. 
Partially Missing Data for Triplicate Measurements of Blood Pressure and 
Abdominal Girth 
Refer to Section 5.7 for the handling of partially missing data for triplicate 
measurements of blood pressure and abdominal girth. 
Partial and Missing Dates 
Imputations of missing and partial dates are given below and to be used only for the 
following: assessment of treatment emergence status of an AE and determination of 
the study phase or study day of onset and duration of the AE (if applicable); for 
definitions of prior and concomitant medications by study phase and for the study 
overall; and for calculation of time since diagnosis of historical conditions of interest 
(e.g. CS).  
Missing or Partial Adverse Event and Prior/Concomitant Medication Start Dates 
• 
If the day is missing but both the month and year are non-missing, then the 
missing day will be imputed as 01.  For an AE, however, if the month and year 
are the same as the month and year of the date of the first dose of study drug, 
then the missing day will be imputed to be the day part of the first dose date. 
• 
If both the day and month are missing but the year is non-missing, then the 
missing day and month will be imputed as 01JAN.  For an AE, however, if the 
year is the same as the year of the date of the first dose of study drug, then 
the missing day and month will be imputed to be the day and month parts of 
the first dose date. 
• 
If the date is completely missing, then the start date will be imputed to be the 
earlier of the date of the first dose of study drug and the AE or medication end 
date.  If the end date is partial, then impute the end date first before imputing 
the start date. 


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Missing or Partial Adverse Event and Prior/Concomitant Medication End Dates 
If the AE or medication is reported as ongoing (or for an AE, not resolved/not 
recovered or recovering/resolving), then the end dates should be blank; otherwise, 
the following rules for imputation should be followed: 
• 
If the day is missing but both the month and year are non-missing, then the 
missing day will be imputed as the last day of the month. 
• 
If both the day and month are missing but the year is non-missing, then the 
missing day and month will be imputed as 31DEC.  For an AE, however, if the 
year is the same as the year of the date of the last dose of study drug, then 
the missing day and month will be imputed to be the day and month parts of 
the last dose date  
• 
If the date is completely missing, then the end date will be imputed to be the 
date of the first scheduled visit that is after the AE or medication start date or 
the subject’s last dose date, if there is no scheduled visit that is after the AE or 
medication start date.  If the start date is partial, then impute the start date 
first before imputing the end date.  
If the imputation rules above result in an end date being earlier than the start date, 
where one or both dates are imputed, the original dates and the imputed dates will 
be reviewed by the CRO statistician on a blinded basis to adjust the imputed dates 
just enough to make the end date no earlier than the start date without changing the 
non-missing parts of a partial date. 
Missing or Partial Diagnosis Dates of Historical Conditions of Interest 
• 
If the day is missing but both the month and year are non-missing, then the 
missing day will be imputed as 01. 
• 
If both the day and month are missing but the year is non-missing, then the 
missing day and month will be imputed as 01JAN. 
• 
If the date is completely missing, then it will not be imputed. 
Outliers 
No rules for outlier detection are planned. 
 
 


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6. Statistical Methods 
6.1 General Principles 
All data processing, summarization and analyses will be performed using SAS Version 
9.4 or later of the SAS statistical software package. 
The following principles will be applied to all TFLs unless otherwise stated. 
Table 4 General Principles for the Presentation of Results in Tables, 
Figures, and Listings 
 
Principles or Values 
Study phase labels and 
order presented 
Dose Titration and Maintenance Phase 
Randomized Withdrawal Phase 
Restoration Phase 
Randomized Withdrawal Phase and Restoration Phase 
Combined (for study drug exposure and shifts from 
Baseline in safety endpoints, where specified, and while on 
levoketoconazole only) 
All Phases Combined (for study drug exposure and AEs 
only and while on levoketoconazole only) 
 
For the Restoration Phase, in addition to the summaries by 
treatment group (see below), separate summaries will be 
presented for subjects who required early rescue during 
the Randomized Withdrawal Phase and continued with 
open-label levoketoconazole during the Restoration Phase 
versus those who did not require early rescue. 
For the Randomized Withdrawal Phase and Restoration 
Phase Combined, data from subjects who required early 
rescue will not be included following the date of the early 
rescue determination in the summaries, because subjects 
requiring early rescue are expected to experience adverse 
events resulting from recurrence of Cushing’s syndrome.  
Excluding data from these subjects in RW will allow for 
comparisons of subject AE incidence between those 
subjects with AEs that are more likely related to disease 
recurrence (i.e. early-rescue subjects in RES Phase) versus 
those with AEs that are less likely related to disease 
recurrence (i.e. those taking study drug during RW and 
RES who did not require early rescue). 
 
Visit labels and order 
presented 
Screening (in listings only) 
 
For the Dose Titration and Maintenance Phase: 
In tables and figures - TM Baseline, Worst Result (for shift 
or threshold analyses of safety endpoints only), Last Non-


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Principles or Values 
missing Result, and Non-missing Result at the Highest 
Dose 
In listings – TM0, TM1, TM2, TM3, TM4, TM5, TM6, TM7 
 
For the Randomized Withdrawal Phase: 
RW Baseline (in tables and figures), RW0 (in listings) 
RW1, RW2, RW3, RW4, RW5 
 
For the Restoration Phase: 
RES Baseline (in tables and figures), RW5 (in listings) 
RES1, RES2 
 
Subject cohort labels (in 
order of presentation) 
For study and study phase disposition, demographics and 
other background characteristics, and prior medications: 
Levoketoconazole-naïve 
SONICS-completer 
All Subjects 
 
For the Dose Titration and Maintenance Phase and for All 
Phases Combined (where specified): 
Levoketoconazole-naïve 
All Subjects  
 
Wherever the SONICS-completer cohort is presented in a 
TFL, there will be an asterisk (*) next to the term and the 
following footnote will be included: 
* Subjects who completed SONICS and directly 
randomized without titration in LOGICS.  
 
Treatment group labels (in 
order of presentation) 
For the Randomized Withdrawal Phase and Restoration 
Phase: 
Levoketoconazole  
Placebo 
All Subjects (where applicable) 
 
For all other study phases: 
All Subjects 
 
Tables 
For the Randomized Withdrawal Phase, Restoration Phase, 
and Randomized Withdrawal Phase and Restoration Phase 
Combined: 
Data in summary tables will be presented by treatment 
group and visit (wherever applicable).  For subjects in the 
Randomized Withdrawal Phase only, summaries will be 
presented by Therapeutic Dose (i.e. the dose at RW0) and 
for all dose groups combined where applicable. 
 
For the Dose Titration and Maintenance Phase, except for 
AEs: 
 


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Principles or Values 
Data in summary tables will be presented by the 
levoketoconazole dose received corresponding to the last 
non-missing results or corresponding to the worst results 
(where specified).  
 
For the Dose Titration and Maintenance Phase for AEs only: 
Data in summary tables will be presented by the  
 levoketoconazole dose received at the day of onset of the 
AE.  
 
For All Phases Combined (where specified): 
Data in summary tables will be presented for All Subjects 
on levoketoconazole only.  
 
Figures 
In general, data will be presented as described above for 
tables, unless otherwise specified 
 
Listings 
All data collected, as well as derived data used in the 
analyses, will be presented in listings by population, 
subject cohort, treatment group (where applicable), Site, 
subject, study phase, and visit (where applicable), unless 
otherwise specified.  
 
Units for quantitative 
measures  
All laboratory test results will be received from the central 
laboratories, and the results will be provided in both 
International System of Units (SI) and conventional units.  
For the TFLs, the results will be summarized or presented in 
SI units, with one exception.  For HbA1c, the results will be 
summarized in the tables and figures in the conventional 
unit (i.e. in %) but will be presented in the listings in both 
SI and conventional units.  Refer to Appendix 1 for the SI 
unit corresponding to each laboratory test. 
Precision levels for 
laboratory values 
Refer to Appendix 2 for the precision level in which each 
laboratory test is reported by the central laboratories. 
Descriptive summary 
statistics for continuous 
variables 
Number of subjects/observations (n), mean, standard 
deviation (SD), standard error (SE; where applicable), 
median, minimum and maximum 
 
For a numeric result presented in the database with a “<”, 
“≤”, “>”, or “≥” preceding the number, the value at (if “≤” 
or “≥”) or just below (if “<’) or just above the numeric part 
will be used in the summary.  For example, if the result is 
“<5”, and the data for the variable are measured to one 
decimal place, then the result will be summarized as 4.9. 
 
Descriptive summary 
statistics for categorical 
variables 
Frequency counts and percentages [n (%)], where 
percentages will be presented to one decimal place 
 


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Principles or Values 
Percentages greater than 0 and less than 0.1 will be 
presented as “<0.1”. 
 
All categories specified in the table and figure shells will be 
presented in the actual tables and figures, even if frequency 
is zero; in this case, no percentage will be presented.  
 
Note that the terms “proportion” and “percentage” of 
subjects are used interchangeably in this SAP.  In the 
descriptive summaries, percentages (e.g. 85.1%) will be 
presented rather than proportions (e.g. 0.851). 
 
Denominator for 
percentages 
Number of subjects in the analysis population, unless 
stated otherwise in table shell(s)  
 
Include “Missing” as 
category 
Yes, when the number missing is greater than zero for at 
least one treatment group, unless otherwise specified. 
 
Display for 0 percentages 
Blank 
Display to the same 
number of decimal place 
as the collected value 
Minimum 
Maximum 
Display to one more 
decimal place than 
collected value 
Mean 
Median 
Confidence Interval (CI) 
Display to two more 
decimal places than 
collected value 
SD 
Limit of precision for 
displays 
3 decimal places, unless otherwise specified 
 
Date Format 
DDMMMYYYY 
Significance tests and CIs 
Two-sided and use a 5% significance level  
 
P-values will be presented to four decimal places, except 
values that are less than 0.0001 will be presented as 
“<0.0001” and values that are greater than 0.9999 will be 
presented as “>0.9999”. 
 
In the two-sample t-test, p-value and 95% CI from the 
Satterthwaite method (instead of pooled method) will be 
used, since the Satterthwaite method doesn’t require 
assumption of equal variance.  
Source footnotes 
Each table will have a footnote that lists the source data 
listing(s).  Each figure will have a footnote that list the 
source table(s), if available, or the source data listing(s), 
otherwise. 
 
Dictionary names and 
versions 
The dictionary names and versions will be included in a 
footnote in all AE and prior or concomitant medication TFLs 
that present coded terms from the dictionaries. 


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6.2 Subject Disposition  
The disposition summary for all subjects will include: 
• 
number of subjects in each analysis population 
• 
number of subjects randomized 
• 
number and percentage of subjects who entered, completed, and discontinued 
the study and their discontinuation reason; overall and by study phase (TM 
Phase, RW Phase, and RES Phase) will also be displayed. 
The subject disposition summary will be presented for the Safety population by subject 
cohort and ITT population by treatment group. 
A subject is considered to have been treated during the study when the subject has 
received at least one dose of study medication (Levoketoconazole or Placebo) during 
any phases.  A subject is considered to have been treated during a study phase when 
the subject has received at least one dose of study medication during the 
corresponding phase. 
Overall study completion is recorded in the clinical database.  Overall study completion 
is defined as follows: 
• 
Subjects who complete the end of the RES Phase (Visit RES2) of the study, 
regardless of their response status, will be considered to have completed the 
study. 
• 
Subjects who receive early rescue medication during the RW Phase will also be 
considered to have completed the study. 
Subjects who entered the study but did not complete the study as defined above are 
considered as discontinuing from the study. 
Study completion by phase is defined as follows: 
• 
TM Phase: Subjects who complete the TM7 visit and do not discontinue in the 
TM Phase. 
• 
RW Phase: Subjects who complete the RW5 visit and do not discontinue in the 
RW Phase.  These include subjects who receive early rescue medication during 
the RW Phase. 
• 
RES Phase: Subjects who complete the RES2 visit and do not discontinue in the 
RES Phase. 
For the RW Phase and the RES Phase, and the study overall, study completion status 
will be presented separately for both Early Rescue used, and Early Rescue not used.  
For the RW Phase and the study overall, early rescue subjects are considered as 


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completers.  For the RES Phase, the reason for discontinuation will also be presented 
separately for Early Rescue used versus Early Rescue not used. 
Subjects who entered a study phase but did not complete the phase as defined above 
are considered as discontinuing from that phase.  The reasons for discontinuation will 
be summarized for each phase. 
Subject disposition with respect to the presence of non-missing and adequate 24-hour 
urine samples for UFC determination will be summarized by visit.  For each visit, the 
number of subjects still in the study as of that visit will be presented.  The number 
and percentage of subjects for each sample corresponding to the visit will determined 
as follows: 
• 
Sample 1 – adequate, not adequate, or no sample taken 
• 
Sample 2 – adequate, not adequate, or no sample taken 
• 
Sample 3 – not required, required and adequate, required but not adequate, or 
required but no sample taken 
In addition, a separate summary will also be provided for each of the following 
categories for all screened subjects: 
• 
Subject disposition for the screening period by subject cohort and overall  
• 
Subject counts by study phase and by site, country, and region (United States 
[US], non-US) 
6.3 Protocol Deviations 
A summary of major protocol deviations will be presented for the Safety population 
by subject cohort (by study phase and overall) and ITT population by treatment group 
(by RW Phase, RES Phase, and combined).  Both major and minor deviations will be 
provided in a listing. 
Subjects affected by COVID-19 related study disruption will be listed by investigational 
site, including descriptions of how the individual’s participation was altered. Protocol 
deviations due to COVID-19 illness and/or COVID-19 public health control measures 
will be clearly identified in the protocol deviation listing and the summary of major 
protocol deviations (if any).  Any major protocol deviations related to COVID-19 will 
be included in the review of major protocol deviations for the purpose of identifying 
subjects to be excluded from the PP population (see Section 4.2.1). 


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6.4 Demographics and Other Background Characteristics 
6.4.1 
Demographics and Baseline Characteristics 
Demographics, baseline, and disease characteristics will be summarized for the Safety 
population by subject cohort, ITT population by treatment group, and PP population 
by treatment group. 
Standard descriptive statistics will be presented for the continuous variables of: 
• 
age (years) 
• 
baseline weight (kg) 
• 
baseline height (cm) 
• 
baseline body mass index (BMI) (kg/m2) 
• 
baseline mUFC 
• 
baseline LNSC 
• 
baseline HbA1C 
• 
time since diagnosis of CS (mos) 
• 
time since last surgery for the management of CS 
• 
baseline systolic and diastolic blood pressure 
• 
baseline QTcF. 
The total counts and percentages will be presented for the categorical variables of: 
• 
sex 
• 
childbearing potential (females only) 
• 
ethnicity 
• 
race 
• 
classification of CS 
• 
prior treatment for CS 
• 
receiving anti-diabetic medication at baseline (determined from concomitant 
medications)  
• 
receiving 
anti-hypertension 
medication 
at 
baseline 
(determined 
from 
concomitant medications) 
No formal tests of statistical significance will be performed on the demographics, 
baseline, and disease characteristics. 


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Baseline value for the L-N cohort is the TM Baseline.  Baseline for the other summaries 
is the RW Baseline. 
6.4.2 
Medical History, Surgical History, and Prior Radiotherapy 
Medical history and surgical history (including both CS related surgeries and not CS 
related ones) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.1.  Medical history and surgical history will be summarized by 
system organ class (SOC) and preferred term (PT) for the Safety population by subject 
cohort and ITT population by treatment group. 
Prior radiotherapy for management of CS will be summarized by the number of prior 
radiotherapies, location (pituitary, adrenal gland, and other), time since the end of 
the last radiotherapy (months), and outcome of the last radiotherapy (complete 
response, partial response, no response, and unknown) for the Safety population by 
subject cohort and ITT population by treatment group.  For location and radiotherapy 
type, a subject who had more than one radiotherapy will be counted once under each 
different location and different radiotherapy type. 
Medical history, surgical history and prior radiotherapy for management of CS will be 
presented in listings. 
6.4.3 
Prior and Concomitant Medications 
Incidence of prior and/or concomitant medications will be presented by drug class (i.e. 
Anatomical Therapeutic Chemical (ATC) Level 3 classification).  Coding will be done 
using the World Health Organization (WHO) Drug September 2018 dictionary.  Prior 
medications will be summarized by subject cohort.  Concomitant medications will be 
presented for TM Phase by subject cohort, and for RW and RES Phase (and RW/RES 
Phases combined) by treatment group.  For the RES Phase, summaries will also be 
presented for Early Rescue used versus Early Rescue not used. 
In addition, separate summaries for prior and concomitant medications will be 
presented by the five medication categories prespecified in the CRF, namely, anti-
diabetic, anti-hypertensive, cholesterol medication, anti-inflammatory, and Cushing’s 
medication. 
If the medication record satisfies the concomitant criteria, then the record will be 
summarized as concomitant.  A medication record will not be classified as both prior 
and concomitant within the same study phase. 
TM Phase: 
• 
Prior medications are medications taken (either started or ongoing) within 3 
months (i.e. 91 days) of the date of informed consent and ended prior to the 
TM0 visit date. 


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• 
Concomitant medications are medications taken during the study phase, 
including those started before but ongoing at first dose (TM0 visit), up through 
end of phase (as defined in Section 5.1).   
• 
To be summarized for the L-N population. 
RW Phase: 
• 
For the S-C population only, prior medications are medications taken (either 
started or ongoing) within 3 months (i.e. 91 days) of the date of informed 
consent and ended prior to the RW0 visit date. 
• 
For all subjects in the RW Phase, concomitant medications are medications 
taken during the study phase, including those started before but ongoing at 
first dose (RW0 visit), up through end of phase (as defined in Section 5.1). 
RES Phase: 
• 
Concomitant medications are medications taken during the study phase, 
including those started before but ongoing at first dose (RW5 visit), up through 
end of phase (as defined in Section 5.1). 
RW Phase and RES Phase Combined: 
• 
Concomitant medications of interest for the two phases combined are those 
taken during levoketoconazole dosing.  As such, for subjects on placebo during 
the RW Phase, only their concomitant medications during the RES Phase, when 
they are on levoketoconazole, will be included. 
• 
Concomitant medications are medications taken during the two study phases 
combined, including those started before but ongoing at first dose (RW0 visit), 
up through end of the subject’s last phase. 
6.5 Study Drug Exposure and Compliance 
Dose Levels and Titration Status during the TM Phase 
Summary of levoketoconazole titration status will be presented by visit and dose level 
established at each visit during and at the end of the TM Phase for the L-N population.  
Titration status at the current visit will be the change in dose level since the last visit 
(up-titration, no change, or down-titration).  Percentages are calculated based on the 
number of total subjects still in the study as of the current visit. 
Therapeutic Dose Levels at Start of RW Phase 
Summary of Therapeutic Dose Level (mg/day) at the end of the TM Phase and at start 
of the RW Phase will be presented.  Percentages are calculated based on the number 


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of total subjects still in study at the start of each phase or combined phases, 
respectively.  
Exposure to Study Drug  
Study drug exposure will be summarized for Safety population and L-N population by 
each of the three phases, the RW Phase and RES Phase combined, and overall (all 
three phases combined); and for ITT population by randomized treatment.  The total 
study drug duration (days), total days on study drug, the cumulative dose of study 
drug (mg), and the average daily dose of study drug (mg/day) will be presented.  For 
the RW Phase and RES Phase Combined and the All Phases Combined, only the 
exposure while on levoketoconazole will be summarized.  
Total study drug duration (days) will be calculated for each subject as the last study 
drug stop date minus first study drug start date plus one day. 
Total days on study drug will be calculated for each subject as the actual total number 
of days the subject received study drug (i.e. gaps in study drug intake are not included 
in the calculation).  If only one out of two daily dosing (i.e. A.M. or P.M. but not both) 
of the study drug is taken, it counts as 0.5 day. 
Actual cumulative dose (mg) of study drug will be calculated as the total number of 
tablets dispensed minus the total number of tablets returned, then multiplying the 
result by 150 mg. 
Average daily dose of study drug (mg/day) will be calculated as the actual cumulative 
dose of study drug divided by total study drug duration. 
Compliance to Study Drug 
Study drug compliance will be summarized separately for Safety population and L-N 
population by each of the three phases, the RW Phase and RES Phase combined, and 
overall (all three phases combined); and for ITT population by randomized treatment.  
Study drug compliance will be calculated by dividing the actual cumulative dose of 
study drug (as described above) by the expected cumulative dose of study drug  and 
multiplying the result by 100.  For the RW Phase, the expected cumulative dose of 
study drug is the total study drug duration for the RW Phase x 150 mg x the expected 
number of tablets for the subject’s dose level in the RW Phase.  For all other phases, 
including combined phases, the expected cumulative dose is first calculated at each 
dose level received and then summed up across all dose levels received. 
For summaries of the RW Phase and RES Phase combined and for the study overall, 
placebo exposure for the subjects who receive placebo during the RW Phase will be 
excluded. 


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6.6 Efficacy 
Descriptive summaries of all efficacy endpoints will be presented for the L-N 
population (for the TM Phase), and by treatment group (for the RW Phase and RES 
Phase), and visit (where applicable for RW Phase and RES Phase).  The by-visit 
summaries in the RW Phase will include summaries at the individual visits and 
summaries at the End of RW Phase time point. In addition, separate summaries will 
be presented for RES Phase for Early Rescue used versus Early Rescue not used.  For 
continuous variables, summaries will be presented for the observed values and for the 
absolute and percent changes from the relevant Baseline.  Statistical testing, whether 
within-treatment or between-treatment, will only be for the all levoketoconazole dose 
groups combined. 
For the TM Phase, efficacy endpoints measured at multiple visits will be summarized 
by the levoketoconazole dose received corresponding to the last non-missing results 
and by the highest levoketoconazole dose received with non-missing results. 
The primary, secondary, and many of the exploratory efficacy analyses will be based 
on the RW Phase and RES Phase.  These efficacy analyses will be based on the ITT 
population and for the primary and secondary efficacy endpoints only, supportive 
analyses will use the PP population. 
There are also exploratory analyses of efficacy during the TM Phase, and these will be 
based on the L-N population. 
For secondary efficacy endpoints that are continuous variables, the within-treatment 
mean changes from the relevant Baseline (see Section 5.1) to each visit in the RW 
Phase and RES Phase and at the End of RW Phase time point will be assessed for 
nominal significance using paired t-test. 
For all efficacy analyses that involve the RES Phase only, the analysis population is 
the subset of ITT that receive at least one dose of study drug in the RES Phase.  
6.6.1 
Primary Efficacy Analysis 
Loss of Therapeutic Response 
The primary efficacy analysis will determine the significance of the difference in 
proportions of subjects losing therapeutic response between the two treatment 
groups.  In addition to the primary analysis based on the ITT population, a supportive 
analysis will be conducted on the PP population. 
Statistical significance testing will be 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 
(SE) for each treatment group, the estimated difference and SE between the two 


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treatment groups, and associated 95% CI and p-value will be derived from the model 
(see SAS STAT Procedure details in Appendix 3). 
A supportive analysis that does not require statistical modeling will be conducted to 
confirm the results of the primary analysis.  The proportions between the treatment 
groups will be compared using a two-sided Fisher’s Exact test and an exact 
unconditional two-sided 95% CI of the difference will be calculated (see SAS STAT 
Procedure details in Appendix 3).  
The primary efficacy analysis will be repeated for the following subgroups: 
1. S-C cohort versus L-N cohort 
2. Subjects who completed SONICS (regardless of their need to titrate in 
LOGICS) versus those who did not participate in SONICS 
The same Fisher’s Exact test as mentioned above will be conducted for subgroups with 
a minimum size of at least 30% of the ITT population only.   
In addition, the number and percentage of subjects who met each of the criteria for 
loss of therapeutic response will be summarized by treatment group and by 
therapeutic dose level, respectively.  No statistical testing will be performed. 
Sensitivity analysis of the primary endpoint that allows subjects who came from the 
SONICS study but are in the L-N cohort, to be included in S-C cohort in the logistic 
regression model described above will be performed (see Section 6.6.3). 
6.6.2 
Secondary Efficacy Analyses 
Inferences derived from secondary efficacy analyses will be gated on results from the 
primary efficacy analysis.  Secondary efficacy analyses will be hierarchically structured 
to ensure control of the family-wise type I error rate at the 0.05 level.  Hypothesis 
tests for secondary efficacy endpoints will be based on null hypotheses that assume 
no a priori differences between placebo and levoketoconazole treatments. 
A closed or sequential testing procedure will be used for testing the key secondary 
efficacy variables.  With this hierarchical procedure, the key secondary efficacy 
variables will only be tested if the primary efficacy analysis is statistically significant. 
Analyses will be carried out for the key secondary variables, ‘Endpoint set 1’, ’Endpoint 
set 2’, ’Endpoint set 3’, ’Endpoint set 4’, ’Endpoint set 5’, and ’Endpoint set 6’.  
The analyses will be carried out on the change from RW Baseline to the End of RW 
Phase time point for the following efficacy parameters in hierarchical order: 
Set 1 - Normalization of mUFC at the end of RW Phase 
Set 2 – mUFC (change from RW Baseline) 


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Set 3 – biomarkers of CS comorbidities (fasting glucose, fasting insulin, HOMA-IR, 
HbA1c, total cholesterol, LDL-C, and hsCRP) 
Set 4 – CS QoL total score and BDI-II total score 
Set 5 – Acne Global Score, Hirsutism Total Score (for females only), and Peripheral 
Edema Total Score 
Set 6 - LNSC 
The secondary efficacy endpoint of proportion of subjects with normalization of mUFC 
at RES is not part of the hierarchical testing since it cannot be analyzed until the end 
of the study, while the endpoints above are at RW5. 
Within each set with multiple endpoints (i.e. Sets 3, 4, and 5), the statistical 
significance level will be adjusted using the Hochberg method, controlling the 
familywise error rate at 5%.  All endpoints within a set with multiple endpoints have 
to be statistically significant in favor of levoketoconazole compared to placebo, after 
the Hochberg adjustment, in order for the next set in the hierarchy to be tested.  The 
testing is only stopped when all of the alpha is ‘exhausted’.  The sequential testing 
will stop at the first endpoint set where levoketoconazole does not demonstrate 
statistical superiority over placebo.   
In addition to the comparisons on the changes from RW Baseline to the End of RW 
Phase time point, comparisons between the two treatments will also be performed on 
the changes from RW Baseline to each of RW1 to RW5.  The p-values from these 
comparisons will be used for descriptive purposes only, i.e. no statistical inferences 
will be made and as such, no multiplicity adjustments. 
For the above efficacy parameters, the absolute and percent changes from RW 
Baseline and from RES Baseline to each of the 2 visits in RES will be summarized (no 
imputation).  Although summaries will be presented separately by the randomized 
treatment group (in addition to all subjects together), there will be no treatment 
comparisons. 
Line plots of the mean +/- SE of actual and change from RW Baseline values by 
treatment group and visit during the RW Phase will be produced for efficacy endpoints 
that are assessed by visit.  Line plots of least squares mean changes from RW Baseline 
(where applicable) during the RW Phase will also be presented. 
6.6.2.1 UFC and LNSC Analyses 
Normalization of mUFC at the end of RW Phase 
The number and proportion of subjects in the RW Phase with mUFC normalization at 
the end of RW Phase will be compared between treatment groups using Fisher’s Exact 
test (with corresponding 95% CIs).  mUFC normalization at the end of RW Phase will 
be based on the subject’s mUFC corresponding to the End of RW Phase time point 


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defined in Section 5.3.  In addition, a subject must not have been early rescued during 
the RW Phase in order to be considered as achieving mUFC normalization at the end 
of RW Phase.  
In addition, this analysis will be repeated for the following subgroups: 
1. S-C cohort versus L-N cohort 
2. Subjects who completed SONICS (regardless of their need to titrate in 
LOGICS) versus those who did not participate in SONICS 
Fisher’s Exact test results will only be provided for subgroups with a minimum size of 
at least 30% of the ITT population.  
Side-by-side needle plots for the two treatment groups of the individual subject mUFC 
from RW Baseline to the end of the RW Phase will be produced, with the ULN as a 
horizontal reference line. 
Changes in mUFC and LNSC from RW Baseline 
Changes from RW Baseline to the End of RW Phase time point in mUFC and LNSC will 
be compared between treatment groups using two-sample t-test (with corresponding 
95% CIs). To allow for possible departures from the assumption of normal distribution 
of the data, the treatment groups will also be compared using Wilcoxon rank sum test 
as a supportive analysis. 
Supportive analyses using a repeated measures mixed effects model with fixed effect 
terms for treatment group, subject cohort, time (i.e. visit), and treatment-by-time 
interaction and with Baseline value as a covariate, with subject as random effect 
(depending on covariance matrix structure) will also be performed on the changes 
from RW Baseline to RW1 to RW5. 
The following covariance matrix structures will be considered for the model: spatial 
power, toeplitz with heterogeneity, and toeplitz.  The final covariance matrix structure 
will be selected as the one resulting in a statistical model that converges and has the 
minimum Corrected Akaike information criterion (AICC)  (i.e., minimum loss of 
information).  The treatment groups will be compared using least squares mean 
differences between treatment groups and associated 95% CIs for each visit will be 
derived from the model.  These CIs will be regarded as descriptive statistics (see SAS 
STAT Procedure details in Appendix 3). 
Two-sample t-tests (with corresponding 95% CIs) will also be performed, as 
supportive analyses, to compare the two treatment groups for the mean change from 
RW Baseline to each nominal visit during the RW Phase.  
In addition to the line plots by visit (in Section 6.6.2), spaghetti plots of the individual 
subjects’ mUFC by visit in the RW Phase will be produced with a horizontal line at ULN. 


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Normalization of mUFC during RES Phase 
The number and proportion of subjects with normalization of mUFC at RES2 is defined 
as the proportion of subjects with abnormal mUFC at RW5 whose mUFC is at or below 
the ULN of the reference range at RES2.  Normalization of mUFC at RES2 will be 
calculated for each treatment group and presented as shift tables from RW5 to RES2 
using three strata of mUFC status: at or below ULN, more than ULN and no more 
than 1.5X ULN, above 1.5X ULN. 
6.6.2.2 CS Comorbidity Biomarkers 
The mean changes from RW Baseline in individual biochemical markers of CS 
comorbidities (fasting glucose, fasting insulin, HOMA-IR, HbA1c, total cholesterol, 
LDL-C, and hsCRP) during the RW Phase will be assessed for treatment group 
differences using two-sample t-test at the End of RW Phase time point and at each 
visit. HOMA-IR is calculated as multiplying fasting plasma insulin (FPI) by fasting 
plasma glucose (FPG), then dividing by the constant 22.5, i.e. HOMA-IR = 
(FPI×FPG)/22.5. Subjects who are using insulin as a concomitant medication during 
the RW phase will be excluded from HOMA-IR summaries.  
In addition, shifts from the relevant Baseline (with regards to laboratory normal 
range) in individual biochemical markers of CS comorbidities will be summarized at 
each visit during the RW Phase and RES Phase and at the End of RW Phase time point. 
In addition for biomarkers fasting glucose, fasting insulin, and HOMA-IR, shifts from 
the relevant Baseline will be presented by diabetes status at Baseline (diabetic, non-
diabetic) by treatment group, where the biomarker values are categorized by tertiles, 
defined within each diabetes status based on the Baseline values (also stated in 
Section 6.6.4.4). 
For CS comorbidities measured at more than one visit after RW0 during the RW Phase, 
changes from RW Baseline during the RW Phase will also be analyzed using a repeated 
measures mixed effects model with fixed effect terms for treatment group, time (i.e. 
visit), and treatment-by-time interaction, the Baseline value and concurrent CS 
medical condition (where applicable) as baseline covariates and with subject as a 
random effect (depending on Covariance structure).  The concurrent CS medical 
condition is the  the presence of diabetes at screening for the biomarkers fasting 
glucose, fasting insulin, HOMA-IR, and HbA1c.  The choice of covariance structure for 
the model and the use of least squares means to compare treatment groups are as 
described above for mUFC and LNSC (see SAS STAT Procedure details in Appendix 3).  
For CS comorbidities measured at more than one visit after RW0 during the RW Phase, 
the analysis at the End of the RW Phase time point is the main analysis, and the 
analyses by visit and using the statistical model above are supportive. 


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6.6.2.3 Cushing’s Syndrome Quality of Life Questionnaire  
The mean changes from RW Baseline in the Cushing QoL total score during the RW 
Phase will be assessed for treatment group differences using two-sample t-test at the 
End of RW Phase time point and at RW5. 
A summary table for Cushing QoL total score will be presented to display the change 
(in categories: <10.1, ≥10.1) from the relevant Baseline at each visit during the RW 
Phase and RES Phase. 
6.6.2.4 BDI-II 
The mean changes from RW Baseline during the RW Phase will be assessed for 
treatment group differences using two-sample t-test at the End of the RW Phase time 
point and at RW5. 
A shift table for BDI-II total score will be presented to display the shift in the range 
categories (minimal, mild, moderate and severe depression) from the relevant 
Baseline at each visit during the RW Phase and RES Phase. 
6.6.2.5 Acne, Hirsutism and Peripheral Edema 
The mean changes from RW Baseline in acne, hirsutism (for females only) and 
peripheral edema total scores during the RW will be assessed for treatment groups 
differences using two-sample t-test at the End of RW Phase time point and at each 
visit. 
Shifts from the relevant Baseline for acne, hirsutism and edema total scores will also 
be summarized in the RW Phase and RES Phase, using the following categories: 
• 
Acne global score: 0, 1-18, >18 (GAGS, Doshi 1997) = none, mild, moderate 
to severe 
• 
Hirsutism total score: 0-7, 8-15, >15 (Ferriman-Gallwey scale) = none to mild, 
mild to moderate, moderate to severe 
• 
Peripheral edema total score: 0-3, 4-6, >6 = none to mild, mild to moderate, 
moderate to severe 
6.6.3 
Sensitivity Analyses 
The following sensitivity analyses of the primary efficacy endpoint (loss of therapeutic 
response in the RW Phase) and the secondary efficacy endpoints of normalization of 
mUFC at the end of RW Phase and change from RW Baseline in mUFC at RW5 (where 
specified) will be conducted on the ITT population (only if the original analysis of the 
efficacy endpoint is statistically significant): 
1) Sensitivity analyses of the primary endpoint and the secondary mUFC 
(normalization at the end of RW Phase and change from RW Baseline) endpoints 


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that allow for the use of a single adequate urine sample that is within the 
analysis visit window (RW1-RW5) to calculate mUFC for that visit or the 
imputation of a missing mUFC due to all missing or inadequate samples for that 
visit in the RW Phase (see Section 5.4).  In the latter case, the imputed value 
will be last non-missing mUFC for that subject prior to that visit. 
2) Sensitivity analyses of the primary endpoint and the secondary mUFC 
(normalization at the end of RW Phase and change from RW Baseline) endpoints 
where UFC values from all samples, regardless of adequacy, will be used to 
calculate mUFC (see Section 5.4). 
3) Sensitivity analysis of the primary endpoint that excludes early rescue subjects 
identified through programmed verification as not having met the quantitative 
element(s) of the early rescue criteria marked as met in the Early Rescue Study 
Completion eCRF (see Section 5.5).  
4) Sensitivity analysis of the primary endpoint that requires more than one RW 
visit with adequate mUFC determination during the RW Phase (RW1-RW5) to 
be available (see Section 5.10). 
5) Sensitivity analysis of the primary endpoint allowing subjects who came from 
the SONICS study but are in the L-N cohort, to be included in the S-C cohort 
instead in the logistic regression model (see Section 6.6.1). 
6) A tipping point analysis will be applied to the primary endpoint.  This analysis 
will explore the effect of missing data on the reliability of the efficacy results by 
determining the extent the missing data have to change for the results of the 
study to tip from statistically significant to not.  The following approach for the 
tipping point analysis will be undertaken: 
The number of placebo subjects losing therapeutic response will be 
incrementally decreased by 1 until all placebo subjects originally categorized as 
losing response due to missing mUFC values during the RW Phase (see Section 
5.10) are re-categorized as not losing response, and the number of 
levoketoconazole subjects losing therapeutic response will be incrementally 
increased by 1 until all levoketoconazole subjects originally categorized as not 
losing response based on an incomplete set of mUFC values during the RW 
Phase (see Section 5.10) are re-categorized as losing response, or until the p-
value for the logistic regression model (see Section 6.6.1) exceeds 0.05. 
7) For the secondary efficacy endpoint of change from RW Baseline to the RW5 
visit in mUFC, if the value at RW5 is missing and the subject had loss of 
therapeutic response, the value from the visit where the subject first exhibits 
the loss of therapeutic response will be imputed for the RW5 value.  This will 
be analyzed for the RW5 data using an analysis of covariance (ANCOVA) with 


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treatment group and subject cohort as fixed effects and Baseline mUFC as a 
covariate.  Subjects who are missing data at RW5 for reasons other than loss 
of therapeutic response or early rescue will not be included in this analysis. 
8) In order to assess the impact of COVID-19, a sensitivity analysis of the primary 
efficacy endpoint at the End of RW Phase will be performed where subjects who 
dropped out before RW4 specifically due to COVID-19 are excluded from the 
analysis (rather than being considered as loss of response in the main analysis). 
If there are subjects rescued early due to, in part, clinically significant 
worsening of signs and symptoms of CS, as described in Section 3.1, and source 
data validation by clinical monitors to confirm the worsening cannot be 
performed due to COVID-19 public health control measures, a sensitivity 
analysis of the primary efficacy endpoint with these subjects excluded will be 
performed.   
6.6.4 
Additional Subgroup Analyses 
In addition to the subgroup analyses described in Section 6.6.1 and Section 6.6.2.1, 
the following subgroup analyses will be performed (unless specified otherwise) for the 
primary efficacy endpoint and the secondary endpoints of change from RW baseline 
to End of RW Phase for biomarkers of CS comorbidities, and normalization of mUFC 
at the end of RW Phase, for a minimum subgroup size of at least 30% of the ITT 
population.  Univariate statistical tests (i.e. Fisher’s Exact tests and two-sample and 
paired t-tests) will be performed for descriptive purposes only. 
6.6.4.1 
Prior Surgery for Cushing’s Syndrome 
Subgroup displays will be generated for subjects who enter the study as surgery-naïve 
versus surgery-experienced, for prior surgeries that were performed for the 
management of CS.   
6.6.4.2 
 Prior Radiotherapy 
Subset displays will be generated for subjects who have not received radiotherapy 
versus those who have previously received radiotherapy at any time prior to the study.   
6.6.4.3  Hypertensive Subjects 
Subgroup displays will be generated for subjects who enter the study while being 
prescribed anti-hypertensive medications versus not and subjects who enter the study 
with a baseline systolic blood pressure (SBP) > 130 mmHg or diastolic blood pressure 
(DBP) ≥ 90 mmHg regardless of anti-hypertensive medication status versus those 
with lower blood pressure measurements. 
6.6.4.4  Pre-diabetic/Diabetic Subjects 


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Subgroup displays will be generated for subjects who enter the study as pre-diabetic 
(Baseline fasting glucose greater or equal to 100 mg/dL (5.6 mmol/L) and less 
than 126 mg/dL (7.0 mmol/L) without concomitant use of anti-diabetic medication) 
versus those with normal fasting glucose versus those who were diabetic (Baseline 
fasting glucose 126 mg/dL or above or lower fasting glucose while being prescribed 
anti-diabetic medications). 
In addition, for biomarkers fasting glucose, fasting insulin, HOMA-IR and Homeostatic 
Model Assessment-Beta Cell Function (HOMA-%B), shifts from the RW and RES 
Baselines will be presented by baseline glycemia status (diabetic, prediabetic, non-
diabetic) by treatment group, where the biomarker values are categorized by tertiles, 
defined within each diabetes status based on the Baseline values.   
If there are < 30% of the ITT population of the subjects in the pre-diabetic subgroup, 
the pre-diabetic subjects and subjects with normal fasting glucose will be combined 
into one subgroup versus those in the diabetic subgroup. 
6.6.4.5 
Region 
Subgroup displays will be generated for subjects enrolled in US sites versus those in 
non-US sites. 
6.6.4.6 
Sex 
Subgroup displays will be generated for female versus male subjects. 
6.6.4.7 
Age 
Subgroup displays will be generated for subjects with age <= the median age (of the 
Safety population for the study overall) versus those with age > the median age.  
6.6.5 
Exploratory Analyses 
Medication Changes 
Frequency of usage and changes from Baseline in frequency of usage of each of the 
concomitant medication categories (anti-diabetic, anti-cholesterol, anti-hypertensive, 
and chronic anti-inflammatory therapies) will be assessed over each study phase 
separately.  TM Phase analysis will be presented for all subjects in the L-N cohort, 
while RW and RES Phase analysis will be presented for ITT population by treatment 
group. 
The number and proportion of subjects with medication changes from the TM/RW 
Baseline will be presented. Subjects whose usage is ongoing or started at the TM/RW 
Baseline will be categorized as follows for each study phase separately: 
1) New and clinically significant medication – New medication is started during the 
study phase and its use was potentially clinically significant  


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2) Medication dose increased – Dose is increased compared to the TM/RW Baseline 
AND the increase is considered potentially clinically significant  
3) Medication dose restarted after a gap – The medication is stopped after TM/RW 
Baseline but is restarted during the study phase AND the restart is considered 
potentially clinically significant  
4) Clinically insignificant change in medication – The change represents either the 
same dose in a different formulation or a pharmaceutically equivalent dose of 
a different drug (i.e. a substitution)  
5) No medication change from the TM/RW Baseline  
6) Medication dose decreased – Dose is decreased compared to the TM/RW 
Baseline AND the decrease is considered potentially clinically significant 
New and clinically significant medication changes, medication dose increased or 
restarted after a gap, clinically insignificant change in medication, and medication 
dose decreased (Items #1,2,3,4,6 above) will be evaluated prior to the first database 
lock of all data through the end of the RW Phase by a medical monitor blinded to 
treatment assignment and again for the RES Phase prior to the final database lock 
after the end of the study. 
Subjects with no usage ongoing or started at the TM/RW Baseline will be categorized 
as follows: 
1) Medication added after TM/RW Baseline 
2) No medication used. 
If a subject has more than one medication in the same medication class that falls 
under different usage categories above, the subject will be counted under the “worst” 
of these categories, i.e. the first applicable category that is listed above.  
 
Biomarkers Change Associated with Medication Usage Changes  
Changes in the corresponding biomarkers of CS comorbidities at End of RW Phase 
relative to changes in medication usage over the entire RW Phase, as described above, 
will be explored through HIGHLOW plots (produced by SAS® software), where the x-
axis corresponds to the medication categories and the y-axis corresponds to the 
highest and lowest changes in the corresponding biomarkers joined by a line with a 
tick mark for the mean changes.  
The following associations will be represented: fasting glucose, fasting insulin, HOMA-
IR, and Hb1Ac with anti-diabetic medications; total cholesterol and LDL-C with anti-
cholesterol medications; blood pressure with anti-hypertensive medications; hsCRP 
with chronic anti-inflammatory therapies. 


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Time-to-Event Analysis 
The time will be calculated from RW0 to the first time when: 
• 
The mUFC is above 1.5X the ULN of the central laboratory’s reference range; 
OR 
• 
The mUFC is over 40% above the Baseline (RW0) value if the RW0 value is 
above the ULN (i.e. >1.0X ULN) for the S-C cohort subjects; OR 
• 
An early rescue criterion is met. 
Time from RW0 to documented loss of therapeutic response will be defined as 
event date (i.e. earliest date a subject meets one of the criteria above) minus the date 
of the first dose of blinded study drug (levoketoconazole or placebo) + 1 day. 
For each of the first two criteria, the date for meeting the criterion is considered to be 
the date of the last adequate sample included in the calculation of the mUFC.  For the 
third criterion for early rescue subjects, the date for meeting the criterion is considered 
to be the date in which the Investigator withdraws blinded study drug in favor of other 
treatments, including open-label levoketoconazole.  This date is the day after the date 
of last dose of blinded study drug recorded in the Early Rescue Study Completion 
eCRF. 
In the absence of loss of therapeutic response where subjects do not meet any of the 
criteria above, subjects will be censored at the last sample date of the last mUFC 
during the RW Phase (i.e. either from RW4 or RW5, see Section 5.10).  Subjects with 
no post-RW Baseline mUFC will be considered as losing therapeutic response.  Time 
(day) from RW0 to documented loss of therapeutic response for these subjects is set 
to 1 (day). 
Time to first normalization of mUFC beginning from RW5 (for the subset of 
subjects with mUFC above 1.5X ULN at RW5 and received at least one dose of study 
drug during the RES Phase) is defined as the time from the first dose of add-on study 
drug (levoketoconazole or placebo) at RW5 to the time when a subject has confirmed 
mUFC no more than ULN (i.e. <=ULN) for the assay reference range (inclusive of both 
dates).  In the absence of normalization of mUFC, a subject will be censored at the 
date of the last adequate sample included in the calculation of the last non-missing 
mUFC during the RES Phase. 
Time to first normalization of LNSC beginning from RW5 (for the subset of 
subjects with LNSC above ULN at RW5 and received at least one dose of study drug 
during the RES Phase) will be estimated as the time from the first dose of add-on 
study drug (levoketoconazole or placebo) at RW5 to the time when a subject has an 
LNSC result no more than the ULN for the assay reference range (inclusive of both 
dates).  In the absence of normalization of LNSC, a subject will be censored at the 


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date of last sample for the assessment of LNSC during the RES Phase.  If there are 
two such samples (in which case the mean LNSC is calculated), the subject will be 
censored at the date of the second sample. 
Time from TM0 to first normalization of mUFC (during TM Phase) is defined as 
the time from the first dose in TM Phase to the time when a subject has confirmed 
mUFC no more than ULN (i.e. <=ULN) for the assay reference.  In the absence of 
normalization of mUFC, a subject will be censored at the date of the last adequate 
sample included in the calculation of the last non-missing mUFC during the TM Phase. 
Each time-to-event endpoint will be calculated in days as end date minus start date 
+ 1 day, where the start date is the RW first dose date for the first endpoint, the RES 
first dose date for the second and third endpoints, and the TM first dose date for the 
fourth endpoint, and the end date is as defined for each endpoint above.  Each time-
to-event endpoint will be analyzed using Kaplan-Meier (KM) methods.  Median time to 
each event along with the associated two-sided 95% CI will be presented by treatment 
group.  The time-to-event distributions will be compared statistically with a two-sided 
log-rank test.  The CI will be regarded as a descriptive statistic.  Corresponding KM 
curves for each time-to-event endpoint will also be presented by treatment group (see 
SAS STAT Procedure details in Appendix 3).  
Normalization of mUFC during the TM Phase 
The number and proportion of subjects meeting the following criteria will be 
summarized by Therapeutic Dose, and for All Subjects (along with 95% CI for the 
proportion): 
• 
Achieved normalization of mUFC (<=ULN for the assay reference range) at 
the end of TM Phase  
• 
Achieved normalization of mUFC (<=ULN for the assay reference range) at 
any time during the TM Phase  
• 
Achieved either normalization of mUFC or partial response (at least 50% 
decrease in mUFC from TM Baseline) at the end of TM Phase  
• 
Achieved either normalization of mUFC or partial response (at least 50% 
decrease in mUFC from TM Baseline) at any time during the TM Phase  
Subject’s last non-missing mUFC result during the TM Phase will be used to determine 
normalization at the end of TM Phase. 
A needle plot of the individual subject mUFC from TM Baseline to the end of the TM 
Phase (i.e. non-missing mUFC at the last dose level; otherwise, non-missing mUFC at 
the penultimate dose level) will be produced, with the ULN as a horizontal reference 
line.   


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Normalization of LNSC during RES Phase 
The number and proportion of subjects in the RES Phase with normalization of LNSC 
at RES2 will be analyzed in the same way as the corresponding normalization of UFC 
at RES2 analyses described in Section 6.6.2.1. 
Serum Cortisol and ACTH 
Serum cortisol and ACTH are primarily considered to be safety endpoints and will be 
descriptively summarized.  Refer to Section 6.7.2 for details. 
Clinical Signs and Symptoms Excluding Acne, Hirsutism and Peripheral 
Edema 
Individual clinical signs and symptoms, which are assessed at each visit, will be 
summarized by number and percentage of subjects with each sign/symptom.  
Individual clinical sign and symptoms severity scores will be summarized using shift 
tables from the relevant Baseline.  Total severity score and changes from the relevant 
Baseline of this total score will be summarized. 
Exploratory Efficacy Endpoint Analysis for the TM Phase, RW Phase, and 
RES Phase 
HOMA-%B 
HOMA-%B is calculated as (20 x FPI)/(FPG - 3.5), where FPI=fasting plasma insulin 
(mU/L) and FPG=fasting plasma glucose (mmol/L).  HOMA-%B is only calculated 
whenever FPI and FPG are collected on the same day.  Collections from different days 
cannot be combined to calculate HOMA-%B. Subjects who are using insulin during the 
study phase will be excluded from all HOMA-%B summaries. 
For TM Phase, HOMA-%B will be summarized for the L-N population, by the 
levoketoconazole dose received corresponding to the last non-missing results and by 
the highest levoketoconazole dose received with non-missing results. 
For the RW Phase and RES Phase, observed values as well as absolute and percent 
changes from Baseline will be summarized by treatment group.  Shift table by 
screening diabetes status will be presented as described in Section 6.6.4.4.  No 
statistical testing will be performed. 
Other Exploratory Efficacy Endpoint Analyses for the RW Phase and RES 
Phase 
Partial loss of response during the RW Phase 
The proportion of subjects with partial loss of response (mUFC that increases from 
Baseline (RW0) to above normal but no more than 1.5X ULN, or LNSC that was normal 
at Baseline (RW0; both values ≤ULN) and becomes abnormal (>ULN) based on each 
of two LNSC collections obtained on different nights) AND clinically significant 


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worsening of signs and symptoms of CS during the RW Phase will be compared 
between treatment groups using a two-sided Fisher’s Exact test and a 95% CI of the 
difference will be calculated. 
Shifts in mUFC and LNSC 
Shifts from RW Baseline in mUFC to RW5 (or last post-RW Baseline visit) and RES2 
(or RES1 if RES2 value is missing) will be summarized based on the following 
categories: 
• 
Less than lower limit of normal (LLN) (< LLN) 
• 
Within the normal range ([LLN; ULN]) 
• 
Greater than ULN and less than or equal to 2x ULN ((ULN; 2 x ULN]) 
• 
Greater than 2x ULN and less than or equal to 5x ULN ((2 x ULN; 5 x ULN]) 
• 
Greater than 5x ULN (>5 x ULN) 
Shifts from RW Baseline in LNSC to RW5 (or last post-RW Baseline visit) and RES2 (or 
RES1 if RES2 value is missing) will be summarized based on the following categories:  
>ULN or ≤ULN. 
Other Exploratory Efficacy Endpoint Analysis for the TM Phase for the L-N 
Cohort 
Selective Efficacy Endpoints at the Last and the Highest Dose Received with 
Non-missing Result 
Observed values as well as change from TM Baseline will be presented for mUFC, 
LNSC, biomarkers of CS comorbidities, CS QoL total score, BDI-II total score, acne 
global score, hirsutism (for females only) total score, and peripheral edema total 
scores, at the last observed result by corresponding dose level, and at the highest 
dose level received with non-missing result by corresponding dose level during the TM 
Phase. 
6.6.6 
Pharmacokinetics Analysis 
The Pharmacokinetics analysis will be detailed in a separate analysis plan. 
6.6.7 
Pharmacodynamics Analysis 
The Pharmacodynamics analysis will be detailed in a separate analysis plan. 
6.7 Safety 
Descriptive summaries of all safety endpoints will be presented by treatment group 
and visit (RW1-RW5 and RES1-RES2; where applicable) for the RW Phase and RES 
Phase and at the End of RW Phase time point.  For continuous variables, summaries 


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will be presented for the observed values and for the absolute and percent changes 
from the relevant Baseline. 
For the TM Phase, safety endpoints measured at multiple visits will be summarized by 
the levoketoconazole dose received corresponding to the last non-missing results, by 
the highest levoketoconazole dose received with non-missing results, and by the 
levoketoconazole dose received corresponding to the worst results (where specified).  
For subjects in the RW Phase, summaries will also be presented by Therapeutic Dose 
and for all dose groups combined.  Statistical testing, whether within-treatment or 
between-treatment, and only where specified, will only be for the all levoketoconazole 
dose groups combined. 
For the RW Phase and RES Phase Combined and the All Phases Combined, where 
applicable, only the safety results while on levoketoconazole will be summarized. 
The Safety population will be determined based on study phase and the study overall 
(i.e. all phases combined).  Refer to Section 4.5 for details on the analysis populations 
to use. 
6.7.1 
Adverse Events 
All adverse events (AEs) will be collected from the date that informed consent was 
signed.  Verbatim terms for each AE will be coded using MedDRA version 21.1 and 
graded per the National Cancer Institute Common Terminology Criteria for Adverse 
Events, version 4.03 [NCI CTCAE, 2010].   
Table 5 
The Severity of AEs and SAEs per NCI CTCAE, Version 4.03 
Grade 1  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2  
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
Grade 3  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living  
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
An AE of scientific and medical concern specific to the study treatment will be identified 
as AESI.  AESIs will be reported regardless of seriousness or causality.  There are 3 
types of AESIs: Persistent QTc prolongation, Potential hepatic events, and Adrenal 
insufficiency. 
All AE summaries will be restricted to Treatment-Emergent AEs (TEAEs), which are 
defined as those AEs with an onset on or after the date of the first study drug dose 
and up to 30 days after the last dose of study drug.  TEAE summaries will be presented 


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by study phase including TM Phase (L-N population only), RW Phase, RES Phase, the 
RW Phase and RES Phase Combined, and All Phases Combined.  For each phase, only 
TEAEs that occur on or after the start of that phase up to the end of that phase will 
be summarized.  For subjects who withdraw during or at the end of the phase, any 
reported TEAE that starts after withdrawal but within 30 days of the last dose will be 
included in the summaries for that phase.  For the TEAE summaries for the RW Phase 
and RES Phase Combined and All Phases Combined, where specified below, only the 
TEAEs while on levoketoconazole will be included (i.e. the TEAEs during the RW Phase 
for subjects randomized to placebo will be excluded). 
For the RW Phase and RES Phase, TEAEs will be summarized by treatment group.  For 
the TM Phase summary, TEAEs will be summarized by dose level.  To determine the 
dose level that is associated with each AE record, the start date of the AE will be 
compared to the dose level start and end dates.  If dose level start date <= AE start 
date <= dose level end date, then the dose level will be assigned to the AE record. 
Details of start and end date for each study phase are provided in Section 5.1.  Details 
of summary presentations for each phase are provided in Section 6.1. 
The number and percentage of subjects will be summarized by SOC and PT and will 
be ordered by descending order of incidence of SOC and PT within each SOC.  A subject 
with more than one occurrence of the same TEAE in a particular SOC or PT will be 
counted only once in in that particular SOC or PT.  If a subject experience the same 
TEAE at more than one severity, or with more than one relationship to study drug, 
the most severe rating or the stronger causal relationship to study drug will be given 
precedence. 
The following TEAE summaries will be produced: 
• 
For the overview summary of all TEAEs - Total number of TEAEs, number of 
subjects with at least one TEAE, number of subjects with at least one treatment-
emergent SAE, number of subjects with at least one TEAE with special interest, 
number of subjects with at least one serious TEAE of special interest, number 
of subjects with at least one severe TEAE (CTCAE grade =3), number of 
subjects with at least one life-threatening TEAE (CTCAE grade =4), number of 
subjects with at least one TEAE leading to discontinuation of study drug, and 
number of subjects with at least one TEAE leading to death.  For the number of 
TEAEs, a unique event for a subject is defined as a unique combination of SOC, 
PT, onset date, CTCAE grade, and relationship to study drug. 
• 
For the overview summary of all study drug-related TEAEs – Same as in the 
previous bullet point. 
• 
Number of subjects with TEAEs by MedDRA SOC and PT. 


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• 
Number of subjects with TEAEs by MedDRA SOC, PT, and closest relationship 
to study drug (Related/Not Related).  Related events are defined as events that 
are definitely or probably related to study drug.  AEs with a missing relationship 
are considered definitely related.  At each level of subject summarization, a 
subject is classified according to the closest relationship if the subject reported 
one or more events. 
• 
Number of subjects with TEAEs by MedDRA SOC, PT, and worst reported 
severity.  Worse severity is defined as first Death, then life-threatening followed 
by Severe, Moderate and by Mild as the lowest level.  AEs with missing severity 
are categorized as severe in the TEAE summary tables.  At each level of subject 
summarization, a subject is classified according to the highest severity if the 
subject reported one or more events.  
• 
Number of subjects with treatment-emergent SAEs by MedDRA SOC and PT. 
• 
Number of subjects of the most common TEAEs (frequency above 5% of all 
subjects in the TM Phase and 5% for at least one treatment group in the RW 
Phase and RES Phase) by MedDRA PT.  
• 
Number of subjects with TEAEs of special interest (AESI) by category, MedDRA 
SOC and PT.  The AESI categories are QTc prolongation, potential hepatic 
events, and adrenal insufficiency. 
• 
Number of subjects with TEAEs of AESI with grades >=3 by category, MedDRA 
SOC and PT. 
• 
Number of subjects with serious TEAEs of special interest by AESI category, 
MedDRA SOC and PT. 
• 
Number of subjects with TEAEs leading to study drug discontinuation by 
MedDRA SOC and PT. 
• 
Descriptive summary of time from start of treatment to first onset of most 
common TEAEs (frequency above 5% of all subjects in the TM Phase and 5% 
for at least one treatment group in the RW Phase and RES Phase). 
For summaries of overall TEAEs, TEAES by SOC and PT, SAEs, AESIs, AEs leading to 
study drug discontinuations, combined summaries of the RW Phase and RES Phase 
and all three phases will also be presented for subjects while they are on 
levoketoconazole.  For the RW Phase and RES Phase Combined, data after early rescue 
will not be included in the summaries. 
Listings of all AEs, SAEs, AESIs, AEs leading to discontinuation of study drug, AEs 
leading to withdrawal from the study, and AEs leading to death will be presented by 
study phase, cohort, treatment group, subject, detailing verbatim term given by the 
Investigator or designee, SOC, PT, onset date, resolution date, severity, seriousness, 


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AESI category, action taken, outcome, and drug relatedness.  The event onset will 
also be shown relative (in number of days) to date of first dose within each phase and 
across all phases.  
TEAE summaries by subgroups of interest will be performed as described in Section 
6.7.7. 
6.7.2 
Laboratory Evaluations 
The following safety laboratory analytes will be analyzed: 
Liver Function Tests: Aspartate Aminotransferase (AST) (SGOT), Alanine 
Aminotransferase (ALT) (SGPT), Gamma-glutamyl transferase (GGT), Alkaline 
phosphatase (ALP), Total bilirubin. 
Hematology: Platelet Count, Red Blood Cell (RBC) Count, White Blood Cell (WBC) 
Count (absolute), Hemoglobin, Hematocrit, RBC indices (Mean corpuscular volume 
(MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin 
concentration (MCHC)), WBC Differentials (Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils). 
Clinical Chemistry, excluding Liver Function Tests: Blood Urea Nitrogen, 
Creatinine, Sodium, Potassium, Chloride, Total CO2, Calcium, Magnesium, Phosphate, 
Uric Acid, Albumin, Total Protein, and Lactate dehydrogenase (LDH). 
Coagulation Tests:  INR, PT, PTT 
Urinalysis: Specific gravity, pH, glucose, protein, blood and ketones.  In addition, 
microscopic examination if blood or protein is > trace positive by dipstick.  
Safety Hormones and Biomarkers: Free and Total Testosterone, Thyroid-
Stimulating Hormone (TSH)/Free T4, Prolactin, High-Density Lipoprotein-Cholesterol 
(HDL-C), LDL-C:HDL-C ratio, Triglycerides 
Other Laboratory Tests:  Serum cortisol, ACTH, urine albumin: creatinine (ratio 
from spot urine) 
Laboratory results will be presented as received from the central laboratory, no data 
conversions will be performed.  Results will be summarized by the SI units (see 
Section 6.1).  
Descriptive summaries by phase and visit (where applicable), as described in     
Section 6.7, will be produced for the laboratory tests.  In addition, the number and 
percentage of subjects with abnormal laboratory values will be summarized. 
Shifts (low/normal/high) from the relevant Baseline tables based on the normal 
ranges will be constructed.  For the TM Phase, the shifts will be from the TM Baseline 
to the last non-missing results, to the non-missing results while on the highest 
levoketoconazole dose, and to the worst results during the phase.  For each of the RW 


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Phase and RES Phase separately, the shifts will be from the relevant Baseline to each 
post-Baseline visit and to the End of RW Phase time point and to the worst results 
during the phase.  For the RW Phase and RES Phase Combined, the shifts will be from 
the RW Baseline to the worst results during the two phases, including only the results 
while the subjects were on levoketoconazole. 
For LFTs, tables will also be created to summarize the incidence at each visit and at 
the End of RW Phase time point and the shifts from the relevant Baseline for ALT, AST 
and total bilirubin (similar to the shifts described above) using the following 
categories: 
ALT and AST: <LLN, within the normal range, > ULN and ≤ 3X ULN, > 3X ULN to ≤ 
5X ULN, > 5X ULN to ≤ 10X ULN and > 10X ULN.  
Total bilirubin: <LLN, within the normal range, > ULN and ≤ 1.5X ULN, >1.5X ULN 
and ≤2X ULN, and >2X ULN.  
In addition, summaries for LFTs using the categories described above at the worst 
post-baseline result and the last observed result, as well as the shift from baseline to 
the worst post-baseline result and the last observed result, will be presented for all 
phases combined while on levoketoconazole. 
An evaluation of drug-induced serious hepatotoxicity (eDISH) plot will be produced to 
assess the liver enzyme abnormalities that occur.  ALT, AST, and Total bilirubin during 
each study phase will be plotted as multiples of the ULN, on a logarithmic scale.  Those 
results that are greater than 2x ULN for Total bilirubin and greater than 3x ULN for 
ALT (or AST) will be easily identified through the use of reference lines.  The following 
6 eDISH plots will be produced with the first variable on the x-axis and the second 
variable on the y-axis, and where the Baseline is the relevant Baseline for the study 
phase being plotted: 
• 
Baseline ALT (expressed as x ULN) x Maximum Post-RW Baseline ALT 
(expressed as x ULN) 
• 
Maximum Post-baseline ALT (expressed as x ULN) x Maximum Post-baseline 
AST (expressed as x ULN) 
• 
Maximum Post-baseline ALT (expressed as x ULN) x Maximum Post-baseline 
Total Bilirubin (expressed as x ULN) 
• 
Baseline AST (expressed as x ULN) x Maximum Post-baseline AST (expressed 
as x ULN) 
• 
Maximum Post-baseline AST (expressed as x ULN) x Maximum Post-baseline 
Total Bilirubin (expressed as x ULN) 


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• 
Baseline Total Bilirubin (expressed as x ULN) x Maximum Post-baseline Total 
Bilirubin (expressed as x ULN) 
A spaghetti plot will be produced for each study phase to show the results for ALT, 
AST, and Total bilirubin relative to the ULN for each subject versus time since start of 
study drug.  The results will be plotted as multiples of the ULN, on a logarithmic scale.  
Box and whisker plots presenting actual and change from Baseline values in the three 
LFTs for each visit in all three phases will be produced. 
Potential clinically significant (PCS) results for selected laboratory tests will be listed, 
according to the criteria listed in Table 6 below: 
Table 6 
Laboratory Test PCS Criteria 
Category 
Analyte 
PCS Criteria – 
Conventional Units 
PCS Criteria – SI Units 
Hematology 
Eosinophils 
≥ 700/µL 
≥ 0.7 × 109/L 
 
Hematocrit (Hct) 
Female: ≤ 32%;  
Male: ≤ 37% 
Female: ≤ 0.32;  
Male: ≤ 0.37 
 
Hemoglobin (Hgb) 
 
Female: ≤ 9.5 g/dL;  
Male: ≤ 11.5 g/dL or 
Decrease of ≥ 20% 
Female: ≤ 95 g/L;  
Male: ≤ 115 g/L or 
Decrease of ≥ 20% 
 
Leukocytes 
Low: ≤ 2800/ µL  
High: ≥ 16000/µL 
Low: ≤ 2.8 × 109/L  
High: ≥ 16 × 109/L 
 
Neutrophils 
≤ 1000/µL 
≤ 109/L 
 
Platelets 
Low: ≤ 75 × 103/µL  
High: ≥ 700 × 103/µL 
Low: ≤ 75 × 109/L or  
High: ≥ 700 × 109/L 
Blood 
Chemistry 
Albumin  
< 2.5 g/dL 
< 25 g/L 
 
Blood Urea 
Nitrogen (BUN) 
> 30 mg/dL 
> 10.71 mmol/L 
 
Calcium  
Low: < 7 mg/dL;  
High: > 12 mg/dL 
Low: < 1.75 mmol/L;  
High: > 3 mmol/L 
 
Cholesterol 
> 300 mg/dL 
> 7.76 mmol/L 
 
Creatinine 
> 2 mg/dL 
> 176.8 umol/L 
 
Glucose 
Low: < 50 mg/dL;  
High: >250 mg/dL 
Low: < 2.8 mmol/L;  
High: >13.9 mmol/L 


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Category 
Analyte 
PCS Criteria – 
Conventional Units 
PCS Criteria – SI Units 
 
LDH 
> 3x ULN 
> 3x ULN 
 
Phosphate 
Low: < 2.0 mg/dL;  
High: > 5.0 mg/dL 
Low: < 0.65 mmol/L;  
High: > 1.62 mmol/L 
 
Potassium  
Low: < 3.0 mEq/L;  
High: > 5.5 mEq/L 
Low: < 3.0 mmol/L;  
High: > 5.5 mmol/L 
 
Sodium  
Low: < 130 mEq/L;  
High: > 150 mEq/L 
Low: < 130 mmol/L;  
High: > 150 mmol/L 
 
Triglycerides 
High: > 500 mg/dL 
> 5.65 mmol/L 
 
Uric Acid 
Female: > 8.0 mg/dL; 
Male: > 10.0 mg/dL 
Female: > 475.8 umol/L; 
Male: > 594.8 umol/L 
Liver Safety 
ALT 
High: > 3x ULN 
High: > 3x ULN 
 
ALP 
High: > 3x ULN 
High: > 3x ULN 
 
AST 
High: > 3x ULN 
High: > 3x ULN 
 
Total Bilirubin  
High: > 2x ULN 
High: > 2x ULN 
 
GGT 
High: > 3x ULN 
High: > 3x ULN 
Urinalysis 
Blood 
Increase of ≥ 2 units 
 
 
Glucose 
Increase of ≥ 2 units 
 
 
Protein 
Increase of ≥ 2 units 
 
Testosterone 
In addition to the summaries described above for laboratory tests in general, all 
summaries for testosterone levels will be done separately by sex (also stated in 
Section 6.7.7).  The mean changes from RW Baseline during the RW Phase in 
testosterone levels by sex will be assessed for treatment group differences using two-
sample t-test at each visit and at the End of RW Phase time point.  Within-treatment 
mean changes from the relevant Baseline to each visit in the RW Phase and RES Phase 
and at the End of RW Phase time point will be assessed for nominal significance using 
paired t-test. 
Serum Cortisol 
In addition to the summaries described above for laboratory tests in general, the mean 
changes from RW Baseline during the RW Phase in serum cortisol will be assessed for 


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treatment group differences using two-sample t-test at each visit and at the End of 
RW Phase time point.  Within-treatment mean changes from the relevant Baseline to 
each visit in the RW Phase and RES Phase and at the End of RW Phase time point will 
be assessed for nominal significance using paired t-test.  
ACTH 
All summaries for ACTH will be presented for subjects with Cushing’s Disease (CD) 
only.  In addition to the summaries described above for laboratory tests in general, 
the following will be done for ACTH: 
• 
ACTH will be transformed to fold-ULN (i.e. multiples of the ULN) and summaries 
of ACTH as fold-ULN will be produced. 
• 
The mean changes from RW Baseline, using both the actual values and the fold-
ULN values, during the RW Phase will be assessed for treatment group 
differences using two-sample t-test at each visit and at the End of RW Phase 
time point.  Within-treatment mean changes from the relevant Baseline to each 
visit in the RW Phase and RES Phase and at the End of RW Phase time point 
will be assessed for nominal significance using paired t-test.  
• 
Subgroup summary: ACTH summary of actual value and change from RW 
Baseline to all post-RW Baseline visits during the RW Phase and at the End of 
RW Phase time point will be presented by sex (also stated in Section 6.7.7). 
• 
Needle plots of individual subject ACTH values plotted as fold-ULN from RW 
Baseline to the end of the RW Phase (i.e. last non-missing post-RW Baseline 
ACTH during the phase, before early rescue in cases where early rescue 
occurred) will also be produced. 
• 
Additional exploratory analysis to examine correlations between ACTH levels 
and the normalization of mUFC during the RES Phase may be also performed. 
6.7.3 
Oral Glucose Tolerance Test (for Pre-diabetic Subjects)  
Pre-diabetic subjects are defined as those who had a Baseline fasting glucose greater 
or equal to 100 mg/dL (5.6 mmol/L) and less than 126 mg/dL (7.0 mmol/L) without 
concomitant use of anti-diabetic medication.  The diabetic and pre-diabetic status is 
recorded on the Oral Glucose Tolerance Test (OGTT) eCRF. 
All pre-diabetic subjects with impaired fasting glucose (subjects who have not been 
previously diagnosed with diabetes and are currently pre-diabetic and not receiving 
medication to lower blood glucose) have an OGTT at Screening, TM7, RW0, RW5, and 
RES2.  Plasma glucose values before (i.e. 0 min) and 30 min, 60 min, 90 min, and 
120 min after glucose administration are to be determined.  Glucose tolerance before 
and after the OGTT is to be determined based on 120-min glucose level as the 
following: 


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Pre-Test: 
• 
Normal: glucose level< 100 mg/dL (5.6 mmol/L) 
• 
Impaired fasting glucose: >= 100 mg/dL (5.6 mmol/L) and < 126 mg/dL (7.0 
mmol/L) 
Post-Test: 
• 
Normal: 2-hour glucose level below 140 mg/dL 
• 
Impaired glucose tolerance (pre-diabetic): glucose level at least 140 mg/dL and  
less than 200 mg/dL 
• 
Provisional diagnosis of diabetes (diabetic): glucose level at least 200 mg/dL 
Note: If 120-min glucose level is missing, then the non-missing 90-min glucose 
level will be used; otherwise, the glucose level will be considered as missing for 
the purposes of determining glucose tolerance.  
The following summaries of OGTT glucose values will be produced: 
• 
Number and percentage of subjects for each pre-test category at Screening and 
TM7 by last dose received at TM7, and at RW0, RW5, End of RW Phase, and 
RES2 by treatment group.  
• 
Number and percentage of subjects for each post-test category of 120-min 
glucose level at Screening, TM7 by last dose received at TM7, and RW0, RW5, 
End of RW Phase, and RES2 by treatment group.  
• 
Shifts from Screening to TM7 by last dose received at TM7, from RW0 to RW5, 
from RW0 to End of RW Phase, and from RW5 to RES2 in glucose post-test 
category by treatment group. 
• 
Descriptive statistics will be determined for the maximum glucose values during 
OGTT at Screening, TM7 (actual and change), RW0, RW5 (actual and change), 
End of RW Phase (actual and change), and RES2 (actual and change).  Paired 
t-test will be used to assess the changes in maximum glucose values during 
OGTT from Screening to TM7, from RW0 to RW5, from RW0 to End of RW Phase, 
and from RW5 to RES2. 
• 
Descriptive statistics will be determined, and paired t-test will be performed, as 
described above, for time (from glucose administration, in minutes) to the 
maximum glucose values during OGTT. 
• 
Descriptive statistics will be determined, and paired t-test will be performed, as 
described above, for total area under curve (AUC) and incremental AUC of 
glucose values in OGTT.  


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• 
For the determination of Maximum, Time to Maximum, AUC and incremental 
AUC for individual subjects – there is no imputation of missing values.  These 
variables will be determined only if there is no more than one time point with a 
missing value and the time point with a missing value cannot be the 0-min and 
120-min time points. 
The calculated indices and their changes from Screening to TM7, from RW0 to RW5, 
from RW0 to End of RW Phase, and from RW5 to RES2 will be summarized by each 
treatment group. 
6.7.4 
Vital Signs 
Descriptive summaries by phase and visit (where applicable) and at the End of RW 
Phase time point, as described in Section 6.7 will be produced for vital signs (blood 
pressure, heart rate, and temperature).  The mean changes from RW Baseline in blood 
pressure during the RW Phase will be assessed for treatment group differences using 
two-sample t-test at each visit and at the End of RW Phase time point. Within-
treatment mean changes in blood pressure from the relevant Baseline to each visit in 
the RW Phase and RES Phase and at the End of RW Phase time point will be assessed 
for nominal significance using paired t-test. 
The number and percentage of subjects by category of vital sign clinical importance, 
presented in Table 7, will be summarized by phase and visit (where applicable) and 
at the End of RW Phase time point, as described in Section 6.7.4.  
Table 7 
Vital Sign Clinical Importance Criteria 
Vital Sign 
Criteria 
Flag 
Heart Rate (HR) 
below 44 bpm 
Low (L) 
 
44-100 bpm 
Normal 
 
 
101-120 bpm 
High (H) 
 
above 120 bpm 
Very High (VH) 
 
 
 
SBP 
below 90 mm Hg 
Low (L) 
 
90-139 mm Hg 
Normal 
 
140-169 mm Hg 
High (H) 
 
170 mm Hg and above 
Very High (VH) 
 
 
 
DBP 
below 50 mm Hg  
Low (L) 
 
50-89 mm Hg 
Normal 
 
90-109 mm Hg 
High (H) 
 
110 mm Hg and above 
Very High (VH) 
Shifts from the relevant Baseline tables based on the categories above will be 
constructed.  For the TM Phase, the shifts will be from the TM Baseline to the last non-
missing results, to the non-missing results while on the highest levoketoconazole 
dose, and to the worst results during the phase.  For each of the RW Phase and RES 
Phase separately, the shifts will be from the relevant Baseline to each post-Baseline 


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visit and at the End of RW Phase time point and to the worst results during the phase.  
For the RW Phase and RES Phase Combined, the shifts will be from the RW Baseline 
to the worst results during the two phases, including only the results while the subjects 
were on levoketoconazole. 
Shifts from the relevant Baseline in blood pressure classification as defined in Table 8 
below, will be summarized in the same manner as described above for the shifts based 
on vital sign values of clinical importance. 
Table 8 
Blood Pressure Classification (Adults Over 18 Years of Age) 
Blood Pressure Classification 
SBP (mmHg) 
DBP (mmHg) 
< 120 
and < 80 
120-139 
or 80-89 
140-159 
or 90-99 
≥ 160 
or ≥ 100 
Subjects with PCS results in vital signs will be listed, according to the criteria listed 
in Table 9 below:  
Table 9 
Vital Sign PCS Criteria 
Vital Sign Parameters 
PCS Criteria  
Pulse  
Increase of ≥ 15 bpm from baseline and ≥ 120 bpm 
Decrease of ≥ 15 bpm from baseline and ≤ 50 bpm 
Systolic Blood Pressure 
Increase of ≥ 20 mmHg from baseline and ≥ 180 
mmHg  
Decrease of ≥ 20 mmHg from baseline and ≤ 90 
mmHg  
Diastolic Blood Pressure 
Increase of ≥ 15 mmHg from baseline and ≥ 105 
mmHg  
≤ 50 mmHg  
Temperature 
Increase of ≥ 2.0 ºC from baseline and ≥ 38.0 ºC 
Weight 
Decrease of ≥ 10% from baseline 
Increase of ≥ 10% from baseline  


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6.7.5 
Electrocardiograms  
The following quantitative ECG measurements will be taken during the study: 
• 
heart rate (bpm); 
• 
RR interval (msec); 
• 
PR interval (msec); 
• 
QRS interval (msec); 
• 
Bazett corrected QT (QTcB) interval (msec)  
• 
Fridericia corrected QT (QTcF) interval (msec)  
Descriptive summaries by study phase and visit (where applicable) and at the End of 
RW Phase time point, as described in Section 6.7 will be produced for the quantitative 
ECG measurements listed above and the qualitative overall ECG interpretation 
(normal versus abnormal).  Within-treatment mean changes in QTcF from the relevant 
Baseline to each visit in the RW Phase and RES Phase and at the End of RW Phase 
time point will be assessed for nominal significance using paired t-test. 
The number and percentage of subjects by category of QTc interval clinical 
importance, presented in Table 8, will be summarized by phase and visit (where 
applicable) and at the End of RW Phase time point, as described in Section 6.7.5.  The 
worst categorical actual and worst categorical change from the relevant Baseline in 
post-Baseline values within each study phase will be summarized.  Using the 
categories for actual values, shifts from the relevant Baseline will be constructed.  For 
the TM Phase, the shifts will be from the TM Baseline to the last non-missing results, 
to the non-missing results while on the highest levoketoconazole dose, and to the 
worst results during the phase.  For each of the RW Phase and RES Phase separately, 
the shifts will be from the relevant Baseline to each post-Baseline visit and at the End 
of RW Phase time point and to the worst results during the phase, and the within-
treatment shifts from Baseline will be assessed for nominal significance using 
McNemar’s test.  For the RW Phase and RES Phase Combined, the shifts will be from 
the RW Baseline to the worst results during the two phases, including only the results 
while the subjects were on levoketoconazole.  
In addition, summary of categorical ECG results at the worst post-baseline result and 
the last observed result, as well as shift from baseline to the worst post-baseline result 
and the last observed result, will be presented for all phases combined while on 
levoketoconazole. QTcF assessments and the time elapsed relative to study drug 
administration and PK blood draws will also be presented in listing.  The elapsed time 
from dosing to each QTcF interval measurement with a valid time stamp was 
summarized by visit and overall within each study phase through descriptive statistics, 
as well as through frequency distributions where the elapsed times were categorized 
into:  <1 hour post-dose, 1 to <2 hours post-dose, 2 to <3 hours post-dose, 3 to <4 
hours post-dose, and ≥4 hours post-dose.  


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ECG readings that have been rejected after Spaulding central reader review will not 
be included in any analysis tables.   
Table 10 
QTcF Interval Clinical Importance Criteria 
QTcF Interval 
Criteria (msec) 
Change from Baseline 
below 30 
 
30-60 
 
above 60 
 
 
Actual Value 
<450 
 
451-480 
 
481-500 
 
above 500 
 
 
Actual Value by Sex 
>450 for Males 
>470 for Females 
 
Subjects with PCS results in ECGs will be listed, according to the criteria listed in Table 
11 below: 
 
Table 11 
Electrocardiogram (ECG) PCS Criteria 
Parameter  
Criteria 
QTcF 
Female: > 470 msec 
Male: > 450 msec 
PR Interval 
> 200 msec  
Heart Rate 
< 48 bpm 
> 96 bpm 
6.7.6 
Pituitary Magnetic Resonance Imaging 
The results from the pituitary magnetic resonance imaging (MRI) will be summarized 
for CD subjects only. The number and percentage of subjects with macroadenoma 
and those with microadenoma will be summarized at Screening, RW Baseline, RW5, 
and End of RW Phase time point.  The observed values in pituitary tumor size (in 
millimeters of maximum diameter), tumor height (sagittal and coronal views), tumor 
length (sagittal view), and tumor width (coronal view) and the changes in these values 
from Screening to RW Baseline, RW5, and End of RW Phase time point (for the L-N 
cohort) and from RW Baseline to RW5 and End of RW Phase time point (for the S-C 
cohort) will be summarized by treatment group.  In addition to all CD subjects, the 
observed and changes values for tumor maximum diameter at each visit will be 


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summarized for the subset of CD subjects with a measurable tumor (ie, those with 
macroadenoma or microadenoma) at that visit. 
The status of overall pituitary size and the status of pituitary tumor size/activity from 
Screening to RW Baseline, RW5, and End of RW Phase time point (for the L-N cohort) 
and from RW Baseline to RW5 and End of RW Phase time point (for the S-C cohort) 
will be summarized by treatment group, with the categories for the status as follows:  
Increase, Stable, Decrease, Unknown or Not Measurable, and Not Applicable.  The 
basis of tumor status assessment will also be summarized with the categories as 
follows:  a) Overall tumor appearance change; b) Maximum tumor diameter change; 
c) Inference from pituitary gland change; both a) and c); both b) and c); All of a), b), 
and c); No change; and Not applicable.  In addition to all CD subjects, the status of 
pituitary tumor size/activity at each visit will be summarized separately for the subset 
of CD subjects with macroadenoma and those with microadenoma at Screening (for 
the L-N cohort) and at RW Baseline (for the S-C cohort). 
6.7.7 
Subgroup Analyses for Safety 
The following safety summaries for the TM Phase and the RW Phase will be produced 
separately for the subgroup of subjects who completed SONICS (regardless of their 
therapeutic response at the end of SONICS) versus those who did not participate in 
SONICS: 
• 
Overview summary of all TEAEs and summary of TEAEs by MedDRA SOC and 
PT (see Section 6.7.1) 
• 
Shift from the relevant Baseline in ALT, AST, and Total bilirubin using the 
categories defined in Section 6.7.2. 
• 
Summary of QTc intervals by the clinically important categories defined in 
Section 6.7.5. 
The same set of summaries for TEAEs and QTc intervals will be produced in the RW 
Phase for subgroups of subjects (with a minimum subgroup size of at least 30% of 
the ITT population) based on the following: 
• 
baseline glycemia status (pre-diabetic, diabetic, normal, as defined in Section 
6.6.4.4)  
• 
receiving anti-hypertension medication at Baseline/presence of high blood 
pressure at screening (Yes/No, as defined in Section 6.6.4.3) 
• 
CD status (Yes/No) 
• 
Region (US sites versus non-US sites) 
• 
Sex (female versus male) 


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• 
Age (≤median age of the Safety population in the study overall versus > median 
age) 
Descriptive summaries by subgroup of interest will be produced in each of the three 
study phases for the following laboratory tests: 
• 
Testosterone levels by sex 
• 
ACTH by sex (for the subset of subjects with CD only). 
6.8 Interim Analysis 
An interim analysis, also referred to as the End of RW Phase analysis, will be conducted 
after all enrolled subjects have either completed the RW Phase or discontinued prior 
to the end of the RW Phase.  The interim analysis will include all data up to the end 
of the RW Phase.  Data from the RES Phase will not be analyzed.  Prior to the database 
lock and treatment unblinding for the interim analysis, the data up to the end of the 
RW Phase will be cleaned and reviewed in a blinded manner to resolve data queries, 
the major protocol deviations will be identified, including those that will lead to 
exclusion of subjects from the PP population, and the compositions of the analysis 
populations (excluding those populations that are based on dosing in the RES Phase) 
will be determined. 
Treatment unblinding will occur after major protocol deviations are identified and used 
to finalize the analysis populations and following database lock for the interim 
analysis.  After the database lock, a request for Unblinding Form, signed and approved 
by the Sponsor and CRO unblinded Biostatistics and unblinded Statistical 
Programming, will be sent to Bracket.  Upon receipt of the approved Unblinding Form, 
Bracket will deliver the unblinded treatment codes (as a SAS dataset) to the 
designated CRO unblinded lead biostatistician via secure FTP server.  Next, the 
unblinded treatment information received from Bracket will be integrated into the 
SDTM and ADaM datasets for generation of top line results first, and then the rest of 
the interim analysis results.  As a result, CRO biostatistics and programming team will 
be unblinded. 
The subjects, Investigators, study site personnel, representatives of the Sponsor and 
CRO involved in the monitoring of the study, and representatives of the CRO involved 
in the data management of the study will continue to be blinded at the individual 
subject level until after the database lock at the end of the study.  The names of 
individuals who will be unblinded at the individual subject level for the interim analysis 
will be documented by the CRO Lead Statistician (and confirmed by the Sponsor Lead 
Statistician).  Results of the interim analysis at the unblinded treatment group level 
(i.e. tabulated results only) may be shared with some of those who remain blinded at 
the individual subject level, if approved by the Sponsor. 


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No changes to the design or conduct of the remainder of the study nor the pre-
specified analyses in the SAP will be made based on the interim analysis results.  The 
results from the interim analysis for the primary efficacy endpoint and the secondary 
efficacy endpoints during the RW Phase will be considered as final.  There will be no 
statistical adjustments of the results at the final analysis that will be conducted after 
the study ends.  
Data up to the end of the RW Phase will be locked for the interim analysis and will 
remain locked for the remainder of the study.  In the unlikely event that new or 
additional data become available after the interim analysis that impacts locked data, 
any data changes will be reviewed on a blinded basis and approved by the Sponsor.  
Such data changes will be discussed in the final study report. 
An independent DSMB reviews all SAEs and AESIs on a rolling basis and assesses 
benefits and risk of therapy (unblinded) systematically at approximately 6-month 
intervals.  There are no plans to stop the study prior to completion based on these 
reviews, and therefore no stopping rules are created.  The DSMB will not report its 
findings other than to indicate whether the protocol must be changed for the study to 
continue as planned or otherwise make recommendations designed to ensure patient 
safety and study integrity.  Details of the DSMB procedures are described in a separate 
charter and a DSMB statistical analysis plan. 
 


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7. Changes from Planned Analyses in the Protocol 
In Section 12.5.2.6 of the protocol, the post-test glucose category of “Impaired 
glucose tolerance (pre-diabetic)” is defined as: “glucose level at least 140 mg/dL 
and no more than 200 mg/dL”. This definition includes 200 mg/dL, which is an 
error as the next category of “diabetic” is defined as “glucose level at least 200 
mg/mL” (ie, it also includes 200 mg/dL). In Section 6.7.3 of this SAP, this error 
has been corrected, and the pre-diabetic category is defined as “glucose level at 
least 140 mg/dL and less than 200 mg/dL”. 
In Section 12.5.6.1 of the protocol, it is stated that insulin values during the OGTT 
will be summarized. However, the blood samples for OGTT have not been analyzed 
for insulin by the central laboratory; therefore, the analysis for insulin cannot be 
performed. 
In Section 12.5.6.1 of the protocol, it is stated that “Subgroup analyses by number 
of prior surgeries, time since last surgery, and category of prior medical treatment 
will also be explored depending on subgroup size.” These subgroup analyses are 
no longer planned. Only those subgroup analyses that are defined in Sections 
6.6.1, 6.6.2.1, 6.6.4, and 6.7.7 will be performed. 
 
 


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8. References 
1 
Doshi A, Zaheer A, Stiller MJ. A comparison of current acne grading systems 
and proposal of a novel system. Int J Derm. 1997;36:416-418. 
2 
ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
http://www.emea.eu.int/pdfs/human/ich/036396en.pd 
3 
Arnett DK, Blumenthal RS, Albert MA1, Buroker AB2, Goldberger ZD3, Hahn 
EJ1, Himmelfarb CD1, Khera A1, Lloyd-Jones D1, McEvoy JW1, Michos ED1, 
Miedema MD1, Muñoz D1, Smith SC Jr1, Virani SS1, Williams KA Sr1, 
Yeboah J1, Ziaeian B4. 2019 ACC/AHA Guideline on the Primary Prevention 
of Cardiovascular Disease: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines. Circulation. 2019 Sep 10;140(11):e596–e646 
 
 


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9. APPENDIX 1 Safety Laboratory and Vital Signs Tests – 
Identifying Worst Values 
The table below presents the direction of interest in determining the worst values for 
safety laboratory tests. 
 
Laboratory Test 
Direction of interest for worst case 
values  
Direction to choose in case of 
both Low and High Values 
HEMATOLOGY 
 
 
Hemoglobin 
Low and High 
Low 
Hematocrit 
Low and High 
Low 
RBC Count 
Low and High 
Low 
MCV 
Low and High 
Low 
MCH 
Low 
 
MCHC 
Low and High 
Low 
WBC Count 
Low and High 
Low 
Basophils 
High 
 
Eosinophils 
High 
 
Neutrophils 
Low and High 
Low 
Monocytes 
High 
 
Lymphocytes 
Low and High 
High 
Platelet Count 
Low and High 
Low 
CHEMISTRY 
 
 
Calcium 
Low and High 
 High 
Magnesium 
Low  
 
Direct Bilirubin 
High 
 
Phosphate 
Low  
 
Sodium 
Low and High 
High 
Potassium 
Low and High 
Low 
BUN (Blood Urea Nitrogen) 
Low and High 
High 
Creatinine 
High 
 
Albumin 
Low 
 
Chloride 
Low 
 
Total CO2 
High 
 
Uric Acid 
High 
 
Total Protein 
Low and High 
Low 
LDH 
High 
 
LIVER SAFETY TESTS 
 
 
Total Bilirubin 
High 
 
AST (SGOT) 
High 
 
ALT (SGPT) 
High 
 
GGT 
High 
 
ALP 
High 
 
COAGULATION TESTS 
(INR/PT/PTT) 
High/High/High 
 


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Laboratory Test 
Direction of interest for worst case 
values  
Direction to choose in case of 
both Low and High Values 
SAFETY HORMONES AND 
BIOMARKERS 
 
 
Free Testosterone 
Low 
 
Total Testosterone 
Low 
 
TSH 
Low and High 
 Low 
Free T4 
High 
 
HDL-C 
High 
 
LDL-C:HDL-C (ratio) 
High 
 
Total Cholesterol 
High 
 
Triglycerides 
High 
 
hsCRP 
High 
 
URINALYSIS 
 
 
Specific Gravity 
 Low and High 
 Low 
pH 
 Low and High 
 Low 
Protein 
 
 
Ketones 
 
 
Creatinine 
High 
 
OTHER MEASURES 
 
 
Serum Cortisol 
High 
 
ACTH 
High 
 
Albumin: Creatinine (ratio) 
Low and High 
 High 
 
 
 
 
The table above will be used in determining the worst values for safety laboratory 
tests within a study phase or a visit window for a subject (see Section 5.3).  If there 
are multiple such values for a laboratory test, then the worst value will be identified 
as follows: 
• 
If all values are within the normal range (NR), then the lowest one will be used 
if 2nd column = Low.  The highest one will be used if 2nd column = High.  The 
one farthest from the midpoint of the NR will be used if 2nd column = Low and 
High.  If two such values are equidistant from the midpoint, the lower one will 
be used if 3rd column = Low, and the higher one if 3rd column = High. 
• 
If one or more values are within the NR and one value is outside the NR, then 
the value outside the NR will be used. 
• 
If two or more values are outside the NR, then the lowest one among these will 
be used if 2nd column = Low.  The highest one will be used if 2nd column = High.  
If the 2nd column = Low and High, then the lowest one will be used if 3rd column 
= Low, and the highest one if 3rd column = High. 
 
 


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The table below presents the direction of interest in determining the worst values for 
Vital Signs assessments tests. 
Vital Signs Test 
Direction of interest for worst case 
values  
Direction to choose in case of 
both Low and High Values 
HR 
Low and High 
 Low 
SBP 
Low, High and Very High 
High  
DBP 
Low, High and Very High 
High  
Temperature 
High 
 
 
 


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10. APPENDIX 2 Laboratory Tests – Precision Levels 
Category 
Analyte 
SI Unit 
Precision 
 (Decimal Point) 
Hematology 
Hemoglobin 
g/L 
0 
Hematology 
Hematocrit 
1 
3 
Hematology 
RBC Count 
1012/L 
1 
Hematology 
MCV 
fL 
1 
Hematology 
MCH 
Pg 
1 
Hematology 
MCHC 
g/L 
0 
Hematology 
WBC Count 
109/L 
1 
Hematology 
Basophils 
% 
1 
Hematology 
Abs. Basophils 
109/L 
2 
Hematology 
Eosinophils 
% 
1 
Hematology 
Abs.Eosinophils 
109/L 
2 
Hematology 
Neutrophils 
% 
1 
Hematology 
Abs.Neutrophils  
109/L 
2 
Hematology 
Monocytes 
% 
1 
Hematology 
Abs.Monocytes 
109/L 
2 
Hematology 
Lymphocytes 
% 
1 
Hematology 
Abs.Lymphocytes 
109/L 
2 
Hematology 
Platelet count 
109/L 
0 
Chemistry 
Calcium 
mmol/L 
2 
Chemistry 
Magnesium 
mmol/L 
2 
Chemistry 
Phosphate 
mmol/L 
2 
Chemistry 
Sodium 
mmol/L 
0 
Chemistry 
Potassium 
mmol/L 
1 
Chemistry 
Blood Urea Nitrogen 
(BUN) 
mmol/L 
1 
Chemistry 
Creatinine 
umol/L 
1 
Chemistry 
Albumin 
g/L 
0 
Chemistry 
Chloride 
mmo/L 
0 
Chemistry 
Total CO2 
mmol/L 
0 
Chemistry 
Uric Acid 
umol/L 
1 
Chemistry 
Total Protein 
g/L 
0 
Chemistry 
Glucose 
mmol/L 
1 
Liver Safety 
LDH 
U/L 
0 
Liver Safety 
Total Bilirubin 
umol/L 
1 
Liver Safety 
Direct Bilirubin 
umol/L 
1 
Liver Safety 
AST(SGOT) 
U/L 
0 
Liver Safety 
ALT(SGPT) 
U/L 
0 
Liver Safety 
GGT 
U/L 
0 
Liver Safety 
ALP 
U/L 
0 
Liver Safety 
LDH 
U/L 
0 
Coagulation 
INR 
Ratio 
1 
Coagulation 
PT 
Seconds  
1 
Coagulation 
APTT 
Seconds 
1 
Safety Hormones and 
Biomarkers 
Testosterone, Free 
nmol/L 
2 


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Category 
Analyte 
SI Unit 
Precision 
 (Decimal Point) 
Safety Hormones and 
Biomarkers 
Testosterone. Total 
nmol/L 
 
2 
Safety Hormones and 
Biomarkers 
TSH 
mU/L  
 
2 
Safety Hormones and 
Biomarkers 
T-4 (Thyroxine) Free  
pmol/L 
 
1 
Safety Hormones and 
Biomarkers 
Prolactin 
pmol/L 
 
1 
Safety Hormones and 
Biomarkers 
HDL-C 
mmol/L 
 
2 
Safety Hormones and 
Biomarkers 
LDL-C 
nmol/L 
2 
Safety Hormones and 
Biomarkers  
(CS Comorbidity) 
LDL-C:HDL-C (ratio) 
Ratio 
2 
Safety Hormones and 
Biomarkers  
(CS Comorbidity) 
Total Cholesterol 
mmol/L 
2 
Safety Hormones and 
Biomarkers  
(CS Comorbidity) 
Hemoglobin A1C 
 
% 
 
1 
Safety Hormones and 
Biomarkers  
(CS Comorbidity) 
Glucose, Plasma (Fasting) 
during OGTT* 
mmol/L 
1 
Safety Hormones and 
Biomarkers  
(CS Comorbidity) 
Insulin, Plasma (Fasting) 
during OGTT* 
pmol/L 
 
2 
Safety Hormones and 
Biomarkers 
Triglycerides 
mmol/L 
 
2 
Urinalysis 
Specific Gravity 
 
3 
Urinalysis 
pH 
 
1 
Biochemical Marker 
Serum Cortisol 
nmol/L 
1 
Biochemical Marker 
LNSC 
nmol/L 
1 
Other-Biochemical Marker 
HOMA-IR 
 
1 
Other-Biochemical Marker 
ACTH 
pmol/L 
1 
Other-Biochemical Marker 
hsCRP 
mg/L 
1 
Other-Biochemical Marker 
Albumin: Creatinine 
(ratio) 
g/mol 
0 
Efficacy - Urinalysis  
Cortisol, 24-hour  
nmol/D 
1 
Efficacy - Urinalysis  
Mean Cortisol, 24-hour  
nmol/D 
1 
Efficacy – Urinalysis 
 
Creatinine Excretion 
(Urine Creatinine) 
nmol/D 
1 
 


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11. APPENDIX 3 SAS STAT Procedure Details 
The SAS codes provided in this section best represent the planned analyses of 
endpoints at the time of the development of this SAP.  Without deviating from the 
planned statistical models and tests, the SAS codes may be subject to change (e.g. 
additional options added to a statement) to provide all the results needed in the 
planned tables, as well as to interpret these results. 
1. Primary Analysis of the Primary Endpoint  
Statistical significance testing will be conducted using a logistic regression model 
containing fixed effect terms for treatment group (levoketoconazole, placebo).  
Example of SAS STAT procedure:  
 
proc genmod data = datain; 
   class trt01pn cohort; 
   model  avalc (event=’Y’) = trt01pn cohort/ 
   dist= binomial link=logit; 
   lsmeans trt01pn/cl pdiff ilink obsmargins; 
run; 
 
where avalc = ’Y’ if there is loss of therapeutic response for the 
subject and ‘N’ if there is no loss of therapeutic response for the 
subject  
trt01pn= treatment group (levoketoconazole, placebo) 
cohort = Cohorts 1 and 2 (levoketoconazole-naïve, SONICS-completer) 
2. Supportive Analysis of the Primary Endpoint  
The proportions between the treatment groups will be compared using a two-sided 
Fisher’s Exact test and a 95% CI of the difference will be calculated.  
Example of SAS STAT procedure:  
 
proc freq data=datain order=data; 
  tables trt01pn*avalc /Fisher riskdiff(cl=exact); 
  exact riskdiff; 
run; 
where avalc and trt01pn are as defined above 
3. Sensitivity Analysis of Key Secondary Efficacy Endpoint: mUFC  
Change from Baseline in imputed mUFC at RW5 will be analyzed using an analysis of 
covariance with treatment group and subject cohort as fixed effects and Baseline 
mUFC as a covariate.  
Example of SAS STAT procedure:   
 
proc mixed data=param noclprint; 
class trt01pn cohort; 


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model chg = trt01pn cohort base/ solution cl; 
lsmeans trt01pn / pdiff cl; 
run; 
trt01pn and cohort are as defined above  
base = RW Baseline value of the mUFC 
chg = Change from RW Baseline in mUFC at RW5  
4. Supportive Analysis of Key Secondary Efficacy Endpoints: mUFC, LNSC, 
and CS Comorbidity Biomarkers  
Example of SAS STAT procedure for the change from Baseline using repeated 
measures mixed effects model:  
 
proc mixed data=param noclprint; 
 class trt01pn cohort avisitn conccond; 
 model chg = trt01pn cohort avisitn trt01pn*avisitn base conccond / 
solution cl ddfm=KR;                   
repeated avisitn / subject= usubjid type=<Model Structure>;                       
lsmeans trt01pn / pdiff cl obsmargins; 
lsmeans trt01pn* avisitn/ pdiff cl obsmargins; 
run; 
 
where avisitn = analysis visit (RW1 - RW5) 
trt01pn and cohort are as defined above  
base = Baseline value of the efficacy parameter  
conccond = concurrent CS medication condition (applicable to the CS 
comorbidity biomarkers only, where specified) 
chg = Change from RW Baseline (in the efficacy parameter)  
where Model Structure = spatial power, toeplitz with heterogeneity, and 
toeplitz 
 
for spatial power option (i.e., REPEATED / type=SP(time), use days 
variable (e.g., LBDY) for time. 
 
Note: For the model with spatial power the following will be added to 
the SAS code:   
Random intercept / subject=usubjid; 
5. Hochberg Adjustment 
proc multtest inpvalues=DATAIN hoc; 
run; 
 
Note: DATAIN contains endpoints and their associated raw p-values.   
6. Analysis of Time-to-Event Exploratory Endpoints: 
Example of SAS STAT procedure:  
 
proc lifetest data=datain plots=survival(atrisk); 
time aval*cnsr(1); 


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strata trt01pn;  
run; 
where aval = Time to event in days  
cnsr = 0 for event, 1 for censored 
trt01pn is as defined above