Conditions: Cushing Syndrome Cushing Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 51
Healthy volunteers: no

Brief summary:
This is a long-term, open-label extension study of levoketoconazole in participants with endogenous Cushing's Syndrome.

Detailed description:
This is a long-term, open-label extension (OLE) study of levoketoconazole in participants with endogenous Cushing's Syndrome (CS) who have completed one or both parent studies or otherwise potentially qualify for this study, as defined in the eligibility criteria.

Arms:
arm 1: Levoketoconazole taken twice daily up to 1200 mg daily

Interventions: intervention 1: Levoketoconazole
Intervention descriptions: intervention 1: Levoketoconazole up to 1200 mg daily

Protocol document:
Prot_000.pdf: 
COR-2017-OLE Protocol Cover Page 
 
Study Title:  
An Open-Label Extension Study of Levoketoconazole (2S,4R-
Ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome 
Most Recent Document 
Version Date: 
23 September 2019 
NCT No. 
NCT03621280 
 
 
 
 
IND No. 
115968 
EudraCT No. 
2017-004647-20 
 


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CONFIDENTIAL 
 
 
 
 
CLINICAL STUDY PROTOCOL 
An Open-Label Extension Study of Levoketoconazole (2S,4R-ketoconazole) in the 
Treatment of Endogenous Cushing’s Syndrome 
Protocol Number 
COR-2017-OLE 
Compound 
Levoketoconazole  
IND No. 
115968 
EudraCT No. 
2017-004647-20 
Phase 
3 
Dates: 
 
Amendment 2 
Amendment 1 
Original 
23 September 2019 
19 July 2018 
26 March 2018 
 
 
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 
26 March 2018 
Original 
19 July 2018 
Amendment 1: 
• Removal of Data Monitoring Committee 
requirement for OPTICS Study 
• Clarified / corrected inconsistencies and 
typographical errors throughout protocol 
• Section 1.2, paragraph 3 added to the last 
sentence - at time of entry into the current 
study). 
• Clarified subjects’ participation may continue 
for at least 3 years. 
• Clarified unit of measure for serum potassium 
is mEq/L 
• Simplified and condensed wording of Inclusion 
Criteria throughout the protocol 
• Addition of Inclusion Criterion for subjects 
who completed COR-2012-01 or COR-2017-01 
but had a break in therapy and the specification 
of washout periods for drugs taken for 
Cushing’s Syndrome 
• Clarified timing of Screening / Baseline 
assessments for subjects that had a break in 
therapy 
• Section 5.2 – In addition, subjects must…. – 
minor text modification  
• Table 2 Title modified to read Expected 
Normal 24-Hour Creatinine Excretion from 
Adequate Urine Collections 
• Modified text in Section 6.2.5.1, paragraph 6 - 
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 values reported in Table 2 
[Petersenn 2013]. Creatinine excretion values 
that are somewhat below the normative value 
will be considered indicative of adequate 
collection when urine volume is adequate.  
Note that the above values were derived from 
populations of generally healthy individuals 
without kidney dysfunction.  
• Section 7 – added bullet to read - 
Levoketoconazole should usually be taken at 


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approximately the same times each day, and for 
the most consistent day-to-day absorption, 
should be ingested with the same types of 
liquids and/or foods each day (see Section 8.2). 
• Section 7 – 2nd bullet modified to read - 
Consumption of grapefruit, lime juice and 
Seville oranges (aka sour orange, bigarade 
orange, or marmalade orange) and its products 
should be limited to once weekly owing to 
potential drug interactions with 
levoketoconazole that may influence its 
bioavailability; 
• Section 10.1 modified Title to read Common 
Permitted Medications 
• Section 10.1, Paragraph 2 – modified text to 
read – For management of hypokalemia, slow-
released potassium…. 
• Section 10.1, Paragraph 7 – deleted anti-
inflammatory 
• Modified text in Section 12.5, paragraph 2 
• Section 14.1.1 modified text to read - If the 
subject is receiving doses greater than 
150 mg/day, persistent and presumed study 
medication-related QTc changes may be 
managed by temporarily withholding study 
medication if deemed necessary.  Note that a 
prolonged QTc interval that is less than 500 
msec may not always warrant temporary 
medication stoppage, depending on patient-
specific clinical factors, e.g. if the QTc does not 
exceed normal reference values (ULN for men 
is 440 msec and for women is 460 msec).   
• Section 14.1.2, Paragraph 1- modified text to 
read - If a persistent and confirmed 
levoketoconazole-related QTc interval 
prolongation above 500 msec as defined in 
Section 6.2.3 is identified, the Investigator 
should attempt to manage such QTc 
prolongations by temporarily stopping study 
medication followed by dose reduction if doing 
so does not eliminate the benefits of treatment.  
If therapeutic benefit cannot be maintained 
following dose reduction for drug-induced QTc 
prolongation above 500 msec, study medication 


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should be stopped permanently and the subject 
should be withdrawn. 
• Section 14.1.2, Paragraph 2 – modified text to 
read - If a persistent and confirmed 
levoketoconazole-related QTc interval 
prolongation above 500 msec is observed at the 
lowest levoketoconazole dose (150 mg/day), 
administration of levoketoconazole should stop 
permanently and the subject should be 
withdrawn.  
• Section 14.1.2 – Paragraph 3 added to read - 
Persistent, confirmed levoketoconazole-related 
QTc interval prolongation that represents an 
increase greater than 60 msec from baseline but 
that may not be of sufficient duration to cause 
concern of arrhythmias (e.g. less than 440 msec 
in men or less than 460 msec in women), 
depending on other clinical factors (e.g. 
recalcitrant hypokalemia) need not be managed 
with dosage reduction or result in withdrawal. 
• Addition of Subject Diary to Appendix A 
• Addition of LDH to Appendix A, footnote 14 
• Addition of LDH to Appendix B 
• Modified text in Appendix I, paragraph 2 to 
specify where prohibited medications are 
categorized into more than one category, the 
most restrictive category should hold precedent. 
• Added Ammonia to Appendix N: Instructions 
for Liver Function Test Abnormalities Follow-
up, item 10. 
• Removal of reference to obtaining PK sample 
and clarification of ‘possible’ study treatment 
interruption in Appendix N. 
• Addition of Administer drug and/or drug 
accountability at Dose Adjustment / Safety 
Monitoring Visit to Appendix A.  


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23 September 2019 
Amendment 2: 
• 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. 
• Addition of lactic acid dehydrogenase to List of 
Abbreviations and Definition of Terms 
• Section 1.2, added a sentence at the end to read: 
Certain subjects that were enrolled in Study 
COR-2017-01 when randomization was closed 
or subjects with a gap in treatment with 
levoketoconazole may require re-establishment 
or establishment of a Therapeutic Dose.  As a 
result, dose titration may be required as 
outlined in Section 8.2. 
• Section 5.1, modified item 2 NOTE to read: 
Subjects meeting criteria 1 or 2 above who have 
had a break in therapy may be eligible only 
after discussion with the Medical Monitor. If 
eligible, such subjects may require re-
establishment of the Therapeutic Dose via 
titration.  All subjects who have had a break in 
therapy should be discussed with the Medical 
Monitor to determine the starting dose of 
levoketoconazole. 
• Section 5.1, added item 5 to read: Achieved a 
clinically meaningful partial response (with 
reduction in UFC) in Study COR-2017-01 at 
dose level 7 or at a maximally tolerated dose of 
levoketoconazole but did not meet the 
randomization criteria for Study COR-2017-01 
at the end of the Dose Titration and 
Maintenance Phase when randomization was 
open. 
• Section 5.1, modified item 6 to read:  Were 
levoketoconazole-naïve prior to entry and were 
enrolled in Study COR-2017-01 in the Dose 
Titration and Maintenance Phase when 
randomization was closed.  (NOTE: Such 
subjects must receive at least 1 dose of 
levoketoconazole before transitioning to this 
study). 
• Section 6.2.5.1, modified paragraph 5 to read:  
Note that the above values were derived from 


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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 
values reported in Table 2 [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 the collection. 
• Section 8.2, added paragraph 4 to read: For 
subjects that have had a gap in treatment with 
levoketoconazole prior to entry in COR-2017-
OLE, re-establishment or establishment of a 
subject’s Therapeutic Dose at the baseline visit 
may be necessary and, as a result, dose titration 
may be required.  Subjects that were in the 
Dose Titration and Maintenance Phase of Study 
COR-2017-01 when randomization was closed 
may also require establishment of a Therapeutic 
Dose.  In both of these instances, the 
Investigator will consult with the Medical 
Monitor to determine the starting dose of 
levoketoconazole.  Subsequent dose increases 
to the subject’s previously established 
Therapeutic Dose or Maximally Tolerated Dose 
should not exceed 150 mg/day per occasion and 
should occur no more frequently than once 
every 2 weeks unless otherwise agreed with the 
Medical Monitor or designee. 
• Section 12.5.5 Table 4, deletion of third column 
(Flag)  
• Addition of footnote 16 to Appendix A to 
clarify subject diary dispensing at Screening 
Visit. 
• Addition of Dispense Drug to Appendix A. 
• Removal of reference to INR evaluations from 
Section 14.2. 
• Removal of the word ‘without’ from the last 
text box on the top line of the Recommended 
LFT Management Guidance in Appendix N. 




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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 Harmonization (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: An Open-Label Extension Study of Levoketoconazole (2S,4R-ketoconazole) in the 
Treatment of Endogenous Cushing’s Syndrome 
Study center(s): This is a multicenter study at approximately 50 sites in North America, Europe and the 
Middle East. 
Phase of development: Phase 3 
Objective:  
The objective of this study is to assess long-term safety and efficacy durability of levoketoconazole as 
chronic treatment for endogenous Cushing’s Syndrome (CS). 
Criteria for evaluation: 
When calculating changes from Baseline for efficacy evaluations, Baseline will be either or both of: 
• 
Open-label extension (OLE) study Baseline; 
• 
The original parent study COR-2012-01 [SONICS] or COR-2017-01 [LOGICS]) Baseline;  
With the choice of Baseline described in the Statistical Analysis Plan for each endpoint/analysis. 
Exploratory efficacy endpoints:  
• 
Proportions of subjects with mean urinary free cortisol (mUFC): 1) Less or equal to the upper limit 
of normal (ULN) of the reference range; 2) Above the ULN to 1.5X the ULN; and 3) Above 1.5X 
the ULN; 
• 
Changes from Baseline in markers of cortisol including mUFC and late night salivary cortisol 
(LNSC); 
• 
Proportion of subjects with LNSC above the ULN of the reference range; 
• 
Changes from Baseline in Clinical Signs and Symptoms of CS, health-related quality of life (QoL), 
and symptoms of depression; 
• 
Changes from Baseline in biomarkers of CS comorbidities (fasting blood glucose [FBG], fasting 
insulin, homeostatic model assessment-insulin resistance [HOMA-IR], hemoglobin A1c [HbA1c], 
blood pressure, total cholesterol, high-density lipoprotein-cholesterol [HDL-C], low-density 
lipoprotein-cholesterol [LDL-C], high-sensitivity C-reactive protein [hsCRP]); 
• 
Frequency of usage and changes from Baseline in frequency of usage of anti-diabetic, anti-
cholesterol and anti-hypertensive therapies; 
• 
Compliance (adherence) and persistence with therapy per tablet counts. 
Safety endpoints: 
Safety will be assessed by incidence and severity of Adverse Events (AEs), Serious Adverse Events (SAEs) 
and Adverse Events of Special Interest (AESIs) as well as by physical examinations, safety laboratory 
panels (including adrenocorticotrophic hormone [ACTH], liver function tests [LFTs], blood chemistry, 
hematology), electrocardiograms (ECGs) (to include assessment of the QTc interval), vital signs and 
pituitary Magnetic Resonance Imaging (MRI) for subjects with a history of a pituitary tumor. 


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Overall Design and Plan: This is a long-term, OLE study of levoketoconazole in subjects with 
endogenous CS who have completed one or both parent studies or otherwise potentially qualify for this 
study, as defined in the entry criteria. 
Long-term safety, tolerability, and efficacy data will be collected at intervals consistent with recognized 
standards of care.  
Subjects will remain on the previously established Therapeutic Dose of levoketoconazole that they were 
last receiving prior to entry into this OLE study unless a change in dose is medically indicated.  Certain 
subjects that were enrolled in Study COR-2017-01 when randomization was closed or subjects with a gap 
in treatment with levoketoconazole may require re-establishment or establishment of a Therapeutic Dose.  
As a result, dose titration may be required, and the Investigator will consult with the Medical Monitor to 
determine the starting dose of levoketoconazole.   Any planned dose increase of levoketoconazole above 
the previously established Therapeutic Dose will require the Medical Monitor’s prior approval and will 
require unplanned visits or additional evaluations to investigate the etiology underlying the need for higher 
dose levels.  If approved, dose increases will generally be made as 150 mg/day and no more frequently than 
once every 2 weeks, and will be accompanied by clinical examination and laboratory tests to assure and 
document safe use.  Dose decreases may be made as needed for reasons of safety or tolerability and will be 
documented but do not require prior Medical Monitor approval.  
The study comprises Screening and Baseline Visits followed by office visits every 3 months. Dose 
Adjustment/Safety Monitoring Visits will also be conducted in the event of a need for a dose increase of 
levoketoconazole during the study.  
Screening and Baseline Visits 
Subjects entering directly from a parent study: The visit schedule for this OLE study can overlap with those 
of the parent studies to ensure a smooth transition to the OLE study with no break in levoketoconazole 
usage.  
Extension Study COR-2017-OLE Visit:  
Screening 
Baseline 
Can overlap with 
 
 
Parent Study COR-2012-01 (SONICS) visit: 
Month 9 (M9) 
Month 12 (M12) 
Parent Study COR-2017-01 (LOGICS) visit: 
Restoration Phase Visit 1 
(RES1) 
Restoration Phase Visit 2 
(RES2) 
 
If necessary, the OLE Screening assessments may be conducted at a separate Screening Visit that must be 
completed approximately 3-4 weeks prior to the final visit of the parent study whenever feasible.  
If a subject is unable to have the OLE Baseline assessments performed at the final regularly scheduled visit 
of the parent study, the Screening and Baseline procedures may be performed at a separate Baseline Visit.  
In some cases, subjects may have a gap between completing a parent study and enrolling in this study that 
may in some cases involve a break in treatment.  For subjects who have completed a parent study within 6 
months, the Screening Phase will rely primarily on data collected during the parent study and completed 
with data collected in OPTICS.  In order for the Screening and Baseline visit to be combined, the ECG, 
LNSCs and LFTs must be obtained within 2 weeks of the Screening/Baseline visit and UFCs must be 
obtained within 6 weeks of the Screening/Baseline visit.   
Subjects entering this study following a break in therapy of greater than or equal to six months will 
undergo all Screening and Baseline procedures as outlined in Appendix A.   
 


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Regular Study Visits 
Regular visits should occur every 3 months (+/- 7 days) or more often as necessary for enhanced safety 
monitoring (e.g. if a dose increase is required). Some procedures, however, are required only every 6 
months, and MRIs are required annually and only for subjects with history of a pituitary tumor. The timings 
of each assessment are shown in the Time and Events Table (Appendix A). 
Number of subjects (planned): Up to 60 subjects are anticipated to be enrolled.  
Inclusion Criteria:  
To be eligible for participation in this study, subjects for whom the investigator believes long-term use of 
levoketoconazole may be beneficial must meet ONE of the following criteria:  
1. Completed the Extended Evaluation Phase of Study COR-2012-01 (i.e. M12).  
2. Completed the Restoration Phase of Study COR-2017-01 (i.e. RES2). 
NOTE: Subjects meeting criteria 1 or 2 above who have had a break in therapy may be eligible 
only after discussion with the Medical Monitor.  If eligible, such subjects may require re-
establishment of the Therapeutic Dose via titration.  All subjects who have had a break in 
therapy should be discussed with the Medical Monitor to determine the starting dose of 
levoketoconazole. Prior to resuming treatment with levoketoconazole, other therapies for 
Cushing’s syndrome must undergo an appropriate washout period, with minimum washout 
durations as follows: 
• 
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. 
3. Currently in a named patient program or other Expanded Access Program receiving 
levoketoconazole. 
4. Were levoketoconazole-naïve prior to entry and received early rescue therapy with open-label 
levoketoconazole in Study COR-2017-01. 
5. Achieved a clinically meaningful partial response (with reduction in UFC) in Study COR-2017-01 
at dose level 7 or at a maximally tolerated dose of levoketoconazole but did not meet the 
randomization criteria for Study COR-2017-01 at the end of the Dose Titration and Maintenance 
Phase when randomization was open. 
6. Were levoketoconazole-naïve prior to entry and were enrolled in Study COR-2017-01 in the Dose 
Titration and Maintenance Phase when randomization was closed.  (NOTE: Such subjects must 
receive at least 1 dose of levoketoconazole before transitioning to this study.) 
 
In addition, subjects must meet ALL the following criteria: 
1. Willing to participate and able 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. 
2. A female is eligible to enter and participate in the study if she is:  
3. Postmenopausal, defined as age 50 years 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) (NOTE:  laboratory values obtained during COR-2012-01 or COR-


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2017-01 protocol will be utilized). 
OR  
4. Surgically sterile—documented hysterectomy and/or bilateral oophorectomy or tubal ligation. 
OR 
5. Of child-bearing potential and agrees to use a highly effective method of birth control while 
participating in the study and for 30 days after the last dose of levoketoconazole. Abstinence is 
considered acceptable birth control if routinely practiced. 
Fertile men must also agree to use a highly effective method of birth control while participating in 
the study and for 90 days after the last dose of levoketoconazole. Abstinence is considered 
acceptable birth control if routinely practiced. 
6. Able to comprehend and comply with procedures. 
 
Exclusion Criteria: 
Subjects will not be eligible for participation in the study if ANY of the following criteria are met: 
1. Discontinued levoketoconazole while participating in Study COR-2012-01 or Study COR-2017-01 
or a named patient program or other Expanded Access program, due to safety or tolerability 
concerns or lack of efficacy. 
2. Pregnant, lactating or intend to conceive while receiving levoketoconazole. 
3. Have a medical condition or other circumstances that, in the opinion of the Investigator, might 
interfere with the subject’s participation or pose unacceptable risk to the subject. 
4. Scheduled for surgical treatment of CS or received surgical treatment of CS within the 6 weeks 
prior to Screening.  
5. Had non-CS major surgery within the 4 weeks prior to Screening. 
6. Treated with mitotane within 6 months prior to 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. QTc interval greater than 470 msec via central-reader interpretation during Screening. 
9. Clinically significant abnormality in 12-lead electrocardiogram (ECG) during Screening requiring 
medical intervention (may be eligible once stable, to be determined case by case). 
10. Clinical or radiological signs of compression of the optic chiasm newly apparent since enrolling in 
a parent study. 
11. Liver safety tests during the Screening Phase as follows:  
• 
ALT and/or AST above 3X ULN (NOTE: transaminase values up to 5X ULN may be allowed 
on an exceptional basis for subjects who have exhibited stable values for at least 3 months) 
• 
AP or TBN above 2X ULN. 
o Subjects with isolated indirect TBN up to 3X ULN that are presumed to have Gilbert’s 
syndrome may be enrolled if all other liver safety tests are within normal levels. 
12. Decreased renal function as defined by eGFR below 40 mL/min/1.73 m2, using MDRD equation 
for eGFR. 
13. Serum potassium below 3.9 mEq/L (may be supplemented to achieve 3.9 mEq/L or above). 
14. 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. 
15. Abused alcohol or drugs since enrolling in a parent study (in the Investigator’s opinion). 


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16. Currently participating in another study or has received any investigational treatment (drug, 
biological agent or device) other than levoketoconazole, within prior 30 days of the Screening visit 
or five half-lives of treatment, whichever is longer. 
17. 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).  [NOTE: A list 
of acceptable oral antacids will be provided; if used, antacids must be ingested at least 2 hours after 
dosing of levoketoconazole.] 
18. Current use of any prohibited concomitant medication that cannot be discontinued safely and 
washed out completely prior to the Baseline Visit, including but not limited to the following (a 
more complete list is included in Appendix I): 
• 
Drugs used to treat Cushing’s Syndrome; 
• 
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 yeast rice, 
danshen, Silybum marianum, Asian ginseng, Schissandra sphenanthera, shankhapushpi, and 
Asian herb mixture (Xiao chai hu tang and saiboku-to); 
• 
Topical or inhaled corticosteroids (other than low potency products to be discussed with 
Medical Monitor first); 
• 
Carbamazepine; 
• 
Drugs that pose unacceptable risk due to overlapping or exaggerated toxicities or 
pharmacological action due to presumed pharmacokinetics (PK) or pharmacodynamic (PD) 
interactions with levoketoconazole. 
Investigational product, dosage and mode of administration:  
Levoketoconazole (2S,4R-ketoconazole); 150-mg immediate release tablets for oral administration. Doses 
of levoketoconazole can range from a total daily dose of 150 mg up to 1200 mg. Levoketoconazole will be 
administered daily, approximately every 12 hours, per the individual Therapeutic Dose previously 
established for each eligible subject during the parent study or as subsequently modified. The minimum 
daily dose is 150 mg once a day for subjects who cannot tolerate 150 mg twice a day. Dose increases 
should not be more than 150 mg/day and should occur no more frequently than once every 2 weeks unless 
first approved by the Medical Monitor or the designee. 
Duration of treatment:  
There is no predefined completion timeframe for this OLE study, and interim analyses may be performed at 
the Sponsor’s discretion.  Subjects may continue receiving or discontinue levoketoconazole based on the 
medical judgement of the Investigator while the study remains open.  It is anticipated that subjects’ 
participation may continue for at least 3 years. 
Reference therapy, dosage and mode of administration:  
Not applicable. 
Analysis Population:  
Intent-to-Treat (ITT) Population: The ITT population will include all subjects who provide informed 
consent and receive at least one dose of levoketoconazole in this OLE study. This population will be used 
for the analyses of safety and efficacy. 
Statistical methods: 


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The overall strategy will be to evaluate the changes or shifts in the efficacy endpoints relative to the OLE 
and original parent study Baselines, as applicable.  All efficacy endpoints are considered exploratory.  
Results will also be compared between the two parent studies, as applicable.  Given that this is a single-arm 
OLE study with exploratory efficacy endpoints only, there is no formal hypothesis to be tested, and the 
sample size to be enrolled is not pre-determined.   
The primary analysis approach for the exploratory efficacy endpoints will be to calculate point estimates 
and construct two-sided 95% confidence intervals. P-values from statistical tests for significance will be 
calculated for descriptive purposes only. For continuous endpoints, the change from each of the two 
Baselines to each regular visit in the OLE study, including the final visit, will be calculated. The 95% 
confidence interval for the mean changes and corresponding p-values will be calculated using paired t-tests. 
For categorical endpoints, the shifts from each of the two Baselines to each regular visit in the OLE study, 
including the final visit, will be presented. The 95% confidence interval for differences in the paired 
proportions will be calculated using the adjusted Wald method, and the shifts will be evaluated for 
significance using McNemar’s test or Bowker test of symmetry. The mean changes from Baseline to each 
regular visit will be compared between the parent studies using unpaired t-test for continuous endpoints, 
and the proportions at each regular visit will be compared between the parent studies using Fisher’s Exact 
test for categorical endpoints. 
Interim analyses may be performed at the Sponsor’s discretion. 


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TABLE OF CONTENTS 
SPONSOR APPROVAL.................................................................................................................................. 7 
INVESTIGATOR AGREEMENT .................................................................................................................. 8 
PROTOCOL SYNOPSIS ................................................................................................................................ 9 
TABLE OF CONTENTS ............................................................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................. 19 
1 
INTRODUCTION ..................................................................................................................... 21 
1.1 BACKGROUND .................................................................................................................................... 21 
1.2 RATIONALE SUPPORTING LONG-TERM STUDY OF LEVOKETOCONAZOLE ............................................... 21 
2 
OBJECTIVES ........................................................................................................................... 22 
3 
ENDPOINTS ............................................................................................................................. 22 
3.1 CRITERIA FOR EVALUATION ................................................................................................................ 22 
3.2 SAFETY ENDPOINTS ............................................................................................................................ 23 
4 
STUDY DESIGN ....................................................................................................................... 23 
4.1 OVERALL DESIGN AND PLAN .............................................................................................................. 23 
4.2 RATIONALE FOR STUDY DESIGN .......................................................................................................... 24 
4.3 STUDY DURATION .............................................................................................................................. 24 
5 
SUBJECT SELECTION CRITERIA ....................................................................................... 24 
5.1 INCLUSION CRITERIA .......................................................................................................................... 24 
5.2 EXCLUSION CRITERIA ......................................................................................................................... 26 
6 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................... 28 
6.1 SUMMARY OF PROCEDURES BY VISIT .................................................................................................. 28 
6.1.1 
OLE Screening Visit .................................................................................................................. 29 
6.1.2 
OLE Baseline Visit .................................................................................................................... 29 
6.1.3 
Regular Study Visits .................................................................................................................. 30 
6.1.4 
Final Study Visit ....................................................................................................................... 30 
6.1.5 
Follow-up Call ......................................................................................................................... 30 
6.1.6 
Dose Adjustment/Safety Monitoring Visits ................................................................................. 30 
6.2 STUDY ASSESSMENTS ......................................................................................................................... 31 
6.2.1 
Physical Examination and Assessment of Clinical Signs and Symptoms of CS ............................ 31 
6.2.2 
Vital Signs ................................................................................................................................ 31 
6.2.3 
Spaulding 12-Lead Electrocardiograms (ECG) ......................................................................... 32 
6.2.3.1 
Procedures for Evaluating and Managing Prolonged QTc Interval Greater than 500 Msec or More than 60 
Msec Above Baseline ................................................................................................................................ 33 
6.2.4 
Clinical Laboratory Tests.......................................................................................................... 34 
6.2.5 
Disease-Related Assessments .................................................................................................... 34 
6.2.5.1 
24-Hour UFC ............................................................................................................................................ 35 
6.2.5.2 
Collection of Late Night Salivary Samples for Free Cortisol ....................................................................... 36 
6.2.5.3 
Morning Cortisol and Adrenocorticotrophic Hormone (ACTH) .................................................................. 36 
6.2.5.4 
Pituitary Magnetic Resonance Imaging (MRI) For Subjects with History of a Pituitary Tumor, Such as 
Cushing’s Disease [CD], Only ................................................................................................................... 37 
6.2.5.5 
Subject Diary ............................................................................................................................................ 37 
6.2.5.6 
Quality of Life and Psychometric Assessments .......................................................................................... 37 
6.2.6 
Situations Requiring Additional Safety Monitoring .................................................................... 37 
6.3 ADDITIONAL CONSIDERATIONS FOR RISK MANAGEMENT ..................................................................... 37 
6.3.1 
Instructions for Subjects ............................................................................................................ 37 
6.3.2 
Considerations for Investigator ................................................................................................. 38 
7 
LIFESTYLE AND DIETARY RESTRICTIONS ..................................................................... 38 


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7.1 PREVENTION OF PREGNANCY .............................................................................................................. 39 
7.2 ACTION TO BE TAKEN IF PREGNANCY OCCURS .................................................................................... 40 
8 
INVESTIGATIONAL PRODUCTS ......................................................................................... 41 
8.1 DESCRIPTION OF INVESTIGATIONAL PRODUCT ..................................................................................... 41 
8.2 DOSAGE AND ADMINISTRATION .......................................................................................................... 41 
8.3 BLINDING ........................................................................................................................................... 42 
9 
DRUG SUPPLIES, DISPENSING, STORAGE AND ACCOUNTING ................................... 42 
9.1 PRODUCT STORAGE ............................................................................................................................ 42 
9.2 PRODUCT ACCOUNTABILITY ............................................................................................................... 42 
9.3 DRUG SUPPLY AND RESUPPLY ............................................................................................................ 42 
9.4 COMPLIANCE ASSESSMENT ................................................................................................................. 42 
9.5 TREATMENT OF INVESTIGATIONAL PRODUCT OVERDOSE ..................................................................... 42 
10 
CONCOMITANT MEDICATIONS ......................................................................................... 43 
10.1 COMMON PERMITTED MEDICATIONS ................................................................................................... 43 
10.2 PROHIBITED MEDICATIONS ................................................................................................................. 43 
10.3 MEDICATIONS TO BE USED WITH CAUTION .......................................................................................... 44 
11 
SUBJECT COMPLETION AND WITHDRAWAL ................................................................. 45 
11.1 SUBJECT COMPLETION ........................................................................................................................ 45 
11.2 SUBJECT WITHDRAWAL CRITERIA AND PROCEDURES .......................................................................... 45 
12 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................................. 46 
12.1 POPULATION FOR ANALYSIS ............................................................................................................... 46 
12.2 HYPOTHESIS ....................................................................................................................................... 46 
12.3 SAMPLE SIZE DETERMINATION ........................................................................................................... 46 
12.4 GENERAL CONSIDERATION FOR DATA ANALYSIS ................................................................................. 46 
12.4.1 
Study Completion, Premature Withdrawal, and Missing Data .................................................... 46 
12.5 SAFETY ANALYSES ............................................................................................................................. 46 
12.5.1 
Extent of Exposure .................................................................................................................... 47 
12.5.2 
Adverse Events ......................................................................................................................... 47 
12.5.3 
Clinical Laboratory Evaluations ............................................................................................... 47 
12.5.4 
Vital Signs ................................................................................................................................ 48 
12.5.5 
Electrocardiograms (ECGs) and QTc Intervals ......................................................................... 48 
12.5.6 
Other Safety Measures .............................................................................................................. 49 
12.6 EFFICACY ANALYSES.......................................................................................................................... 49 
12.6.1 
UFC and LNSC Analyses .......................................................................................................... 49 
12.6.2 
Clinical Signs and Symptoms .................................................................................................... 50 
12.6.3 
Cushing’s Syndrome Quality of Life Questionnaire .................................................................... 50 
12.6.4 
Beck’s Depression Questionnaire .............................................................................................. 50 
12.6.5 
CS Comorbidity Biomarkers ...................................................................................................... 50 
12.6.6 
Usage of Anti-diabetic, Anti-cholesterol, and Anti-hypertensive Therapies ................................. 50 
12.6.7 
Compliance (Adherence) and Persistence with Therapy ............................................................. 50 
12.7 SUBGROUP ANALYSES ........................................................................................................................ 51 
13 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ............................... 51 
13.1 DEFINITION OF AN AE......................................................................................................................... 51 
13.2 DEFINITION OF A SAE ......................................................................................................................... 52 
13.2.1 
Disease-Related Events ............................................................................................................. 52 
13.2.2 
Adverse Events of Special Interest (AESI) .................................................................................. 53 
13.3 TIMING, FREQUENCY, AND METHOD OF DETECTING AES AND SAES .................................................... 53 
13.4 RECORDING OF AES AND SAES ........................................................................................................... 53 
13.5 EVALUATING AES AND SAES ............................................................................................................. 54 
13.5.1 
Severity Rating ......................................................................................................................... 54 


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13.5.2 
Relationship to Study Drug ....................................................................................................... 54 
13.6 FOLLOW-UP OF AESIS AND SAES ....................................................................................................... 55 
13.7 PROMPT REPORTING OF SAES AND AESIS TO SPONSOR ....................................................................... 55 
14 
ADVERSE EVENTS OF SPECIAL INTEREST (AESI): DEFINITIONS AND 
MANAGEMENT................................................................................................................ 56 
14.1 PERSISTENT QTC PROLONGATION: ...................................................................................................... 56 
14.1.1 
Temporarily Stopping Study Medication for Prolonged QTc and Considerations for Restarting . 56 
14.1.2 
Withdrawal due to QTc Interval Prolongation ........................................................................... 57 
14.2 HEPATIC ABNORMALITIES: ................................................................................................................. 57 
14.2.1 
Safety Monitoring and Dose Interruptions for Hepatic Abnormalities: ....................................... 58 
14.2.2 
Withdrawal due to Abnormal Liver Function Tests .................................................................... 59 
14.3 ADRENAL INSUFFICIENCY ................................................................................................................... 59 
14.3.1 
Safety Monitoring for Adrenal Insufficiency .............................................................................. 60 
15 
REFERENCES.......................................................................................................................... 61 
APPENDIX A 
TIME AND EVENTS SCHEDULE ................................................................................... 62 
APPENDIX B 
LABORATORY ANALYTES ........................................................................................... 65 
APPENDIX C 
STUDY MANAGEMENT AND MATERIALS ................................................................. 67 
APPENDIX D 
ADMINSTRATION AND REGULATORY POLICIES ................................................... 68 
APPENDIX E 
PUBLICATION POLICY .................................................................................................. 70 
APPENDIX F 
PROTOCOL AMENDMENT(S) ....................................................................................... 71 
APPENDIX G CRITERIA FOR DIAGNOSES OF PREDIABETES AND DIABETES .......................... 72 
APPENDIX H GUIDELINES FOR HYPERTENSION ............................................................................ 73 
APPENDIX I 
CONCOMITANT MEDICATIONS PROHIBITED OR TO BE USED ONLY WITH 
PRIOR PERMISSION ....................................................................................................... 74 
APPENDIX J 
SIGNS AND SYMPTOMS OF CONDITIONS TO BE CONSIDERED FOR RISK 
MANAGEMENT................................................................................................................ 82 
APPENDIX K QUALITY OF LIFE QUESTIONNAIRE ......................................................................... 83 
APPENDIX L 
ASSESSMENT OF CLINICAL SIGNS AND SYMPTOMS OF CUSHING’S 
SYNDROME ...................................................................................................................... 86 
APPENDIX M BECK DEPRESSION INVENTORY (BDI-II) .................................................................. 90 
APPENDIX N 
ADDITIONAL INFORMATION ON ADVERSE EVENTS OF SPECIAL INTEREST 
(QTC INTERVAL, INSTRUCTIONS FOR LIVER FUNCTION TEST 
ABNORMALITIES FOLLOW-UP AND ADRENAL INSUFFICIENCY) ...................... 92 
 
 
 
 
 


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TABLE OF TABLES 
Table 1 
Safety Monitoring Assessments and Timing Following Dose Increase 
 
  
29 
Table 2 
Expected Normal 24-Hour Creatinine Excretion from Adequate Urine Collections  
 
34 
Table 3  
Vital Sign Values of Clinical Importance  
 
 
 
 
 
46 
Table 4  
QTc Interval Values of Clinical Importance  
 
 
 
 
 
46 
Table 5 
Classification of Blood Pressure Levels for Adults Above 18 Years of Age   
 
71 
Table 6 
Recommendations for Follow-up Based on Initial Blood Pressure Measurements for Adults 
Without Acute End Organ Damage  
 
 
 
 
 
 
71 
Table 7 
Steroidogenesis Inhibitors and Systemic Corticosteroids  
 
 
 
 
72 
Table 8 
Dopamine Agonists  
 
 
 
 
 
 
 
 
73 
Table 9 
Synthetic Progestins that Bind with Moderate to High Affinity to Glucocorticoid receptor (GR) 
or Mineralocorticoid Receptor (MR)  
 
 
 
 
 
 
73 
Table 10 
Somatostatin Analogs   
 
 
 
 
 
 
 
73 
Table 11  Weight Loss Medications  
 
 
 
 
 
 
 
74 
Table 12  Drugs Predicted to Interfere with the Absorption of Levoketoconazole  
 
 
74 
Table 13  Drugs Whose Systemic Exposure is Predicted to be Significantly Increased by  
Levoketoconazole via CYP3A4 inhibition  
 
 
 
 
 
75 
 
Table 14 
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  
 
 
 
 
 
 
 
 
76 
Table 15 
Drugs that can Cause QTc Prolongation   
 
 
 
 
 
77 
Table 16  Drugs Whose Systemic Exposure is Predicted to be Increased Moderately by  
Levoketoconazole  
 
 
 
 
 
 
 
 
78 
Table 17  Topical or Inhaled Steroids  
 
 
 
 
 
 
 
78 
Table 18  Other Medications Contraindicated or Relatively Contraindicated with Ketoconazole  
79 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase 
βhCG 
Beta human chorionic gonadotropin 
BDI-II 
Beck Depression Inventory  
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CD 
Cushing’s disease 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CS 
Cushing´s syndrome 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DST 
Dexamethasone Suppression Test 
ECG 
Electrocardiogram/electrocardiograph 
eGFR 
Estimated glomerular filtration rate 
FBG 
Fasting blood glucose 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GR 
Glucocorticoid receptor 
HbA1c 
Hemoglobin A1C 
HDL-C 
High-density lipoprotein-cholesterol 
HOMA-IR 
Homeostatic model assessent – insulin resistance 
HR 
Heart rate 
hsCRP 
High-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational new drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LDH 
Lactic acid dehydrogenase 
LDL-C 
Low-density lipoprotein-cholesterol 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LNSC 
Late night salivary cortisol 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 


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MDRD 
Modified Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Mineralocorticoid receptor 
MRI 
Magnetic Resonance Imaging 
mUFC 
Mean Urinary Free Cortisol 
NCI CTCAE 
National Cancer Institute Common Terminology for Adverse Events  
OGTT 
Oral glucose tolerance test 
OLE 
Open-label extension 
PD 
Pharmacodynamic 
PK 
Pharmacokinetics 
PT 
Prothrombin time 
PTT 
Prothromboplastin time 
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 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SPM 
Study procedures manual 
TBN 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
UFC 
Urinary free cortisol  
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 


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1 
INTRODUCTION  
1.1 Background 
Levoketoconazole is currently being evaluated in two Phase 3 studies. Study COR-2012-
01 (also known as SONICS) is a single-arm, open-label, dose titration and maintenance 
study to assess efficacy, safety, tolerability, and pharmacokinetics (PK) of 
levoketoconazole in subjects with endogenous Cushing’s Syndrome (CS). Following 
initial Screening and washout periods, as applicable, SONICS comprises three treatment 
phases: a Dose Titration Phase to achieve an effective and tolerable maximum dose (i.e., 
the Therapeutic Dose) lasting approximately 2 to 21 weeks; a Maintenance Phase of 6 
months treatment at the Therapeutic Dose, and an Extended Evaluation Phase of 6 
months of continued treatment. Levoketoconazole is administered as 150 mg immediate 
release tablets for oral twice daily dosing; total daily dose is titrated in 150 mg 
increments from a starting dose of 300 mg up to a maximal daily dose of 1200 mg. 
Ninety-four (94) subjects were enrolled into the Dose Titration Phase of Study COR-
2012-01 with a goal of at least 70 subjects completing the 6-month Maintenance Phase.  
Study COR-2017-01 (also known as LOGICS) is a double-blind, randomized, placebo-
controlled withdrawal following single-arm, open-label levoketoconazole study to assess 
efficacy, safety, tolerability, and PK of levoketoconazole in subjects with endogenous 
CS. A blinded-treatment Restoration Phase is included for subjects who do not require 
early rescue and tolerate the 8-week blinded, randomized-withdrawal through to 
completion. Study methodology varies by cohort prior to randomization only. 
Approximately 35 subjects will be enrolled into the Randomized Withdrawal Phase of the 
study to provide at least 26 study completers (either completed all visits in the 
Randomized Withdrawal Phase or required early rescue).  
Please refer to the Investigator’s Brochure (IB) for a detailed description of all preclinical 
and clinical studies conducted with levoketoconazole. 
1.2 Rationale Supporting Long-term Study of Levoketoconazole 
As most medically treated CS patients receive life-long drug therapy, it is to the 
advantage of medical practice to obtain as much long-term data in the setting of a 
carefully monitored clinical trial setting as feasible.  Individual study subjects benefit 
directly via their participation.  Continued access to an investigational drug that appears 
to be working well is desirable, particularly when the few commercially available drugs 
for chronic treatment of CS have been used previously without satisfactory results, the 
situation of many subjects enrolled in the parent studies.  
The emerging safety profile of levoketoconazole supports its use in an open-label 
extension (OLE) study (OPTICS).  Aggregate safety data from Study COR-2012-01 has 
been reviewed systematically at 6-month intervals, by an independent Data Monitoring 
Committee (DMC). There have been no changes to the study design or conduct required 
based on DMC reviews. Accumulating adverse reaction information from Study COR-
2012-01, as described in the IB, is consistent with the safety profile gathered during the 
investigational use of levoketoconazole in patients with type 2 diabetes.  


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This proposed OLE study will be limited to subjects who have already demonstrated 
tolerability to levoketoconazole. Cortendo will provide levoketoconazole only to subjects 
who have:  completed Study COR-2012-01 (defined as those who complete the Extended 
Evaluation Phase) or Study COR-2017-01 (defined as those who complete the 
Restoration Phase; or who are rescued early with levoketoconazole); or who subsequently 
joined a named patient program or other Expanded Access Program; or who were 
receiving treatment in Study COR-2017-01 in the Dose Titration and Maintenance Phase 
when randomization to the double-blind Withdrawal Phase was closed. Therefore, all 
potentially eligible subjects will have been prior users of levoketoconazole.  Many 
subjects will have had experience using a prior-established safe and effective Therapeutic 
Dose (most will have been levoketoconazole users for over 1 year at time of entry into 
the current study).  Certain subjects that were enrolled in Study COR-2017-01 when 
randomization was closed or subjects with a gap in treatment with levoketoconazole may 
require re-establishment or establishment of a Therapeutic Dose.  As a result, dose 
titration may be required as outlined in Section 8.2. 
2 
OBJECTIVES 
The objective of this study is to assess long-term safety and efficacy durability of 
levoketoconazole as chronic treatment for endogenous CS. 
3 
ENDPOINTS 
3.1 Criteria for Evaluation  
When calculating changes from Baseline for efficacy evaluations, Baseline will be either 
or both of: 
• Open-label extension (OLE) study Baseline; 
• The original parent study COR-2012-01 [SONICS] or COR-2017-01 [LOGICS] 
Baseline; 
with the choice of Baseline described in the Statistical Analysis Plan for each endpoint 
analysis.   
Exploratory Efficacy Endpoints  
• Proportions of subjects with mean urinary free cortisol (mUFC): 1) Less or equal 
to the upper limit of normal (ULN) of the reference range; 2) Above the ULN to 
1.5X the ULN; and 3) Above 1.5X the ULN; 
• Changes from Baseline in markers of cortisol including mUFC and late night 
salivary cortisol (LNSC); 
• Proportion of subjects with LNSC above the ULN of the reference range; 
• Changes from Baseline in Clinical Signs and Symptoms of CS, health-related 
quality of life (QoL), and symptoms of depression; 
• Changes from Baseline in biomarkers of CS comorbidities (fasting blood glucose 
[FBG], fasting insulin, homeostatic model assessment-insulin resistance [HOMA-
IR], hemoglobin A1c [HbA1c], blood pressure, total cholesterol, high-density 


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lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C], 
high-sensitivity C-reactive protein [hsCRP]); 
• Frequency of usage and changes from Baseline in frequency of usage of anti-
diabetic, anti-cholesterol and anti-hypertensive therapies; 
• Compliance (adherence) and persistence with therapy per tablet counts. 
3.2 Safety Endpoints 
Safety will be assessed by incidence and severity of Adverse Events (AEs), Serious 
Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) as well as by 
physical examinations, safety laboratory panels (including Adrenocorticotropic Hormone 
[ACTH], liver function tests [LFTs], blood chemistry, hematology), electrocardiograms 
(ECGs) (to include assessment of the QTc interval), vital signs and pituitary Magnetic 
Resonance Imaging (MRI) for subjects with history of a pituitary tumor. 
4 
STUDY DESIGN 
4.1 Overall Design and Plan 
This is a long-term, OLE study of levoketoconazole in subjects with endogenous CS who 
have completed one or both parent studies or otherwise potentially qualify for this study, 
as defined in the Inclusion Criteria (Section 5.1):  
For subjects entering directly from parent studies, the visit schedule for this OLE study is 
designed to overlap with those of the parent studies to ensure a smooth transition to the 
OLE study with no break in drug supply for subjects as shown below.  
Extension Study COR-2017-OLE Visit 
Screening 
Baseline 
Can overlap with 
Parent Study COR-2012-01 (SONICS) visit: 
Parent Study COR-2017-01(LOGICS) visit: 
 
Month 9 (M9) 
Restoration Phase Visit 
1 (RES1) 
 
Month 12 (M12) 
Restoration Phase Visit 
2 (RES2) 
 
Subjects will remain on the previously established Therapeutic Dose of levoketoconazole 
that they were last receiving prior to entry in this OLE study.  
The study comprises Screening and Baseline Visits followed by visits every 3 months. 
Dose Adjustment/Safety Monitoring Visits will also be conducted in the event of a need 
for a dose increase of levoketoconazole during the study.  
Details of study assessments and procedures are provided in Section 6.  Details of AE 
monitoring are available in Section 13.5. The timings of assessments are shown in the 
Time and Events Table (Appendix A). 
Adequate medical coverage will be provided by the Investigator continuously during the 
study (including nights, weekends and holidays) to ensure that prompt safety decisions 
can be made and appropriate medical interventions provided.  The Investigator should 


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provide all subjects with instructions how to access the medical staff regardless of day 
and time to obtain medical care. 
 
4.2 Rationale for Study Design 
The chosen design has taken into consideration the reported experience treating subjects 
with CS with ketoconazole [Castinetti et al., 2014].  Like ketoconazole, dosing of 
levoketoconazole needs to be individualized, since therapeutic need varies considerably 
among subjects. As such, entry into the study is limited to subjects who have established 
a safe, tolerated and effective Therapeutic Dose of levoketoconazole in one of the two 
parent studies.  
Long-term safety and tolerability data will be collected at 3-month intervals, with 
efficacy measures also regularly assessed.  Details of safety and efficacy data collection 
and reporting in this study are provided in Section 6.  
If needed, dose increases of levoketoconazole are associated with enhanced monitoring 
and reporting requirements as summarized in Section 6.1.6. Dose increases must be 
approved by the Medical Monitor, and should not exceed 150 mg/day, and the dose 
should not be increased more frequently than every 2 weeks. 
Any SAEs and AESIs (i.e. adrenal insufficiency, persistent QT prolongation and potential 
hepatic events) require reporting within 24 hours as outlined in Section 13.7. All AEs, 
SAEs and AESIs are anticipated to be reported spontaneously, with inquiries by 
participating sites at least every 3 months at the clinic visits.  
4.3 Study Duration 
There is no predefined completion timeframe for this OLE study, and interim analyses 
may be performed at the Sponsor’s discretion.  Subjects may continue receiving or 
discontinue levoketoconazole based on the medical judgement of the Investigator while 
the study remains open.  It is anticipated that subjects’ participation may continue for at 
least 3 years. 
5 
SUBJECT SELECTION CRITERIA 
The Sponsor will review each subject’s enrollment criteria to ensure that subjects meet 
the eligibility criteria. 
5.1 Inclusion Criteria 
To be eligible for participation in this study subjects for whom the investigator believes 
long-term use of levoketoconazole may be beneficial must meet ONE of the following 
criteria:  
1. Completed the Extended Evaluation Phase of Study COR-2012-01 (i.e. M12). 
2. Completed the Restoration Phase of Study COR-2017-01 (i.e. RES2). 
NOTE:  Subjects meeting criteria 1 or 2 above who have had a break in therapy 
may be eligible only after discussion with the Medical Monitor.  If eligible, such 


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subjects may require re-establishment of the Therapeutic Dose via titration.  All 
subjects who have had a break in therapy should be discussed with the Medical 
Monitor to determine the starting dose of levoketoconazole. Prior to resuming 
treatment with levoketoconazole, other therapies for Cushing’s syndrome must 
undergo an appropriate washout period, with minimum durations as follows: 
• 
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. 
3. Currently in a named patient program or other Expanded Access Program receiving 
levoketoconazole. 
4. Were levoketoconazole-naïve prior to entry and received early rescue therapy with 
open-label levoketoconazole in Study COR-2017-01. 
5. Achieved a clinically meaningful partial response (with reduction in UFC) in Study 
COR-2017-01 at dose level 7 or at a maximally tolerated dose of levoketoconazole 
but did not meet the randomization criteria for Study COR-2017-01 at the end of the 
Dose Titration and Maintenance Phase when randomization was open. 
6. Were levoketoconazole-naïve prior to entry and were enrolled in Study COR-2017-01 
in the Dose Titration and Maintenance Phase when randomization was closed.  
(NOTE: Such subjects must receive at least 1 dose of levoketoconazole before 
transitioning to this study.) 
In addition, subjects must meet ALL the following criteria: 
1. Willing to participate and able 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. 
2. A female is eligible to enter and participate in the study if she is:  
• Postmenopausal, defined as age 50 years 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) (NOTE: 
laboratory values obtained during COR-2012-01 or COR-2017-01 protocol 
will be utilized). 
OR  


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• Surgically sterile with documented hysterectomy and/or bilateral 
oophorectomy or tubal ligation. 
OR  
• Of child-bearing potential and agrees to use a highly effective method of birth 
control, as defined in Section 7.1 of this protocol, while participating in the 
study and for 30 days after the last dose of levoketoconazole. Abstinence is 
considered acceptable birth control if routinely practiced. 
Fertile men must also agree to use a highly effective method of birth control, as 
defined in Section 7.1 of this protocol, while participating in the study and for 90 
days after the last dose of levoketoconazole. Abstinence is considered acceptable 
birth control if routinely practiced. 
3. Able to comprehend and comply with procedures. 
 
5.2 Exclusion Criteria 
Subjects will not be eligible for participation in the study if ANY of the following criteria 
are met:  
1. Discontinued levoketoconazole while participating in Study COR-2012-01 or Study 
COR-2017-01 or a named patient program or other Expanded Access program, due to 
safety or tolerability concerns or lack of efficacy. 
2. Pregnant, lactating or intend to conceive while receiving levoketoconazole. 
3. Have a medical condition or other circumstances that, in the opinion of the 
Investigator, might interfere with the subject’s participation or pose unacceptable risk 
to the subject. 
4. Scheduled for surgical for treatment of CS or received surgical treatment of CS 
within the 6 weeks prior to Screening.  
5. Had non-CS major surgery within 4 weeks prior to Screening. 
6. Treated with mitotane within 6 months prior to 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. QTc interval greater than 470 msec via central-reader interpretation during Screening. 
9. Clinically significant abnormality in 12-lead electrocardiogram (ECG) during the 
Screening requiring medical intervention (may be eligible once stable, to be 
determine case by case). 
10. Clinical or radiological signs of compression of the optic chiasm newly apparent 
since enrolling in a parent study. 
11. Liver safety tests during the Screening Phase as follows:  


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• ALT and/or AST above 3X ULN (NOTE: transaminase values up to 5X ULN 
may be allowed on an exceptional basis for subjects who have exhibited stable 
values for at least 3 months) 
• AP or TBN above 2X ULN. 
Subjects with isolated indirect TBN up to 3X ULN that are presumed to have 
Gilbert’s syndrome may be enrolled if all other liver safety tests are within normal 
levels. 
12. Decreased renal function as defined by eGFR below 40 mL/min/1.73 m2, using 
MDRD equation for eGFR. 
13. Serum potassium below 3.9 mEq/L (may be supplemented to achieve 3.9 mEq/L or 
above). 
14. 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. 
15. Abused alcohol or drugs since enrolling in a parent study (in the Investigator’s 
opinion). 
16. Currently participating in another study or has received any investigational treatment 
(drug, biological agent or device) other than levoketoconazole, within prior 30 days 
of the Screening visit or five half-lives of treatment, whichever is longer. 
17. 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).  [NOTE: A list of acceptable oral antacids will be provided; if used, 
antacids must be ingested at least 2 hours after dosing of levoketoconazole.] 
18. Current use of any prohibited concomitant medication that cannot be discontinued 
safely and washed out completely prior to the Baseline Visit, including but not 
limited to the following (a more complete list is included in Appendix I): 
• Drugs used to treat Cushing’s Syndrome; 
• 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 yeast rice, danshen, Silybum marianum, Asian ginseng, Schissandra 
sphenanthera, shankhapushpi, and Asian herb mixture (Xiao chai hu tang and 
Saiboku-to); 
• Topical or inhaled corticosteroids (other than low potency products to be 
discussed with Medical Monitor first); 
• Carbamazepine; 


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• Drugs that pose unacceptable risk due to overlapping or exaggerated toxicities 
or pharmacological action due to presumed PK or pharmacodynamic 
interactions with levoketoconazole. 
6 
STUDY ASSESSMENTS AND PROCEDURES 
All subjects must meet all inclusion criteria and none of the exclusion criteria prior 
to OLE study entry. A screen failure occurs when a signed informed consent is obtained 
but a subject fails to meet some or all eligibility criteria at the OLE Baseline or Screening 
Visits (if an exclusion criterion cannot be removed or an inclusion principle cannot be 
met).  
The exact timings of each assessment are provided in Appendix A.  Detailed procedures 
are provided in the study manuals.   
Throughout the study, subjects should be monitored and managed by the Investigator for 
diseases or conditions associated with CS or its treatment, per recommended guidelines 
for diagnosis and standard of care (refer to Appendix J for additional details on 
conditions potentially associated with levoketoconazole administration).  
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.  Such written instructions will be provided to Investigators for 
distribution to other medical care providers. 
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 standard of care, at 
the discretion of the Investigator. Changes to the medical conditions, history and 
medications and all other medical interventions will be documented in the 
Electronic Case Report Forms (eCRFs). 
6.1 
Summary of Procedures by Visit 
The visit schedule for this OLE study may overlap with those of the parent studies. This 
is to ensure a smooth transition to the OLE study and no break in drug supply for subjects 
transitioning from a parent study. Appendix A indicates the procedures and assessments 
that are required for each of the OLE study visits, including those overlapping with a 
parent study. Data collected from parent studies will be used in this OLE study and 
assessments that overlap should be performed once (e.g. data from vital signs may be 
recorded in an eCRF for the parent study and in an eCRF for this OLE study). 
Subjects who have completed a parent study and are currently receiving drug in a named 
patient program (or equivalent study e.g., individual subject IND) or other Expanded 
Access Program and are to be rolled over into this OLE study will also follow the visit 
schedule outlined below and in Appendix A.   


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6.1.1 OLE Screening Visit 
In addition to scheduled assessments conducted for the parent study (i.e., Visit M9 for 
Study COR-2012-01 or Visit RES1 for Study COR-2017-01) when there is an overlap of 
parent and OLE study visits, the following assessments will be performed at Screening 
for enrollment into this OLE study: 
• Informed consent: prior to any study procedures, all subjects must understand and 
sign the informed consent. 
• Review and confirmation of eligibility (inclusion/exclusion criteria).  NOTE: 
Assessments from the parent study will also be used to support eligibility 
assessment for this OLE study. 
For subjects whose parent study visits align with the OLE Screening and/or Baseline, 
Appendix A does not account for additional tests required as part of Study COR-2012-01 
or Study COR-2017-01. Refer to the parent study’s respective Time and Events Schedule 
to ensure all required tests are completed.  Subjects from an Expanded Access Program 
will have all tests conducted per Appendix A. 
In some cases, subjects may have a gap between completing a parent study and enrolling 
in this study that may in some cases involve a break in treatment.  For subjects who have 
completed a parent study within 6 months, the Screening Phase will rely primarily on 
data collected during the parent study and completed with data collected in OPTICS.  In 
order for the Screening and Baseline visit to be combined, the ECG, LNSCs and LFTs 
must be obtained within 2 weeks of the Screening/Baseline visit and UFCs must be 
obtained within 6 weeks of the Screening/Baseline visit.   
Subjects entering this study following a break in therapy of greater than or equal to six 
months will undergo all Screening and Baseline procedures as outlined in Appendix A. 
6.1.2 OLE Baseline Visit 
The Baseline Visit for the OLE study will usually occur on the same calendar day as the 
last treatment visit of the parent study (Appendix A). This visit will include a final 
assessment of subject qualifications for this OLE study, prior to treatment being 
dispensed. Subjects from an Expanded Access Program will have all assessments 
conducted per Appendix A. 
In addition to the scheduled assessments being conducted for the parent study at either 
M12 or RES2 (depending on the corresponding parent study), the following assessments 
will be performed at the Baseline Visit: 
• Reconfirm no changes in eligibility (inclusion/exclusion criteria) from OLE 
Screening Visit.  NOTE: Assessments from the parent study will also be used to 
support eligibility assessment for this OLE study.  
• Fasting insulin and hsCRP (For COR-2012-01 subjects only, as these assessments 
are not included in M12). 


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For subjects whose parent study visits align with OLE Screening and/or Baseline, 
Appendix A does not account for additional tests that need to be collected as part of 
Studies COR-2012-01 and COR-2017-01.  Refer to the parent study’s respective Time 
and Events Schedule to ensure all required tests are completed.  Also, for those 
assessments overlapping between the parent study’s corresponding visit to OLE Screen 
and/or Baseline the parent study’s material will be used.  Assessments not overlapping 
will be conducted using the materials from COR-2017-OLE.   
After eligibility is confirmed and the assessments shown in Appendix A are recorded, 
levoketoconazole will be dispensed for continued use. 
NOTE:  ECGs from the parent study will occur prior to taking the morning dose of 
levoketoconazole.  Following the first dose of drug in this study, another ECG will be 
performed 1-2 hours later.   
6.1.3 Regular Study Visits 
Regular visits are to occur every 3 months (+/- 7 days), or more often as necessary for 
enhanced safety monitoring (e.g. if a dose increase is required). Some procedures, 
however, are required only every 6 months, and MRIs are required annually and only for 
subjects with history of a pituitary tumor. The timings of each assessment are shown in 
Appendix A.  
6.1.4 Final Study Visit 
At a subject’s Final Study Visit, all procedures that occur every 3 months, every 6 
months, and annually, will be performed (as shown in Appendix A). 
6.1.5 Follow-up Call  
One week following the Final Study Visit, subjects will be contacted via telephone by the 
Investigator or designee.  The subject will be asked about any changes in their health 
since the Final Study Visit. 
6.1.6 Dose Adjustment/Safety Monitoring Visits 
In the event of a need for a dose increase of levoketoconazole during the study, regardless 
of dose level or prior treatment at that dose level, additional safety monitoring, as 
described in Table 1 and in Appendix A, is required in addition to all other assessments 
listed in Appendix A under Dose Adjustment/Safety Visits.  
NOTE: Doses should not be increased without permission of the Medical Monitor. 
Dose increases should not exceed 150 mg/day and the dose should not be increased 
more frequently than every 2 weeks. A careful history should be obtained to look for a 
precipitant of apparently decreased drug effectiveness (e.g. use of concomitant 
medication that interferes with levoketoconazole absorption). 
 
 


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Table 1 
Dose Adjustments/Safety Monitoring Assessments and Timing Following 
Dose Increase 
 
Any Dose Increase 
LFTs (AST, ALT, GGT, AP, LDH and total and 
direct bilirubin) 
Biweekly for 1 month (twice in total) unless total 
daily dose is greater than 600 mg, then weekly (4 
times for 1 month) 
12-lead ECG - To check for evidence of QTc 
prolongation 
1 to 2 hours after dosing at the new (higher) dose 
and again after 1 month 
Cortisol monitoring (e.g. UFCs, Serum Cortisol, 
Salivary Cortisol) 
Biweekly for 1 month (twice in total) 
Dose interruptions or decreases are allowed at any time the discretion of the Investigator 
without prior consultation in cases of intolerability or adverse effects, including excessive 
cortisol reduction (i.e. adrenal insufficiency) and will be reported to the Medical Monitor 
as soon as possible.   
A decrease of levoketoconazole requires additional reporting if it occurs as a reaction to 
an AESI associated with the use of levoketoconazole.   
6.2 Study Assessments 
6.2.1 Physical Examination and Assessment of Clinical Signs and Symptoms 
of CS 
Full physical examinations will be performed by a study physician or designee (e.g. a 
nurse practitioner or physician’s assistant) at the times indicated in Appendix A. The 
physical examinations will be inclusive of all body systems (except genitourinary and 
rectal) and should include height (cm) and weight (kg).  Body mass index will be derived 
based on data entered in the eCRF during the visit.  
At some visits, the examining physician will be asked to complete a questionnaire related 
to the assessment of Clinical Signs and Symptoms of CS (see Appendix L).  The results 
will be used to quantify changes in Clinical Signs and Symptoms of CS.   
6.2.2 Vital Signs 
Vital sign measurements will include temperature, sitting systolic blood pressure (SBP), 
sitting diastolic blood pressure (DBP) and heart rate (HR) at the OLE Baseline Visit and 
at each subsequent visit throughout the study (see Appendix A). Blood pressure and HR 
will be done in triplicate at each visit. 
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;  
• 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 
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• Subjects should void prior to the measurement and; 
• Blood pressure measurements will be made in triplicate over a minimum of 
approximately 10 minutes after the subject has rested in a sitting position for at 
least 10 minutes. The three measurements will be recorded individually in the 
eCRF and a mean value 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 the OLE 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 H. 
6.2.3 Spaulding 12-Lead Electrocardiograms (ECG) 
QTc interval prolongation is considered an important identified risk of levoketoconazole 
therapy (as discussed in the IB).  The mechanisms by which levoketoconazole may 
prolong the QTc interval are multiple and may include: direct hERG (IKr potassium 
channel) inhibition (observed in vitro), interference with metabolism of drugs that 
prolong the QTc (observed in vitro and in clinical studies), changes in adrenal hormone 
levels that lead to hypokalemia (theoretical) and induction of nausea (observed in clinical 
studies). 
The QTc interval is highly variable and readily influenced by exogenous factors.  For 
examples, food intake increases the QTc interval. Nausea, vomiting, upset stomach, 
dizziness and electrolyte abnormalities (especially relevant to this study, 
hypokalemia/hypomagnesemia) can also prolong the QTc interval.  Such factors should 
be avoided when possible (e.g. electrolytes should be replaced as needed to maintain 
serum levels well within the normal range) during QTc measurements and should be 
considered when interpreting QTc interval findings.     
In this study, ECG monitoring is being performed at the designated times shown 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 via central reading 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 on a local 
device or a device other than the Spaulding device supplied for this study and transmitted 
to Spaulding for central reading via printout.  A 12-lead ECG will be obtained within 
approximately 1 to 2 hours after drug administration (i.e., at approximately the peak 
plasma concentration of levoketoconazole) after the subject has rested in a supine 
position for at least 5 minutes and after the subject has not eaten for at least 2 hours 
(small snacks may be allowed for subjects with diabetes).  


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In general, QTc interval measurements are considered “normal” or “abnormal prolonged 
(clinically significant)” or “abnormal prolonged (not clinically significant)”.  If the QTc 
results have been identified as “abnormal prolonged”, whether it is deemed clinically 
significant or not, these results should be reported to the Sponsor’s designated safety 
group as an AESI (Section 14.1.1 and 14.1.2), appropriate action taken and the event 
recorded in the eCRF.  Other than the AESI for QTc interval prolongation, there is no 
additional formal reporting of ECG findings required for this study; however, clinically 
significant findings other than QTc prolongation should be reported as an AE, SAE or 
AESI, as applicable per definitions in Section13.5 and 14. 
NOTE: For subjects entering directly from Study COR-2012-01, the Spaulding device 
previously used in the parent study is not planned for use in this OLE study. However, it 
is acceptable to use the prior device for the OLE Screening and/or Baseline Visit. 
Additional information for assessment of QTc interval is available in Appendix N. 
6.2.3.1 
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 I).  If such a drug is identified, it should be stopped 
immediately.  
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 
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• 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 at a minimum magnesium, calcium and potassium. 
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 (i.e. 4 mEq/L 
or higher). 
o If electrolytes are normal and no other cause can be identified to account for 
the absolute QTc interval above 500 msec, 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, should be considered an AE and be recorded in the eCRF.  
6.2.4 Clinical Laboratory Tests 
Clinical laboratory testing should, at a minimum, be conducted at the times indicated in 
Appendix A. As noted in Section 6.1.6, subjects require more frequent (biweekly or 
weekly) monitoring of liver function in the month following an increase in dose during 
the OLE study.  Clinically significant changes in laboratory analyte values should be 
reported as an AE, SAE or AESI, as applicable per definitions in Section 14. 
A complete list of all the analytes is provided in Appendix B.  
All testing will be conducted in the morning following a 12-hour fast (small snacks may 
be allowed for subjects with diabetes; any food intake should be recorded in the subject 
source documents for reference) unless indicated otherwise in the laboratory manual.  
Routinely scheduled laboratory tests will be assayed at the study’s central laboratory. 
6.2.5 Disease-Related Assessments 
Cortisol will be routinely assessed throughout the study.   
Cortisol assessments will be used to monitor durability of the therapeutic effect of 
levoketoconazole and for evidence that might suggest increased risk of adrenal 


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insufficiency.  If the clinical status requires a dose increase of levoketoconazole, cortisol 
levels should be monitored biweekly for 1 month (Section 6.1.6).  
NOTE: The clinical diagnosis of adrenal insufficiency (for which guidance is provided in 
Section 14.3 should be reported as an AESI. 
6.2.5.1  24-Hour UFC 
24-hour urine collections for determination of UFC are needed for drawing reliable 
efficacy inferences from this study.  Subjects should be fully informed prior to initiating 
procedures that they will be asked to collect 24-hour urine samples at regular intervals 
throughout the study, possibly including during work days and holidays. 
Please see the SPM and the Laboratory Manual for details on urine collection procedures.  
Note that, lifestyle and dietary restrictions listed in Section 7 state 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 provided containers. The parent study’s materials will be used 
for all tests that overlap with this OLE study. Three adequate 24-hour urine collections 
for UFC will occur at every visit indicated in Appendix A, except if subject’s OLE 
Baseline Visit overlaps with M12 (as part of COR-2012-01), then 2 collections will be 
collected. 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 should be repeated; the rationale for repeat 
collections should be captured in the eCRFs.  
Urine collections will ideally begin enough in advance of a visit to allow discussion of 
the results at the visit (i.e. usually 7-14 days prior) if being delivered by courier.  
Collections can also be delivered by the subject between visits personally. Careful 
instructions must be provided to the subject for proper urine collection and cold-storage 
of samples until delivery.  All supplies (i.e. waterproof pen, urine jugs, urine hats and 
labels) 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 


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be between 400 and 4000 mL/day.  Expected values for normal 24-hour creatinine 
excretion rates for subjects up to age 70 years are provided in Table 2. 
 
Table 2 
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 values 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 values reported in Table 2 [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 the collection. 
Urinary Free Cortisol Sample Analysis 
UFC levels from the 24-hour urine collections will be assayed at a central laboratory per 
validated methodology using high pressure liquid chromatography tandem mass 
spectroscopy.  
6.2.5.2 Collection of Late Night Salivary Samples for Free Cortisol 
LNSC samples from 2 nights will be collected by each subject at the times indicated in 
Appendix A.  Saliva collections must be done between 11 PM and midnight and 
following the dietary restrictions listed in Section 7.  Subjects should not sleep and 
subsequently awaken within 2 hours of collecting the saliva sample.  
All samples will be analyzed at a central laboratory.  Details for collection and handling 
of samples are provided in the SPM and laboratory manual. 
6.2.5.3 Morning Cortisol and Adrenocorticotrophic Hormone (ACTH) 
Morning serum cortisol (untimed) will be measured in all subjects every 3 months and at 
Dose Adjustment/Safety Monitoring Visits in the event of a need for a dose increase of 
levoketoconazole during the study.  ACTH levels will be measured in all subjects every 6 
months and at Dose Adjustment/Safety Monitoring Visits, as listed in Appendix A. 


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6.2.5.4 
Pituitary Magnetic Resonance Imaging (MRI) For Subjects with 
History of a Pituitary Tumor, Such as Cushing’s Disease [CD], 
Only 
Pituitary MRIs will be obtained for all subjects with history of a pituitary tumor, 
including those with CD, at the OLE Baseline Visit (if not previously done within the last 
6 months).  The scheduled interval between MRIs should be one every 12 (± 2) months.  
The main purpose is to assess tumor size, which will be measured by a central 
neuroradiologist. 
6.2.5.5 
Subject Diary 
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.  Subjects will be instructed to bring the completed diary to each regular 
study visit at which time a new diary will be dispensed. 
6.2.5.6 
Quality of Life and Psychometric Assessments 
The Cushing QoL questionnaire [Webb 2008] [Appendix K] and the Beck Depression 
Inventory (BDI-II) [Appendix M] instrument will be administered at the times indicated 
in Appendix A. 
6.2.6 Situations Requiring Additional Safety Monitoring 
Additional safety monitoring will be required for AESIs outlined in Section 14.  The list 
is not intended to be an all-inclusive list of situations that could prompt additional safety 
monitoring. 
Dose Increases 
If a dose increase is required, additional safety monitoring is required (Section 6.1.6).  
Dose increases (regardless of dose level or prior treatment at the higher dose level) 
should be reported on the eCRF along with the rationale for dose increase.  
6.3 Additional Considerations for Risk Management 
6.3.1 Instructions for Subjects 
Subjects will be instructed to carry a card or other identifier (e.g. bracelet or pendant) 
always 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 of an AE.  Clear instructions should be provided to the subject on how to 
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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. Subjects must be 
instructed on the proper use of the emergency glucocorticoid. 
6.3.2 Considerations for Investigator 
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 G for testing 
recommendations. 
• Hypertension: See Appendix H for guidelines for classification of blood pressure 
levels and follow-up recommendations.  
• Hypocortisolemia: See Appendix J for evaluations of signs and symptoms. 
• Hypomineralocorticoidism: See Appendix J for evaluations of signs and 
symptoms. 
• Hypogonadism: See Appendix J 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 J).  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 Section 14.3 for management of adrenal insufficiency. 
 
7 
LIFESTYLE AND DIETARY RESTRICTIONS 
Subjects must follow these lifestyle and dietary restrictions throughout the study. 
• Levoketoconazole should usually be taken at approximately the same times each 
day, and for the most consistent day-to-day absorption, should be ingested with 
the same types of liquids and/or foods each day (see Section 8.2). 
• Consumption of grapefruit, lime juice and Seville oranges (aka sour orange, 
bigarade orange, or marmalade orange) and its products should be limited to once 
weekly owing to potential drug interactions with levoketoconazole that may 
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• Genuine licorice (not the same as licorice-flavored candy) should be limited to 
once weekly due to its mineralocorticoid effects; 
• Consumption of excessive alcohol should be avoided (note: there is no known 
safe amount in relation to use of levoketoconazole); 
• Subjects should not smoke or exercise for at least 30 minutes before blood 
pressure measurements; and 
• Subjects should not eat for at least 2 hours prior to ECG. 
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; and 
o Use of medicines or other products containing corticosteroids, whether 
administered topically (e.g. drops, creams), inhaled, or ingested.  
• 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; and 
 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; and 
 Smoking cigarettes, pipe, cigar or any other substance. 
 
Information on each subject’s sleeping hours will be collected. 
 
7.1 Prevention of Pregnancy 
Regardless of menopausal status, all female participants must have a negative pregnancy 
test at study visits indicated in Appendix A. Urine beta human chorionic gonadotropin 
(βhCG) will be assayed on site. Definition of postmenopausal is found in the Inclusion 
Criteria (Section 5.1) 
Women of child-bearing potential must agree to use a highly effective method of birth 
control, as defined below, while participating in the study and for 30 days after last dose 
of levoketoconazole. 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  


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• Implant of levonorgestrol 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; 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 acceptable 
form of contraception if routinely practiced. 
Fertile men must also agree to use a highly effective method of birth control as defined 
above, while participating in the study and for 90 days after the last dose of 
levoketoconazole.  Abstinence is considered acceptable birth control if routinely 
practiced. 
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.  
7.2 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 pregnancy 
informed consent form (ICF) must be signed if a male subject's female partner becomes 
pregnant. This ICF is to allow for pregnancy and outcome information to be collected. 
The Investigator will record pregnancy information on the appropriate form and submit it 
to the Medical Monitor 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 Medical Monitor. However, Investigators are not obligated to seek such 
information proactively from former study participants. 


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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 bottles. Refer to the 
Pharmacy Manual for details of labeling of the investigational product. 
8.2 Dosage and Administration 
Subjects will receive an adequate amount of the investigational product at each visit, 
starting at the Baseline 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 in relationship to dosing, 
which can affect gastric acid, or the type of beverage routinely ingested during 
establishment of the Therapeutic Dose, is not recommended, as doing so might lead to 
excessive variability in levoketoconazole blood levels and thus a changed response to 
therapy. 
Doses of levoketoconazole can range from a total daily dose of 150 mg up to 1200 mg.  
Levoketoconazole will be administered daily, approximately every 12 hours, per the 
individual Therapeutic Dose previously established for each eligible subject during the 
parent study or as subsequently modified. The minimum daily dose is 150 mg once a day 
for subjects who cannot tolerate 150 mg twice a day.  
Increases of dose are allowed, but only after consultation with and approval by the 
Medical Monitor, and are accompanied by enhanced safety monitoring, as per the Dose 
Adjustment/Safety Monitoring Visits in Appendix A and Section 6.1.6.  Dose increases 
should not exceed 150 mg/day per occasion and should occur no more frequently than 
once every 2 weeks unless first discussed with the Medical Monitor or designee.  Dose 
increases should be recorded on the eCRF.  Dose interruptions or decreases are allowed 
at any time at the discretion of the Investigator without prior consultation in cases of 
intolerability or adverse effects, including excessive cortisol reduction (i.e. adrenal 
insufficiency) and will be reported to the Medical Monitor as soon as possible.   
For subjects that have had a gap in treatment with levoketoconazole prior to entry in 
COR-2017-OLE, re-establishment or establishment of a subject’s Therapeutic Dose at the 
baseline visit may be necessary and, as a result, dose titration may be required.  Subjects 
that were in the Dose Titration and Maintenance Phase of Study COR-2017-01 when 
randomization was closed may also require establishment of a Therapeutic Dose.  In both 
of these instances, the Investigator will consult with the Medical Monitor to determine 
the starting dose of levoketoconazole.  Subsequent dose increases to the subject’s 
previously established Therapeutic Dose or Maximally Tolerated Dose should not exceed 
150 mg/day per occasion and should occur no more frequently than once every 2 weeks 
unless otherwise agreed with the Medical Monitor or designee. 


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8.3 Blinding 
Not applicable. 
9 
DRUG SUPPLIES, DISPENSING, STORAGE AND ACCOUNTING 
9.1 Product Storage 
Levoketoconazole should be stored at 20°C to 25°C (68°F to 77°F). Avoid excessive 
exposure to light or humidity.  Records of the actual storage conditions during the period 
of study must be maintained (i.e. Records of the date, time and initials of the person 
checking, daily temperature or continuous temperature recordings, or regularly 
maintained temperature alarm systems used in conjunction with temperature records).  
Daily temperature monitoring and documentation are required to confirm no temperature 
excursions have occurred. 
9.2 Product Accountability 
Levoketoconazole is considered an Investigational Drug Product for purposes of this 
OLE study, regardless of its marketing approval status.  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 Sponsor designee (when applicable), the amount supplied and/or 
administered to and returned by subjects, if applicable.  
9.3  Drug Supply and Resupply 
Please refer to the Pharmacy Manual for details of drug supply, dispensing, 
accountability, reconciliation and destruction or return. 
9.4  Compliance Assessment 
Subjects should bring all empty medication bottles and unused medication with them to 
all visits except for additional Dose Adjustment/Safety Monitoring Visits (where empty 
medication bottles and unused medication will not be collected and accountability will 
not be performed).  Accountability to determine treatment compliance will be performed 
at all other in-clinic visits. 
9.5 Treatment of Investigational Product Overdose 
There is no known direct antidote to levoketoconazole once absorbed.  However, if a 
large overdose of 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).  


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10 CONCOMITANT MEDICATIONS 
10.1 Common Permitted Medications 
For management of dyslipidemia, pravastatin, fluvastatin, pitavastatin and rosuvastatin 
are the only allowed “statins”. 
For management of hypokalemia, slow-release potassium supplements are encouraged.  
Maintenance of serum potassium levels within the normal range and above 4.0 mEq/L 
may reduce the risk of drug-induced QTc prolongation. 
Most medications used to treat type 2 diabetes mellitus are allowed.  Metformin is 
allowed, although its levels might be increased by levoketoconazole.  Routine monitoring 
of glucose and kidney 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 country-specific list will be 
provided. 
Most commonly used treatments for osteopenia or osteoporosis—excluding certain 
hormonal treatments—are allowed.  Calcium supplements should be taken at least 
2 hours after ingesting study medication, as they may interfere with levoketoconazole 
absorption via antacid effects. 
All medications should be scrutinized at the OLE Screening Visit, using Appendix I as a 
guide and with help from the Medical Monitor if needed.  Medication additions or 
switches after the OLE Screening Visit should be kept to a minimum and should likewise 
prompt a check against Appendix I, 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, 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 I.  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, Appendix I, Table 12; 
• Statins other than pravastatin, fluvastatin, pitavastatin and rosuvastatin (Appendix 
I, Table 13); 
• Carbamazepine (Appendix I, Table 14); 


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• Steroidogenesis inhibitors or dopamine agonists (interference with study drug 
assessment, Appendix I, Table 7 and Table 8); 
• Megestrol acetate or medroxyprogesterone acetate and selected other synthetic 
progestins (see Appendix I, Table 9) [Schindler 2003]; 
• Any other drug treatments used to lower cortisol in CS that are subject to washout 
(Appendix I, Table 10) are prohibited throughout the study; 
• Weight loss medications, either prescription or over the counter (Appendix I, 
Table 11); 
• Drugs whose systemic exposure is potentially increased significantly by 
concomitant use of levoketoconazole (Appendix I, Table 13); 
• Drugs that pose unacceptable risk due to overlapping or exaggerated toxicities or 
pharmacological action due to presumed PK or pharmacodynamic interactions 
with levoketoconazole (Appendix I). 
• 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 I, Table 14);  
• Medications resulting in QTc prolongation as a direct effect or as a result of 
interaction with levoketoconazole, examples include: cisapride, dofetilide, 
pimozide, and quinidine. (Appendix I, Table 13 and Table 15).  However, in 
selected cases where no alternative medications are available, permission from the 
Medical Monitor may be sought; 
• Topical or inhaled corticosteroid preparations, except for low potency 
preparations (interference with study drug assessment, Appendix I, Table 17);  
• The following herbal medicines: St John’s Wort (Appendix I, Table 14), 
echinacea, gingko, goldenseal, yohimbe, red yeast rice (Appendix I, Table 18), 
danshen, Silybum marianum, Asian ginseng, Schissandra sphenanthera, 
shankhapushpi, and Asian herb mixture (Xiao chai hu tang and Saiboku-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 I, Table 18).  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 I, Table 16). 


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11 SUBJECT COMPLETION AND WITHDRAWAL 
11.1 Subject Completion 
There is no specific completion timeframe for this OLE study.  Subjects may continue 
receiving or discontinue levoketoconazole based on the medical judgement of the 
Investigator until the study is closed.   
11.2 Subject Withdrawal Criteria and Procedures 
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 or lost to follow-up; 
• Safety reasons, as stipulated in Section 13 and 14 either at the discretion of the 
Investigator or at the subject’s request; 
• Protocol violations at the discretion of the Sponsor; 
• Plan to receive or need concomitant therapy that could interfere with the safety of 
the subject including, but not limited to use of prohibited medications (Section 
10.2 and Appendix I),  
• Use of any other medications to treat CS or CD due to the lack of data on the 
safety of levoketoconazole used in combination with other CS medications, or 
• Subjects scheduled for surgery or radiotherapy for treatment of their CS or CD 
should be withdrawn and such subjects should be transitioned to an alternative 
medication if necessary.  
All study withdrawals and their causes must be documented, to include the specific 
reason(s) prompting withdrawal, by the Investigator on the eCRF, and, if need be, on the 
SAE form, AESI form and/or AE eCRF. The reason for withdrawal will be entered in the 
eCRF. 
If the subject chooses to withdraw or is otherwise withdrawn from the study, the 
Investigator should make every attempt to have the subject return to the clinic to 
complete safety assessments as outlined for the Final Visit in Appendix A.  All data 
gathered on the subject prior to termination will be made available to the Sponsor.  
All safety data pertaining to a causally related AE, SAE or AESI associated with study 
withdrawal must be provided to the Sponsor.  All AEs should be followed until resolution 
or a minimum of 30 days after the last dose of levoketoconazole.  
 


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12 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
12.1 Population for Analysis 
Intent-to-treat (ITT) Population: The ITT population will include all subjects who 
provide informed consent and receive at least one dose of levoketoconazole in this OLE 
study. This population will be used for the analyses of safety and efficacy. 
12.2 Hypothesis 
There is no formal hypothesis to be tested in this OLE study. 
12.3 Sample Size Determination 
Given that this is a single-arm OLE study with exploratory efficacy endpoints only, there 
is no formal hypothesis to be tested, and the sample size to be enrolled is not pre-
determined.   
12.4 General Consideration 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) will be summarized using the number of observations (n) 
and percentage in each category.   
Data summaries will be presented for all subjects combined and, where appropriate, by 
dose group (i.e., the previously established Therapeutic Dose that subjects were last 
receiving prior to entry to this OLE study) as well. 
For the purposes of analyzing changes or shifts from Baseline, whether for safety or 
efficacy evaluations, two Baselines will be used, namely, the OLE study Baseline and the 
original (i.e., parent) study Baseline, as applicable. 
All data used in analyses and/or collected during the study will be provided in listings. 
A more detailed description of the planned summaries and analyses of the data collected 
in this OLE study will be provided in the Statistical Analysis Plan (SAP). 
12.4.1 Study Completion, Premature Withdrawal, and Missing Data 
Subject completion status and subject withdrawals, as described in Section 11.1 and 11.2 
will be summarized.  
In general, missing data will not be replaced or imputed for the main analyses of the 
exploratory efficacy endpoints and safety endpoints. Imputation may be performed for 
some endpoints as part of supportive or sensitivity analyses. Details of such imputations 
will be described in the SAP. 
12.5 Safety Analyses 
Ongoing AEs/AESIs/SAEs that first occurred during a parent study will continue to be 
reported in the parent study eCRF until resolution.  An AE/AESI/SAE that worsens 


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during the OLE will be reported using the OLE study process.   Only new treatment-
emergent adverse events (TEAEs) including AEs, AESIs and SAEs that first occurred 
during the OLE study are to be reported using the OLE study process).  
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 analyses may include the worsening of any TEAEs relative to the original parent 
study and relative to the OLE Baseline.  The effect of cumulative dose and 
levoketoconazole treatment exposure may be evaluated as risk factors for increased AE 
incidence and severity.  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.   
12.5.1 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. 
The occurrence and timing of dose discontinuations as well as dose increases will be 
displayed in a listing. Reasons for discontinuation and dose increases will also be 
reported in the listing. 
12.5.2 Adverse Events 
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].  
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%) will also be reported.   
TEAE summaries will include frequency by levoketoconazole dose and all doses and 
relative onset time of TEAEs (e.g., by visit, by study days).  Additional summaries and 
listings will be created to explore TEAE signals over time. 
12.5.3 Clinical Laboratory Evaluations 
A laboratory value (from LFTs, blood chemistry, hematology, urinalysis) that is within 
the central laboratory’s normal range will be considered normal.  A laboratory value that 
is outside the central laboratory’s normal range will be considered an abnormal value.  
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.   


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12.5.4 Vital Signs 
HR, SBP and DBP will be measured in triplicate 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 for each measurement at each visit will be summarized.  In 
addition, values of clinical importance (Table 3) will be identified in the data listings.   
Table 3 
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) 
12.5.5 Electrocardiograms (ECGs) and QTc Intervals 
Summary ECGs, based on the measurement of ECGs as described in Section 6.2.3 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 
will be summarized descriptively by dose and time point.  ECG results will be available 
to the Investigator shortly after being obtained and all ECGs will be reviewed by a central 
reading by Spaulding who will provide an “over-reading” that will serve as the definitive 
study value.  While on study treatment, a QTcF above 500 msec or above 60 msec above 
OLE Baseline will be an AESI (See Section 14.1). 
Categorical changes from Baseline (increases only) and QTc values from each visit will 
be summarized by worst change and by visit and by dose of levoketoconazole. The 
clinically important categories (Table 4) of actual and change values will be tabulated 
and provided as listings.  
Table 4. 
QTc Interval Values of Potential Clinical Importance 
QTc Interval 
Criteria (msec) 
Increase from Baseline 
<30 
 
30-60 
 
above 60 
 
 
Actual Value 
451-480 
 
481-500 
 
above 500 


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12.5.6 Other Safety Measures 
All other safety laboratory measures (e.g. morning serum cortisol, ACTH) will be listed 
by subject and time point and descriptively summarized, including changes from Baseline 
by dose of levoketoconazole.  
Changes in the size of pituitary tumor (in millimeters largest diameter and/or estimated 
volume), if estimable, from Baseline will be summarized descriptively.   
Clinically significant physical examination findings after the first dose of 
levoketoconazole in the OLE study will be reported as AEs by the Investigators.  All 
physical examination findings will be listed. 
12.6 Efficacy Analyses 
The overall strategy for the efficacy analyses will be to evaluate the changes or shifts in 
the efficacy endpoints relative to the OLE and original parent study Baselines, as 
applicable. All efficacy endpoints are considered exploratory. Results will also be 
compared between the two parent studies, as applicable. The primary analysis approach 
will be to calculate point estimates and construct two-sided 95% confidence intervals. P-
values from statistical tests for significance will be calculated for descriptive purposes 
only. For continuous endpoints, the change from each of the two Baselines to each 
regular visit in the OLE study, including the final visit, will be calculated. The 95% 
confidence interval for the mean change and corresponding p-value will be calculated 
using paired t-test. For categorical endpoints, the shifts from each of the two Baselines to 
each regular visit in the OLE study, including the final visit, will be presented. The 95% 
confidence interval for the difference in the paired proportions will be calculated using 
the adjusted Wald method, and the shifts will be evaluated for significance using 
McNemar’s test or Bowker test of symmetry. The mean changes from Baseline to each 
regular visit will be compared between the parent studies using unpaired t-test for 
continuous endpoints, and the proportions at each regular visit will be compared between 
the parent studies using Fisher’s Exact test for categorical endpoints. 
12.6.1 UFC and LNSC Analyses 
The number and proportion of subjects with mean UFC (mUFC) and LNSC less or equal 
to the ULN will be summarized at each visit. In addition, the numbers and proportions of 
subjects with mUFC above the ULN to 1.5X the ULN and above will be summarized at 
each visit.  Shifts from Baseline will be evaluated using McNemar’s test or Bowker test 
of symmetry. 
Changes in UFC and LNSC from Baseline 
The mUFC will be calculated from adequate 24-hour urine collections only.  The mUFC 
will be calculated only if there are at least two adequate samples.  The mUFC from the 
collections at each visit will be used in the analysis of UFC unless only one adequate 
sample is available, in which case the single sample will substitute for the mUFC. 
The mUFC will be summarized by time point using descriptive statistics and displayed 
over time.  Paired t-tests will be performed for the change from Baseline to each nominal 
visit.  


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12.6.2 Clinical Signs and Symptoms 
Individual clinical signs and symptoms, defined in Appendix L, will be summarized at 
each time point for assessment by number and percent of subjects.  For signs and 
symptoms other than acne, hirsutism and edema, each sign and symptom present at 
Baseline will be graded on a 0 to 3 severity scale (0=none, 1=mild, 2=moderate, 
3=severe), and the severities reported at each visit will be added to derive a total score. 
Total severity score and changes from Baseline of the severity total score will be 
presented by visit. Acne, hirsutism, and edema scores will be calculated as per their 
respective instrument-derived instructions, and results will be summarized at each visit, 
including changes from Baseline. 
A paired t-test will be used to test if there is a significant change in severity at each visit.  
In addition, shift tables in individual clinical signs and symptoms at each visit will be 
created to demonstrate any changes during the course of treatment and will be analyzed 
using McNemar’s test or Bowker test of symmetry. 
12.6.3 Cushing’s Syndrome Quality of Life Questionnaire  
QoL (Appendix K) measures and changes from Baseline will be summarized by time 
point using descriptive statistics and analyzed using a paired t-test.   
12.6.4 Beck’s Depression Questionnaire 
Changes from Baseline for the Beck’s Depression questionnaire (Appendix M) will be 
summarized by time point using descriptive statistics and analyzed using a paired t-test. 
12.6.5 CS Comorbidity Biomarkers 
The changes from Baseline and percentage changes from Baseline in individual 
biochemical markers of CS comorbidities (FBG, fasting insulin and HOMA-IR, HbA1c, 
blood pressure, total cholesterol, HDL-C, LDL-C, and high-sensitivity CRP) will be 
summarized by time point using descriptive statistics and the changes from Baseline will 
be analyzed using a paired t-test.  In addition, shifts from Baseline (with regards to 
laboratory normal range) in individual biochemical markers of CS comorbidities will be 
analyzed using Bowker test of symmetry at each scheduled visit.   
12.6.6 Usage of Anti-diabetic, Anti-cholesterol, and Anti-hypertensive 
Therapies  
The number and proportion of usage of each medication class of interest 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 
time point. The proportions with dose increases and decreases, including new and 
discontinued medications will be displayed. 
12.6.7 Compliance (Adherence) and Persistence with Therapy 
Study drug compliance between visits and cumulative study drug compliance will be 
calculated by dividing the number of study drug tablets used (total number dispensed 


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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.  Study drug compliance will be 
summarized. Persistence with therapy will be assessed by the number and proportion of 
subjects who complete 1, 2, and 3 years of treatment in this OLE study, with at least 80% 
compliance with study drug. 
 
12.7 Subgroup Analyses 
Subgroup analyses for selected exploratory efficacy endpoints and safety endpoints will 
be performed for a minimum subgroup size of at least 15 subjects. The subgroups of 
interest will include, but not be limited to, subgroups based on diagnosis of CD, prior 
therapy for CS, hypertension at Baseline, and prediabetes or diabetes at Baseline. Details 
will be presented in the SAP. 
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.  
• A laboratory abnormality worsening or newly occurring after the start of the study 
(i.e., after the OLE Baseline Visit) that results in subject withdrawal from the study or 
medical treatment or further follow-up. 


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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 as 
a result 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 judgement 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. 
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. 


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13.2.2 Adverse Events of Special Interest (AESI) 
Adverse Events of Special Interest are defined in Section 14. 
AESIs should be reported to the Sponsor’s designated safety group with 24 hours as 
per Section 13.7 regardless of seriousness or causality. Upon receipt, these AEs will be 
captured in the safety database and targeted follow-up queries will be sent to sites. 
13.3 Timing, Frequency, and Method of Detecting 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?"  
Ongoing AEs/AESIs/SAEs that first occurred during a parent study will continue to be 
reported in the parent study eCRF until resolution. An AE/AESI/SAE that worsens 
during the OLE will be reported using the OLE study process.  In addition, any new AEs, 
AESIs and SAEs that first occurred during the OLE study (after subject completes parent 
study) are to be reported using the OLE study process. All new 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. Resolution of AEs should be 
documented to include the date of resolution and any interventions made. Changes in 
intensity or frequency of AEs should be recorded as separate AEs (i.e., a new event 
record started). 
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 AEs page(s) of the eCRF. 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 presumed cause of the event (if not 
thought to be study drug related) must be recorded in the AEs section of the eCRF. AEs 
believed to be possibly related to study drug must be followed until event resolution or a 
minimum of 30 days after the last dose of levoketoconazole. 


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13.5 Evaluating AEs and SAEs 
13.5.1 Severity Rating 
The severity of AEs and SAEs will be graded per NCI CTCAE, Version 4.03.  
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 that is assessed as severe should not be confused with an SAE. An event is 
defined as ‘serious’ when it meets one of the predefined outcomes as described in Section 
13.2 “Definition of a SAE”. 
13.5.2 Relationship to Study Drug 
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 AE). 
• Unlikely: There is no reasonable association between the study treatment and the 
suspected event, and a precipitant of the AE 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. 


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• 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 AESIs and SAEs 
After the initial AESI/SAE report, the Investigator is required to follow the event status 
actively. Further information on SAEs should 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 on SAEs should also be recorded on the “SAE” eCRF within 
24 hours. 
13.7 Prompt Reporting of SAEs and AESIs 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 AESIs (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 13.7). 
During both business and non-business hours, the email address listed below should be 
used to report SAEs and AESIs. 
 Reportable Events Hotline 
Email: GlobalSAEInbox@Chiltern.com 
 
An SAE Report form must be completed and forwarded via email to the Sponsor’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 the Sponsor’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 the Sponsor’s designated safety group will also ensure that the appropriate IRBs/ 
IECs are notified of the SAE. 


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14 
ADVERSE EVENTS OF SPECIAL INTEREST (AESI): 
DEFINITIONS AND MANAGEMENT 
An AESI is defined as 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.   
The AESIs for this study are defined in the sections that follow along with instructions 
for the management of AESIs. 
14.1 
Persistent QTc Prolongation:  
Persistent elevation of the QTc interval is defined as absolute QTc interval above 500 
msec (or above 60 msec above the OLE Baseline), with an ECG evaluation on repeat 
determination continuing to demonstrate QTc prolongation in the absence of plausible 
alternative explanations. 
Determination of persistent and confirmed QTc prolongation 
To decide whether a QTc prolongation is persistent and likely to be related to 
levoketoconazole, QTc will be evaluated via central reading of the ECG by Spaulding. 
The Investigator should consider alternative possibilities as causative or contributory to 
QTc prolongation prior to discontinuation of levoketoconazole, including concomitant 
medications that may result in prolongation of the QTc interval either directly or through 
interference with the metabolism of levoketoconazole, recent food ingestion (temporary 
QTc elevation), and electrolyte abnormalities (particularly serum calcium, magnesium 
and potassium). Interfering concomitant medications with QT prolongation potential are 
contraindicated in co-administration with levoketoconazole and must be stopped (Section 
10.2). Please see Appendix N for guidance on the assessment of apparent QTc interval 
prolongation. Regardless of seriousness or causality, instances of persistent QTc 
prolongation should be reported to the Sponsor’s designated safety group within 24 hours 
from the time the persistent prolongation has been confirmed, in the same manner as 
SAEs (see Section 13.7).  
In the event QTc prolongation occurs additional safety monitoring is required, including 
medical observation of the subject until the QTc interval has returned to a value less than 
or equal to 500 msec.  
Additional evaluation of the subject will include the potential requirement for additional 
ECGs and laboratory assessments (see Appendix N).  Cases of persistent, confirmed QTc 
prolongation as described above should be reported to Sponsor’s designated safety group 
as AESIs (Section 13.7). 
14.1.1 Temporarily Stopping Study Medication for Prolonged QTc and 
Considerations for Restarting 
If the subject is receiving doses greater than 150 mg/day, persistent and presumed study 
medication-related QTc changes may be managed by temporarily withholding study 
medication if deemed necessary.  Note that a prolonged QTc interval that is less than 500 


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msec may not always warrant temporary medication stoppage, depending on patient-
specific clinical factors, e.g. if the QTc does not exceed normal reference values (ULN 
for men is 440 msec and for women is 460 msec).    
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 to monitor. 
Temporarily withheld study medication for QTc prolongation may be resumed using the 
prior regimen, after confirmed QTc correction.  However, unless an etiology other than 
study drug has been implicated, QTc prolongation reoccurrence above 500 msec will 
usually result in permanent study medication discontinuation and study withdrawal unless 
the dose can be lowered permanently (see Section 14.1.2). 
14.1.2 Withdrawal due to QTc Interval Prolongation 
If a persistent and confirmed levoketoconazole-related QTc interval prolongation above 
500 msec as defined in Section 6.2.3 is identified, the Investigator should attempt to 
manage such QTc prolongations by temporarily stopping study medication followed by 
dose reduction if doing so does not eliminate the benefits of treatment.  If therapeutic 
benefit cannot be maintained following dose reduction for drug-induced QTc 
prolongation above 500 msec, study medication should be stopped permanently and the 
subject should be withdrawn. 
If a persistent and confirmed levoketoconazole-related QTc interval prolongation above 
500 msec is observed at the lowest levoketoconazole dose (150 mg/day), administration 
of levoketoconazole should stop permanently and the subject should be withdrawn.  
Persistent, confirmed levoketoconazole-related QTc interval prolongation that represents 
an increase greater than 60 msec from baseline but that may not be of sufficient duration 
to cause concern of arrhythmias (e.g. less than 440 msec in men or less than 460 msec in 
women), depending on other clinical factors (e.g. recalcitrant hypokalemia) need not be 
managed with dosage reduction or result in withdrawal. 
Additional information for QTc Interval is available in Appendix N. 
14.2 Hepatic Abnormalities:  
Signs and/or symptoms indicative of hepatic dysfunction or injury, including 
asymptomatic but clinically relevant abnormalities of LFTs, should be reported as an AE, 
AESI, or SAE, as applicable.  Events meeting the below criteria should always be 
reported as either an AESI or SAE, as applicable, and should prompt temporary (or 
permanent—see below) study medication interruption: 
• 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 TBN above 2X ULN not explained by any other 
cause such as viral hepatitis; 


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• 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, or 
• 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 TBN above 2X ULN in 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 TBN. 
Please see Appendix N for guidance on the assessment of abnormal LFTs and Section 
14.2.1 for monitoring abnormal LFTs 
14.2.1 Safety Monitoring and Dose Interruptions for Hepatic Abnormalities: 
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.   
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 TBN, 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.   
The need for levoketoconazole interruption will be influenced by the Baseline 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 too 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 TBN 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 on serial measurements and in the absence of clinical signs or symptoms, the ALT 
and/or AST continue to rise and do not meet the criteria for immediate treatment 
interruption, subjects may continue levoketoconazole without interruption.   
If abnormally elevated liver safety tests return to the subject’s OLE 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 N).   
Rechallenge with Study Medication 
If levoketoconazole dosing has been interrupted and liver safety tests normalize, subjects 
may be rechallenged (i.e. restarted on medication at prior or lower dose) at the discretion 


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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 recheck 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. 
14.2.2 Withdrawal due to Abnormal Liver Function Tests 
Any event qualifying as an AESI or SAE as per Section 14.2 may prompt consideration 
of study withdrawal.  However, Section 14.2.1 describes monitoring and management 
procedures that may be followed in lieu of withdrawing from medication permanently, as 
the clinical condition warrants. 
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 TBN, or if abnormal 
liver safety test studies are accompanied by clinical signs or symptoms referable to liver 
injury, the study medication must be stopped immediately.  In nearly all such cases, study 
medication should not be restarted owing to the heightened risk of liver injury, and the 
subject will discontinue from the study and be followed until resolution or normalization 
of the laboratory abnormality that resulted in the withdrawal. 
If other clinically significant LFT elevations persist beyond 4 weeks after interruption of 
therapy or demonstrate a trend of worsening following interruption, then the subject 
should be withdrawn from the study. The subject should continue to be followed after 
withdrawal until resolution or normalization of the laboratory abnormality that resulted in 
the withdrawal. 
More detailed information on evaluation of LFTs is available in Appendix N.  
14.3 Adrenal Insufficiency  
It is well recognized that subjects with a good response to treatment for CS resulting in 
decreased, but not low, cortisol concentrations may exhibit signs and symptoms of 
adrenal insufficiency (not life-threatening) which may not be different than those of acute 
adrenal crisis, which is a life-threatening event warranting immediate medical 
intervention.  Discrimination between the two may not be readily evident by history or 
physical examination.  Furthermore, subjects may have adrenal insufficiency without 
abnormal cortisol concentrations, but the cortisol concentrations, while within or above 
the normal range, are 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.  


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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. 
14.3.1 Safety Monitoring for Adrenal Insufficiency 
Subjects with suspected adrenal insufficiency should be assessed for signs and symptoms 
of adrenal insufficiency and cortisol levels as described above.   
Should adrenal insufficiency be deemed present or probable, study drug should be 
temporarily discontinued for mild symptoms/signs.  For moderate or severe 
symptoms/signs, study drug should be temporarily discontinued and rescue 
glucocorticoids administered as indicated.  Study drug at the same or an appropriately 
lower dose may be restarted once the medical situation is deemed sufficiently resolved by 
the Investigator.  Cases of suspected adrenal insufficiency should be reported to 
Sponsor’s designated safety group as AESIs (Section 13.7). 
If the dose associated with adrenal insufficiency is the lowest 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. 
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 and (if 
possible) morning serum cortisol.  Laboratory evidence of hypoadrenalism is 
defined as morning serum cortisol level less than 3 μg/dL ([LLN] or the lower 
limit of the assay being used for clinical testing).  Even if serum cortisol and/or 
24-hour UFC are within the normal range, the possibility of adrenal insufficiency 
should be considered, based on other clinical signs and symptoms.  Please see 
Appendix J for a list of clinical signs and symptoms; 
• Full review of systems; 
• Lying and standing blood pressure measurements and pulse to evaluate postural 
changes; 
• Random glucose and electrolytes; 
All cases of suspected adrenal insufficiency, whether deemed to be drug-related or not, 
should be reported as AESIs to the Sponsor/CRO (Section 13.7). 
 


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15 REFERENCES 
American Diabetes Association: Classification and Diagnosis of Diabetes. American 
Diabetes Association. Sec. 2. In Standards of Medical Care in Diabetes—2016. Diabetes 
Care 2016;39(Suppl. 1): S13-S22. 
Brodovicz, KG, McNaughtan K, Uemura N, Meininger G, Girman CJ, Yale SH. 
Reliability and Feasibility of Methods to Quantitatively Assess Peripheral Edema. Clin 
Med Res 2009;7(1/2):21-31 
Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing's disease: is it worth a 
try? J Clin Endocrinol Metab. 2014;99:1623-1630. 
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 
Hatch R, Rosenfield RL, Kim MH, Tredway D. Hirsutism: implications, etiology, and 
management. Am J Obstet Gynecol. 1981;140:815-830. 
The Seventh Report of the Joint National Committee on Prevention, Detection, 
Evaluation, and Treatment of High Blood Pressure (JNC 7)—Complete Report. August 
2004. 
Ketoconazole HRA Assessment Report. September 25, 2014. Committee for Medicinal 
Products for Human Use. EMA/CHMP/534845/2014. 
Macfarlane PW, Devine B, Clark E.  The University of Glasgow (Uni-G) ECG Analysis 
Program.  Computers in Cardiology 2005;32:451-454. 
National Cancer Institute. Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 4.03. June 14, 2010 available at 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf /  
Petersenn S, Newell-Price J, Finding JW, Gus F, Maldonado M, et al. High variability in 
Baseline urinary free cortisol values in patients with Cushing’s disease. Clin Endocrinol. 
2013; 0: 1-9. 
Schindler AE, Campagnoli C, Druckmann R, Humber J, Pasqualini JR, Schweppe KW, 
Thijssen JHH. Classification and pharmacology of progestins. Maturitas. 2003; 46S1: S7-
S16. 
Webb SM, Badia X, Barahona MJ, et al. Evaluation of health-related quality of life in 
patients with Cushing’s syndrome with a new questionnaire. Eur J Endocrinol 
2008;158;623-30. 
 
 


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APPENDIX A 
TIME AND EVENTS SCHEDULE 
Refer to the Section 6 (Study Assessments and Procedures) and the Study Procedures Manual for more specific details on the assessments. 
Assessments 
Screening 
Baseline 
Every 
3 Months 
(± 7 Days) 
Every 
6 Months (or 
12 Months if 
indicated) 
(± 10 Days)11, 
13 
Dose 
Adjustment / 
Safety 
Monitoring 
Visit12,14 
Final Study 
Visit 
Safety 
Follow-Up 
Call15 
COR-2012-01 Visit Alignment1,2 
M9 
M12 
 
 
 
 
 
COR-2017-01 Visit Alignment1,2 
RES1 
RES2 
 
 
 
 
 
Expanded Access Program  
Screening & Baseline should occur 
within 3-4 weeks of each other 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility Check  
X 
X 
 
 
 
 
 
Prior/concomitant Medications 
X3 
X3 
X 
 
X 
X 
 
Pregnancy Test (urine βhCG), females 
X3 
X3 
X 
 
X 
X 
 
Adverse Events 
X3 
X3 
X 
 
X 
X 
X 
ECG (central read) 4 
X3 
X3 
X 
 
X 
X 
 
Vital Signs (temperature, BP, heart rate) 5  
 
X3 
X 
 
X 
X 
 
Body weight/height/BMI (derived) 
 
X3 
X 
 
X 
X 
 
Physical Examination 
 
X3 
 
X 
 
X 
 
CS Signs and Symptoms 
 
X3 
 
X 
 
X 
 
Safety Laboratory Tests (including 
hematology, chemistry, LFTs, urine dipstick)6  
X3 
X3 
X 
 
X 
X 
 
Serum Cortisol (am)  
 
X3 
X 
 
X 
X 
 
Late Night Salivary Cortisol (2 nights) 
 
X3, 7 
X 
 
X 
X 
 
ACTH 
 
X3 
 
X 
X 
X 
 
24-h UFC (2-3 collections)8 
 
X3 
 
X 
X 
X 
 
CS Biomarkers FBG, fasting insulin, HOMA-
IR, HbA1C, total cholesterol, HDL-C, LDL-
C, hsCRP 
 
X9 
 
X 
 
X 
 
Pituitary MRI (pituitary tumor patients only) 
 
(X) 10 
 
  X10, 13 
 
X 
 


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Assessments 
Screening 
Baseline 
Every 
3 Months 
(± 7 Days) 
Every 
6 Months (or 
12 Months if 
indicated) 
(± 10 Days)11, 
13 
Dose 
Adjustment / 
Safety 
Monitoring 
Visit12,14 
Final Study 
Visit 
Safety 
Follow-Up 
Call15 
Cushing QoL questionnaire 
 
X3 
 
X 
 
X 
 
BDI-II instrument 
 
X3 
 
X 
 
X 
 
Subject Diary 
X16 
X 
X 
 
X 
 
 
Dispense drug 
 
X 
X 
 
 
 
 
Administer drug and/or drug accountability 
 
X 
X 
 
X 
X 
 
  
 
` 
1 
Procedures performed during the listed parent study visits should not be repeated for the OLE. Rather the OLE will make use of data already captured for 
these parent study visits.  The informed consent and eligibility check may occur on a date that is different from the parent study clinic visit, if this is 
completed > 1 month prior to the anticipated date for the end of treatment on the parent study. 
2 
This Time and Events Schedule does not account for additional tests that need to be collected as part of COR-2012-01 or COR-2017-01, for subjects whose 
parent study visits align with OLE Screening and/or Baseline. Refer to parent study’s respective Time and Events Schedule. 
3 
Assessment overlaps with parent study.  
4 
12-lead ECGs should be obtained prior to first dose of drug as a Baseline and every 3 months (or after dose increases) after enrollment. ECGs should be 
obtained within approximately 1 to 2 hours after drug administration and after the subject has rested in a supine position for at least 5 minutes after the 
subject has not eaten for at least 2 hours. NOTE: For subjects entering from Study COR-2012-01 the Spaulding device previously used in the parent study is 
not planned for use in this OLE study. However, it is acceptable to use the prior device for the OLE Screening and/or Baseline Visit. 
5 
BP and heart rate will be done in triplicate. 
6 
If urine dipstick is positive for protein and ketones, send urinalysis to the lab for assessment. 
7 
Ensure that 2 collections are done immediately prior to Baseline and results are available 
8 
Three collections of 24-hr UFC will occur at every visit marked in the Time and Events Schedule, except for if a subject’s OLE Baseline Visit overlaps with 
M12 (as part of COR-2012-01), then 2 collections will be collected. 
9 
hsCRP and fasting insulin are not assessed in COR-2012-01 but are assessed in this OLE study, in addition to performing the parent study’s assessments 
(including CRP) if M12 aligns with OLE Baseline, Investigators would also conduct a hsCRP and fasting insulin assessment at Baseline. 
10 If not done within 6 months of the OLE Baseline Visit.  
11   Assessments listed here are in addition to those done every 3 months. 
12 Dose Adjustment/Safety Monitoring Visits will be conducted in accordance with the requirements specified in Section 6.1.6.  
13 Annually (the scheduled interval between MRIs should be once every 12 (± 2) months). 


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14 Liver Function tests (AST, ALT, GGT, AP, LDH, total and direct bilirubin) to be done biweekly for 1 month (twice in total) unless total daily dose is greater 
than 600 mg, then weekly (4 times for 1 month), 12-lead ECG (to check for evidence of QTc prolongation) to be conducted 1 to 2 hours after dosing at the 
new (higher) dose and again after 1 month and cortisol monitoring (e.g. UFCs, Serum Cortisol, Salivary Cortisol) biweekly for 1 month (twice in total). 
15 Safety Follow-Up Call to be conducted 1 week following the Final Study Visit 
16 To be dispensed for subjects entering from Expanded Access Program or for those that had a gap in treatment with levoketoconazole 
 


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APPENDIX B 
LABORATORY ANALYTES 
Laboratory studies to be collected as per Time and Events Schedule (Appendix A).  Other 
analytes may be required to follow-up certain abnormalities.  While the central laboratory 
will be used for most analytes, in some cases additional studies may be assayed at a local 
laboratory, for example, when a rapid result is needed; prior discussion with the Medical 
Monitor is suggested.  For example, AESIs and SAEs indicative of liver injury will 
usually require additional laboratory tests that will need to be sent to the central 
laboratory in addition to the local laboratory. 
 
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 
Albumin 
Creatinine 
Total Protein 
Glucose, fasting 
 
Sodium 
Liver Function Tests (LFTs) 
Potassium 
AST (SGOT) 
Chloride 
ALT (SGPT) 
Total CO2 
GGT 
Calcium, Magnesium, Phosphate 
Alkaline phosphatase 
Uric Acid 
Total and direct bilirubin 
 
LDH 
 
Other analytes/measures 
Urine dipstick: if positive for protein or ketones, send urinalysis to central laboratory for 
assessment 
Pregnancy test (urine βHCG, women only) 
Disease-related Assessments 
Urinary free cortisol, total creatinine and total volume from 24-hour urine collections 
Salivary cortisol 
Serum cortisol 
ACTH 
 
 
 


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CS Biomarkers 
 
Fasting blood glucose [FBG] 
Fasting Insulin 
Hemoglobin A1c [HbA1c] 
 
High-sensitivity C-reactive protein [hsCRP] 
Total cholesterol 
High-density lipoprotein-cholesterol [HDL-C] 
Low-density lipoprotein-cholesterol [LDL-C] 
 
 
 
   
 


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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 eCRFs 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 eCRFs 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 years following the date that 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 years after the investigation is discontinued and the Food and Drug 
Administration (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 eCRFs 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, 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 and applicable data protection 
regulations in the countries concerned. 
Institutional Review/Ethical Review 
The protocol and ICF for this study must be approved by an IRB/IEC. A copy of the 
Letter of Approval from the Board/Committee, which contains specific identification of 


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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 
situations, 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/or 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 ICFs. 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, 
Archiving of Study Documentation).  
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—particularly impact on study design and conduct and 
experience with the study as determined by enrollment of subjects—with rights of final 
authorship decisions to be held by Cortendo, unless superseded by an agreement 
stipulating otherwise.  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 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 
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 standards for the diagnosis of prediabetes consider 
three different categories of prediabetes, based on measures 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, as follows: 
Prediabetes is defined by a fasting glucose of ≥ 100 mg/dL (5.6 mmol/L) and less than 
126 mg/dL (7.0 mmol/L) (after no caloric intake for ≥ 8 hours and in the absence of 
antihyperglycemic medications).  
Diabetes Is Diagnosed by One of the Following Criteria: 
1. A fasting glucose of ≥ 126 mg/dL (7.0 mmol/L) after no caloric intake for ≥ 8 hours 
  
 
 
 
OR 
2. 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 
3. 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 
4. A1C ≥ 6.5% (48 mmol/mol). The test should be performed in a laboratory using a 
method that is National Glycohemoglobin Standardization Program-certified and 
standardized to the Diabetes Control and Complications Trial 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 H 
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 5 
Classification of Blood Pressure Levels for Adults Above 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 6 
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 year c 
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. above 
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 I 
CONCOMITANT MEDICATIONS PROHIBITED OR 
TO BE USED ONLY WITH PRIOR PERMISSION 
Table 7 through Table 15 provide examples of drugs that are PROHIBITED for 
concomitant use in COR-2017-OLE. Table 16 through Table 18 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. 
A. Prohibited concomitant medications 
Table 7 
Steroidogenesis Inhibitors and Systemic Corticosteroids  
Interfere with study drug assessment; must be avoided or washed out prior to Baseline 
Visit 
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 
 
 


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Table 8 
Dopamine Agonists  
Interfere 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) 
 
Table 9 
Synthetic Progestins that Bind with Moderate to High Affinity1 to 
Glucocorticoid Receptor (GR) or Mineralocorticoid Receptor (MR)  
Interfere with study drug assessment and/or influence underlying signs/symptoms of 
disease; must be avoided or washed out 
Medroxyprogesterone acetate  
Megestrol acetate  
Micronized progesterone 
Segesterone (nesterone) acetate 
Drospirenone 
Gestodene 
 
Table 10 
Somatostatin Analogs  
Interfere with study drug assessment and/or influence underlying signs/symptoms of 
disease; must be avoided 
Octreotide (all forms) 
Lanreotide (all forms) 
Pasireotide (all forms) 
 
                                               
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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Table 11 
Weight Loss Medications  
Interfere with endpoints assessment; must be avoided or washed out 
Amfepramone 
Diethylpropion 
Orlistat 
Benzphetamine 
Ephedrine 
Phendimetrazine 
Bupropion/naltrexone 
Etilamfetamine 
Phentermine 
Buproprion 
Fenfluramine 
Rimonabant 
Cathine 
Lorcaserin 
Sibutramine 
Clobenzorex 
Mazindol 
Topiramate 
Dexfenfluramine 
Mefenorex 
 
 
Table 12 
Drugs Predicted to Interfere with the Absorption of Levoketoconazole  
Must be avoided; use an allowed substitute or washout 
Histamine H2-receptor antagonists: 
Sucralfate, cimetidine, famotidine, nizatidine, ranitidine, 
 
Proton-pump inhibitors: dexlansoprazole, esomeprazole, 
lansoprazole, omeprazole, pantoprazole, rabeprazole 
 
 
 
 


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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 13). 
• 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 14). 
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 
judgement of the Medical Monitor or delegate: 
https://mor.nlm.nih.gov/RxNav/search?searchBy=String&searchTerm=ketoconazole 
 
Table 13 
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 14 
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 15 
Drugs that can Cause QTc Prolongation  
Must be avoided, unless no acceptable alternative is available; permission prior to use is 
required 
Alfuzosin 
Eliglustat  
Perphenazine 
Amiodarone 
Erythromycin 
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 
Disopyramide 
Mirtazapine 
Tolterodine 
Dolasetron  
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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B. Concomitant medications that require prior permission to be used 
Table 16. 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 17 
Topical or Inhaled Steroids (other than low potency products) 
Interfere 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 
Triamcinolone acetonide 
 


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Table 18 
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 J 
SIGNS AND SYMPTOMS OF CONDITIONS TO BE 
CONSIDERED FOR RISK MANAGEMENT 
Disease 
Symptoms 
Signs 
Laboratory values 
Adrenal Insufficiency 
Fatigue/Tiredness/Malaise 
Weakness 
Anorexia 
Nausea 
Vomiting 
Constipation 
Abdominal pain 
Diarrhea 
Headache 
Salt craving 
Arthralgias/Myalgias 
Dizziness (esp. on 
standing) 
Less common: 
Irritability 
Depression 
Sweating 
Fever 
Weight loss 
Hypotension 
Hyperpigmentation 
Less common: 
Hypoglycemia 
 
Serum cortisol level 
less than 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 K 
QUALITY OF LIFE QUESTIONNAIRE 
CUSHING’S SYNDROME QUALITY OF LIFE 
QUESTIONNAIRE 
(Cushing QoL) 
 
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 
9. I have had to give up my social or leisure activities due to my illness. 
□ Always  


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□ 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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APPENDIX L 
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 
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 
 
In addition, the following physical signs of CS will be quantified by the Investigator using specific grading 
systems described below:  
 
7. Acne (grading according to Doshi 1997) 
8. Hirsutism (grading according to Hatch 1981) 
9. Peripheral edema (grading according to Brodovicz 2009) 
 
Name of Investigator completing assessment (Printed)_______________________________ 
 
Signature of Investigator completing Assessment____________________________ 
 
Date______________________ 








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APPENDIX M 
BECK DEPRESSION INVENTORY (BDI-II)  
 


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APPENDIX N 
ADDITIONAL INFORMATION ON ADVERSE EVENTS OF 
SPECIAL INTEREST (QTC INTERVAL, INSTRUCTIONS FOR 
LIVER FUNCTION TEST ABNORMALITIES FOLLOW-UP AND 
ADRENAL INSUFFICIENCY) 
Additional Information for QTc Interval Monitoring 
In this study, ECG monitoring is recommended at least every 3 months using a 12-lead ECG. ECGs 
will be obtained prior to the first dose of drug in the OLE as an OLE Baseline and every 3 months 
after enrollment.  


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Additional Information for LFT evaluation 
Although newly recognized LFT abnormalities will be less likely in the population for 
this extension study than in the parent studies, subjects will be monitored and withdrawal 
due to abnormal liver function tests will likewise be prompted per the criteria and 
evaluation procedures outlined in Sections 13.7and 14.2. 
The recommendations within the FDA Guidance on Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation (May 2009) have been adopted for use in this protocol 
to address abnormal LFTs. LFTs, including AST, ALT, TBN, LDH and AP, will be 
measured at every study visit. In addition, LFTs will be measured immediately if subjects 
develop 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, appropriate medical evaluation of such 
symptoms must include assessment of LFTs.  
Testing that is performed to evaluate abnormal LFTs, including laboratory assessments to 
exclude confounding causes (such as, hepatitis [A, B, C, E], autoimmunity), imaging and 
consultation with a liver specialist should be done prior to planned withdrawal of 
subjects due to elevated LFTs, so that the etiology of the abnormalities might be 
determined definitively while the subject remains available for evaluation. The Medical 
Monitor will provide Investigators with suggested evaluation procedures as outlined in 
Instructions for Liver Function Test Abnormalities Follow-up below. All such 
evaluations and any interventions to address LFT abnormalities should be recorded in the 
eCRF. While LFTs 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.  
Evaluation of LFT Abnormalities and Study Medication Dosing Interruption 
Prior to considering study withdrawal, subjects meeting the above criteria at any visit 
should be evaluated with serial (repeated) LFTs and potentially additional diagnostic 
evaluative testing to establish an etiology of the abnormality.  
The first repeated LFT assay should be performed as soon as possible after initial 
determination of abnormality to confirm the observation and thereafter at 3- to 4-day 
intervals or as the clinical situation dictates. Appropriate diagnostic evaluations and 
interventions should be implemented based on the clinical presentation of the subject and 
following the instructions for AESI-LFT abnormality follow-up (Instructions for Liver 
Function Test Abnormalities Follow-up).  
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 LFTs), with start/end dates were known. 


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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/pruritis 
Eosinophilia 
Dark urine 
Acholic stool 
Fever 
Right upper quadrant pain/tenderness 
6. Information regarding liver specialist consultation. 
7. Results of any LFTs performed to date (including Baseline and repeat testing). 
8. All INR, prothrombin time (PT) and prothromboplastin time (PTT) readings 
(NOTE: coagulation tests are not routinely performed in this study but should be 
performed and followed if abnormal in the event of suspected liver injury). 
9. Imaging procedures. 
10. Any other tests performed (liver panel below can be ordered from central 
laboratory).  
Hepatitis A Antibody, immunoglobulin M (Focus) 
Hepatitis B Core IgM AB (Centaur) 
Hepatitis B Virus DNA Quant polymerase chain reaction (Panel) 
Hepatitis D Antibody, Total 
Hepatitis E Ab IgM 
Cytomegalovirus IgM Antibody 
Epstein-Barr Viral Capsid Antigen IgM Antibody (Focus) 
Acetaminophen Adduct 


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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. 
 
 


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SAP_001.pdf: 
COR-2017-OLE Statistical Analysis Plan (SAP) Cover Page 
 
Study Title:  
An Open-Label Extension Study of Levoketoconazole (2S,4R-
Ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome 
Most Recent Document 
Version Date: 
28 February 2023 
NCT No. 
NCT03621280 
 
 
 
 
IND No. 
115968 
EudraCT No. 
2017-004647-20 
 


 
 
 
 
 
Protocol COR-2017-OLE (OPTICS) 
An Open-Label Extension Study of 
Levoketoconazole (2S,4R-ketoconazole) in the 
Syndrome 
 
Statistical Analysis Plan 
 
 
 
Author: 
  
Director, Biostatistics and Statistical Programming  
Xeris Pharmaceuticals, Inc. 
Document version: 
Amendment 2 
Release date: 
28 FEB 2023 
 
 
Property of Xeris Pharmaceuticals, Inc.        
Confidential 


Statistical Analysis Plan
Amendment 2
Sponsor: Xeris Pharmaceuticals, Inc.
Protocol ID: COR-2017-OLE 
 
 
 
 
Page 2 of 56 
 
 
 
 
 
 
 
 
Table of Contents 
Approvals ....................................................................................................... 6 
Version History ............................................................................................... 7 
Glossary of Abbreviations ................................................................................. 9 
1. 
Source Documents ................................................................................ 11 
2. 
Protocol Details .................................................................................... 12 
2.0 
Study Objectives ............................................................................... 12 
2.1 
Overall Study Design .......................................................................... 12 
2.2 
Sample Size and Power ...................................................................... 16 
3. 
Study Endpoints ................................................................................... 17 
3.0 
Exploratory Efficacy Endpoints ............................................................. 17 
3.1 
Safety Endpoints ............................................................................... 17 
4. 
Analysis Populations .............................................................................. 18 
4.1 
Intent-to-treat (ITT) Population ........................................................... 18 
4.2 
Per-protocol (PP) Population................................................................ 18 
5. 
Data Handling ...................................................................................... 19 
5.1 
Baseline, First Dose Date, and Last Dose Date....................................... 19 
5.2 
Study Day ........................................................................................ 19 
5.3 
Time Points and Visit Windows ............................................................ 19 
5.4 
Urinary Free Cortisol  Determination of Adequacy and Calculation of Mean
 
21 
5.5 
Late Night Salivary Cortisol  Calculation of Means ................................ 21 
5.6 
Blood Pressure and Heart Rate  Calculation of Means ............................ 21 
5.7 
-II 
 Calculation of Total Scores and Subscale Scores .......................................... 22 
5.8 
Acne, Hirsutism, Peripheral Edema, and Other Clinical Signs and Symptoms 
 Calculation of Total Scores ...................................... 23 
5.9 
Handling of Missing Data .................................................................... 24 
6. 
Statistical Methods ................................................................................ 27 
6.1 
General Principles .............................................................................. 27 
6.2 
Subject Disposition ............................................................................ 29 


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6.3 
Protocol Deviations ............................................................................ 30 
6.4 
Demographics and Other Background Characteristics ............................. 30 
6.4.1 
Demographics and Baseline Characteristics ................................................ 30 
6.4.2 
Medical History ....................................................................................... 31 
6.4.3 
Prior and Concomitant Medications ............................................................ 31 
6.5 
Levoketoconazole Exposure and Compliance ......................................... 31 
6.6 
Efficacy ............................................................................................ 32 
6.6.1 
UFC and LNSC Analyses ........................................................................... 33 
6.6.2 
Clinical Signs and Symptoms .................................................................... 34 
6.6.3 
 ....................................... 35 
6.6.4 
BDI-II ................................................................................................... 35 
6.6.5 
CS Comorbidity Biomarkers and HOMA-%B ................................................ 35 
6.6.6 
Medication Changes ................................................................................ 36 
6.6.7 
Subgroup Analyses ................................................................................. 37 
6.7 
Safety .............................................................................................. 38 
6.7.1 
Adverse Events ....................................................................................... 38 
6.7.2 
Laboratory Evaluations ............................................................................ 40 
6.7.3 
Vital Signs ............................................................................................. 44 
6.7.4 
Electrocardiograms ................................................................................. 45 
6.7.5 
Pituitary Magnetic Resonance Imaging ....................................................... 46 
6.7.6 
Physical Examinations ............................................................................. 47 
6.7.7 
Subgroup Analyses for Safety ................................................................... 47 
6.8 
Interim Analysis ................................................................................ 48 
7. 
Changes from Planned Analyses in the Protocol ........................................ 49 
7.1 
Imputation ........................................................................................ 49 
7.2 
UFC Adequacy ................................................................................... 49 
7.3 
Efficacy Analysis ................................................................................ 49 
7.4 
Subgroup Analyses ............................................................................ 49 
7.5 
Clinical Signs and Symptoms............................................................... 50 
7.6 
Medication Changes ........................................................................... 50 
7.7 
Electrocardiograms ............................................................................ 50 
7.8 
Interim Analysis ................................................................................ 51 
8. 
References ........................................................................................... 52 


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9. 
APPENDIX 1 Safety Laboratory and Vital Signs Tests  Identifying Worst 
Values ......................................................................................................... 53 
10. 
APPENDIX 2 Laboratory Tests  Precision Levels ....................................... 55 
 
 


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TABLE OF TABLES 
Table 1 
Overlap with the Parent Study .......................................................... 12 
Table 2 
Time and Events Schedule................................................................ 14 
Table 3 
Visit Windows for by-visit Analysis of Efficacy and Safety ..................... 19 
Table 4 
General Principles for the Presentation of Results in Tables, Figures, and 
Listings 
27 
Table 5 
The Severity of AEs and SAEs per NCI CTCAE, Version 4.03 ................. 38 
Table 6 
Laboratory Test PCS Criteria ............................................................. 42 
Table 7 
Vital Sign Clinical Importance Criteria ................................................ 44 
Table 8 
Blood Pressure Classification (Adults Over 18 Years of Age) .................. 44 
Table 9 
Vital Sign PCS Criteria ..................................................................... 45 
Table 10 
QTcF Interval of Potential Clinical Importance Criteria ....................... 46 
Table 11 
ECG PCS Criteria .......................................................................... 46 
 
 
 
 










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mUFC 
Mean Urinary Free Cortisol 
n 
Number of subjects/observations 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
OLE 
Open-label Extension 
PT 
Preferred Term 
QoL 
Quality of Life 
QTcB 
Bazett corrected QT  
QTcF 
Fridericia corrected QT 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
International System of Units 
SOC 
System Organ Class 
TFLs 
Tables, Figures, and Listings 
TSH 
Thyroid-stimulating Hormone 
UFC 
Urinary Free Cortisol 
ULN 
Upper Limit of Normal 
US 
United States 
WBC 
White Blood Cell  
WHO 
World Health Organization 
 
 
 




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2. Protocol Details 
2.0 Study Objectives 
The objective of this study is to assess long-term safety and efficacy durability of 
levoketoconazole as chronic treatment for endogenous 
yndrome (CS). 
2.1 Overall Study Design 
This is a long-term, open-label extension (OLE) study of levoketoconazole in subjects 
with endogenous CS who have completed one or both parent studies or otherwise 
potentially qualify for this study, as defined in the entry criteria in the protocol. 
For subjects entering directly from parent studies, the visit schedule for this OLE study 
is designed to overlap with those of the parent studies to ensure no break in drug 
supply for subjects as shown below in Table 1. 
Table 1 
Overlap with the Parent Study   
Extension Study COR-2017-OLE Visit 
Screening 
Baseline 
Can overlap with 
Parent Study COR-2012-01 (SONICS) visit: 
Parent Study COR-2017-01 (LOGICS) visit: 
 
Month 9 (M9) 
Restoration Phase Visit 1 
(RES1) 
 
Month 12 (M12) 
Restoration Phase Visit 2 
(RES2) 
Subjects were to remain on their most recent therapeutic dose of levoketoconazole at 
entry. Certain subjects that were enrolled in the Titration and Maintenance Phase of 
Study COR-2017-01 when randomization was closed or subjects with a gap in 
treatment with levoketoconazole may require re-establishment or establishment of a 
Therapeutic Dose. As a result, dose titration may be required. Post-enrollment, 
levoketoconazole dose changes are permitted as needed. However, dose increases, 
which require prior Medical Monitor approval, are not to exceed 150 mg daily at one 
time nor be more frequent than every 2 weeks. 
The study is comprised of Screening and Baseline Visits followed by scheduled visits 
every 3 months. In addition, Dose Adjustment/Safety Monitoring Visits are to be 
conducted in the event of a levoketoconazole dose increase.  
Per Section 4.3 of the protocol, subject participation in the study was anticipated to 
continue for at least 3 years. The sponsor decided that effective 01 March 2022, 
subjects remaining in the study could continue participating through their Month 36 
visit or 31 December 2022, whichever came first, with the following exception. 


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Subjects who already completed or were to have their Month 36 visit before 01 March 
2022 will have their Month 39 visit after 01 March 2022 as their end-of-study visit. 
The timings of study assessments are shown in Table 2 below. 






 
 
 
2.2 Sample Size and Power 
Given that this is a single-arm OLE study with exploratory efficacy endpoints only, 
there is no formal hypothesis testing, and the sample size to be enrolled is not pre-
determined. 
 
 
 


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3. Study Endpoints 
3.0 Exploratory Efficacy Endpoints 
The following efficacy endpoints will be assessed. All efficacy endpoints are 
considered exploratory. Refer to Section 5.1 for the definitions of Baseline. 
than or 
equal to the upper limit of normal (ULN) of the reference range; 2) Above the ULN 
to 1.5X the ULN; and 3) Above 1.5X the ULN; 
 
 
Changes from Baseline in Clinical Signs and Symptoms of CS, health-related 
quality of life (QoL), and symptoms of depression; 
[FBG], fasting insulin, homeostatic model assessment-insulin resistance [HOMA-IR], 
hemoglobin A1c [HbA1c], blood pressure, total cholesterol, high-density lipoprotein-
cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C], high-sensitivity C-
reactive protein [hsCRP]); 
hanges from Baseline in frequency of usage of anti-
diabetic, anti-cholesterol, and anti-hypertensive therapies; 
 
3.1 Safety Endpoints 
Safety will be assessed by incidence and severity of all Adverse Events (AEs), 
Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) as 
well as by physical examinations, safety laboratory panels (including 
Adrenocorticotropic Hormone [ACTH], liver function tests [LFTs], blood chemistry, 
hematology), electrocardiograms (ECGs) (to include assessment of the QTc 
interval), vital signs and pituitary Magnetic Resonance Imaging (MRI) for subjects 
with history of a pituitary tumor. 
 
 


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4. Analysis Populations 
4.1 Intent-to-treat (ITT) Population  
The ITT population will include all subjects who provide informed consent and receive 
at least one dose of levoketoconazole. This population will be used for the analyses of 
safety and efficacy.  
4.2 Per-protocol (PP) Population 
The PP population will include all subjects in the ITT population who have no major 
protocol deviations during the study that could affect mUFC related efficacy endpoints. 
This population will be used for selected efficacy analyses if the PP population is < 
90% of the ITT population.  
Additional subsets of the ITT and/or PP populations (for example, ITT population with 
diagnosis of C
Disease [CD]) may also be used for efficacy analyses as 
applicable. 
 
 
 




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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 the 
reference 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 ECG intervals (specifically QT, QTcF, QTcB, PR, and QRS), the worst result 
for a subject in a visit window is defined as the maximum value for that subject 
in that visit window. For the safety laboratory tests, the worst result for a 
subject in a 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.  
 
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. 
M9 
274 
Days 230 to 320 
M12 
365 
Days 321 to 411 
M15 
457 
Days 412 to 503 
M18 
548 
Days 504 to 594 
M21 
639 
Days 595 to 685 
M24 
731 
Days 686 to 777 
M27 
822 
Days 778 to 868 
M30 
913 
Days 869 to 959 
M33 
1004 
Days 960 to 1050 
M36 
1096 
Days 1051 to 1142 
End of Study 
No specific target day 
(range) specified 
No specific study day analysis visit 
window range specified, so long as it is 
during the study. The last non-missing 
post-baseline result in the study for a 
subject will be used for the End of Study 
time point. 


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5.4 Urinary Free Cortisol  Determination of Adequacy and Calculation 
of Mean 
Three 24-hour urine collections for UFC are scheduled (usually 7-14 days prior) at 
every visit indicated in Table 2, except when a 
with M12 (as part of SONICS), when two 24-hour collections are scheduled.   
For the analyses of all 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. For 
analysis purposes, a urine sample for UFC is considered to be adequate if its 
 
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 times standard error) 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 this 
study 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.  These 
thresholds were the same ones applied for analysis purposes in the LOGICS study. 
These thresholds are different from the criteria for adequacy that are defined in 
Section 6.2.5.1 of the protocol, which were used by sites for purposes of determining 
whether 24-hour urine samples were acceptable.  
At every visit, the corresponding mUFC will be calculated using only UFC values from 
adequate 24-hour urine collections. A minimum of two adequate samples are required 
for calculation of mUFC. If only one adequate sample is available, then mUFC will be 
set to missing.  
5.5 Late Night Salivary Cortisol  Calculation of Means 
LNSC samples from 2 nights will be collected between 11 PM and midnight at each 
visit indicated in Table 2. For mean LNSC analyses, only adequate samples, defined 
as those collected between 10 PM and midnight (i.e., a 1-hour allowance earlier), and 
with collection dates within the analysis window for that visit will be included in the 
calculation. If only one adequate sample is available, then the single sample will 
substitute for the mean. Collection time to midnight (in minutes) will also be averaged 
for the mean LNSC using the same criteria. 
5.6 Blood Pressure and Heart Rate  Calculation of Means 
Blood pressure and heart rate are measured in triplicate at each visit. The mean of 
the measurements will be used as the result for each visit, to be calculated only if 




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5.8 Acne, Hirsutism, Peripheral Edema, and Other Clinical Signs and 
 Calculation of Total Scores 
Acne Global Score 
A total of six locations (Forehead, Right Cheek, Left Cheek, Nose, Chin, and Chest and 
Upper Back) are evaluated with the following grading scale, depending on the severity 
of the acne: 0 - No Lesions, 1  One or more comedones, 2  One or more papules, 
3  One or more pustules, 4  One or more nodules. The following Factor is assigned 
to the locations of the lesion(s) as follows: 2 
 Forehead, 2- Right Cheek, 2- Left 
Cheek, 1  Nose, 1  Chin and 3 - Chest and Upper Back. 
The score for each location (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 location has a missing local score, 
then the missing local score will be imputed as the average of the non-missing local 
scores for that location. If more than 25% of locations (i.e., 2 or more locations out 
of 6) are missing a local score, then the global score will be set to missing. 
Hirsutism Total Score (for females only) 
Hirsutism will be assessed for females only. The total score is the sum of all the scores 
obtained in each of the 9 locations assessed (Upper Lip, Chin, Chest, Abdominal, Pubic, 
Arm, Thigh, Back, Buttocks). Each location is graded from 0 for no hirsutism to 4 for 
frank virilization. Total score can vary between 0 and 36. A high score means that the 
hirsutism is more visible. If one or two locations have 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 more than 25% of the locations (i.e., 3 or more 
locations out of 9) are missing a location score, 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 (Lower 
calf at 7 cm proximal to the midpoint of the medial malleolus; behind the medial 
malleolus; and dorsum of the foot). Each location is graded from 1 (barely detectable) 
to 4 (>30 seconds to rebound). 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. 


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Total Score for the Other Clinical Signs and Symptom
Syndrome 
The other clinical signs and symptoms, defined in Appendix L of the protocol, are moon 
facies, facial plethora, striae, bruising, supraclavicular fat, irregular menstruation 
(females only), and dysmenorrhea (females only). Each sign/symptom, if present, is 
graded as Mild (=1), Moderate (=2), or Severe (=3). If not present, the sign/symptom 
is graded as None (=0). If the irregular menstruation or dysmenorrhea grade is 
missing for a female subject who is post-menopausal or surgically sterile, the missing 
grade will be set to 0.  
Two total severity scores will be calculated as follows: 
The Total Signs Score is the sum of the severities for the first 5 clinical signs assessed 
by the investigator (moon facies, facial plethora, striae, bruising, and supraclavicular 
fat). This total score can range from 0 (none) to 15 (worst). If 2 or more of the 
individual signs have missing scores at a given visit for a subject, then the Total Signs 
Score will be set to missing. If at least 4 of 5 individual signs are actually assessed, 
the Total Signs Score will be standardized by dividing it by the number of non-missing 
individual signs and then multiplying by 5.  
The Menstrual Abnormalities Total Score is the sum of the severities for the last 2 
subject-reported 
symptoms 
(for 
females 
only: 
irregular 
menstruation 
and 
dysmenorrhea). This total score can range from 0 (none) to 6 (worst). If either of the 
two individual symptoms has a missing score at a given visit for a subject, then the 
Menstrual Abnormalities Total Score will be set to missing. 
5.9 Handling of Missing Data 
Missing or Inadequate UFC/LNSC Collections 
Refer to Section 5.4 and Section 5.5 for the handling of missing or inadequate 
UFC/LNSC collections. 
Handling of Missing Data for the Analysis of Exploratory Efficacy Endpoints 
by Visit 
For exploratory efficacy endpoints assessed at multiple visits, at-visit analyses will be 
performed using by-visit univariate methods. Imputation of a missing endpoint value 
for a subject at a visit may be applied as part of supportive or sensitivity analyses. 
Any imputation used for these purposes will be reported in the Clinical Study Report. 
Partially Missing Data for Triplicate Measurements of Blood Pressure and 
Heart Rate 
Refer to Section 5.6 for the handling of partially missing data for triplicate 
measurements of blood pressure and heart rate. 


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Partial and Missing Dates 
Imputations of missing and partial dates are to be used only for the following: 
assessment of treatment emergence status of an AE and determination of study day 
of onset and duration of the AE (if applicable); for definitions of prior and concomitant 
medications; 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 
levoketoconazole, 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 levoketoconazole, 
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 levoketoconazole and the AE or medication 
end date. If the end date is partial, then impute the end date first before 
imputing the start date. 
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 levoketoconazole, 
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 
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.  


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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 study statistician 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. 
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6.3 Protocol Deviations 
A summary of major protocol deviations (a subset of protocol deviations that may 
significantly impact the correctness, accuracy, and/or reliability of the study data or 
-being) will be presented 
by deviation category, subcategory, and the specific deviation description. Both major 
and minor deviations will be provided in a listing. 
Protocol deviations due to COVID-19 illness and/or COVID-19 public health control 
measures will be summarized and listed separately. 
6.4 Demographics and Other Background Characteristics 
6.4.1 
Demographics and Baseline Characteristics 
Demographics, baseline, and disease characteristics will be summarized for both ITT 
and PP populations. 
Standard descriptive statistics will be presented for the continuous variables of: 
 
age (years) 
 
OLE baseline weight (kg) 
 
OLE baseline height (cm) 
 
OLE baseline body mass index (BMI) (kg/m2) 
 
time since diagnosis of CS (months) 
 
time since last surgery for the management of CS 
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 (yes or no) 
 
OLE baseline glycemia status (pre-diabetic, normal, diabetic, as defined in 
Section 6.6.7 )  


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6.4.2 
Medical History  
Medical history conditions will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 21.1. Medical history conditions will be summarized by 
system organ class (SOC) and preferred term (PT).  
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.  
Separate summaries for prior and concomitant medications will be presented by the 
four medication categories prespecified in the CRF, namely, anti-diabetic, anti-
 
A medication record will be classified as either prior or concomitant according to the 
criteria below: 
 
Prior medications are medications taken (either started or ongoing) before the 
study and ended prior to the OLE Baseline visit. 
 
Concomitant medications are medications taken during the study, including 
those started before but ongoing at first dose (OLE Baseline visit), up through 
end of study.  
In addition, new concomitant medications, defined as medications started on or after 
first dose (OLE Baseline visit), will be summarized. 
Non-drug therapies given or procedures performed during the study will be listed only 
(i.e., no table). 
6.5 Levoketoconazole Exposure and Compliance 
Exposure to Levoketoconazole  
The total levoketoconazole (i.e., levoketoconazole) duration (days) during this OLE 
study will be summarized under each dose level received as well as across all dose 
levels for all subjects. Total days on levoketoconazole, the cumulative dose of 
levoketoconazole (mg), and the average daily dose of levoketoconazole (mg/day) 
during this OLE study will be presented for all subjects.  
In addition, pooled results from all three studies for total days on levoketoconazole 
will also be presented for all subjects as follows: 
- 
Total days on levoketoconazole prior to OPTICS (SONICS and or LOGICS, 
where applicable)   
- 
Total days on levoketoconazole, all three studies combined 


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- 
Total days on levoketoconazole  all three studies combined by duration 
category (frequencies of subjects, >=1 year, >= 2 years, >=3 years, >=4 
years of exposure) 
Similar summaries of total days on levoketoconazole will also be presented for 
subjects with continuous levoketoconazole exposure (i.e., continuous study 
participation in SONICS and/or LOGICS plus OPTICS). 
Total levoketoconazole duration (days) will be calculated for each subject as the last 
levoketoconazole stop date minus first levoketoconazole start date plus one day. 
Total days on levoketoconazole will be calculated for each subject as the actual total 
number of days the subject received levoketoconazole (i.e., gaps in levoketoconazole 
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 levoketoconazole is taken, it counts as 0.5 day. 
Actual cumulative dose (mg) of levoketoconazole 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 levoketoconazole (mg/day) will be calculated as the actual 
cumulative dose of levoketoconazole divided by total levoketoconazole duration. 
The levoketoconazole dispensing, accountability, as well as occurrence, timing, and 
reasons for dose discontinuations and dose increases will be displayed in listings. 
Compliance to Levoketoconazole 
Overall levoketoconazole compliance during this study will be calculated by dividing 
the actual cumulative dose of levoketoconazole (as described above) by the expected 
cumulative dose of levoketoconazole and multiplying the result by 100. The expected 
cumulative dose is first calculated at each dose level received (dose level x duration 
at current dose level) and then summed up across all dose levels. 
Persistence with therapy will be assessed by the number and proportion of subjects 
who complete 1, 2, and 3 years of treatment (based on total days on 
levoketoconazole) in this study, with at least 80% compliance with levoketoconazole. 
6.6 Efficacy 
Descriptive summaries of all efficacy endpoints will be presented by visit, according 
to visit windows (as defined in Section 5.3), for all subjects combined and, where 
appropriate, by dose level (as described in Section 6.1) for the ITT population.  For 
continuous variables, summaries will be presented for the observed values and for the 
absolute and percent changes from each of the Original and OLE Baselines (as defined 
in Section 5.1, where applicable) to each visit window. The 95% confidence interval 


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for the mean change and corresponding p-value will be calculated using paired t-test. 
For categorical variables, the shifts from each of the Original and OLE Baselines will 
be presented, where specified, and the shifts will be evaluated for significance using 
  
The p-values from these comparisons will be used for descriptive purposes only, i.e., 
no statistical inferences will be made.  
6.6.1 
UFC and LNSC Analyses 
mUFC Categorization Based on ULN 
At each visit, the number and proportion of subjects in the following categories will be 
summarized for mUFC: 
- 
mUFC less than or equal to the ULN  
- 
mUFC above the ULN to 1.5X the ULN 
- 
mUFC above 1.5X the ULN 
Shifts from each of the Original and OLE Baselines will be evaluated using Bowker test 
of symmetry. 
A separate mUFC analysis will be performed by summarizing the number and 
proportion of subjects in the following categories:  
- 
mUFC less than or equal to the ULN (complete response) 
- 
mUFC above the ULN to 1.5X the ULN and at least a 50% decrease from the 
Original Baseline (partial response) 
- 
mUFC above 1.5X the ULN, or mUFC above the ULN to 1.5X the ULN without at 
least a 50% decrease from the Original Baseline (no response) 
Shifts from each of the Original and OLE Baselines will also be evaluated using Bowker 
test of symmetry. Baseline results will be categorized as follows: 
- 
mUFC less than or equal to the ULN 
- 
mUFC above the ULN to 1.5X the ULN 
- 
mUFC above 1.5X the ULN 
In addition, proportion of subjects with mUFC less than or equal to the ULN will be 
compared between subjects with continuous exposure (defined as subjects who had 
no gap in study participation in SONICS and/or LOGICS and OPTICS) versus those 
with gaps between studies 
.  
LNSC Categorization Based on ULN 


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At each visit, the number and proportion of subjects in the following categories will be 
summarized for LNSC: 
- 
LNSC less than or equal to the ULN 
- 
LNSC above the ULN  
Shifts from each of the Original and OLE Baselines will also be evaluated using 
 
 
Changes in mUFC and LNSC from Baseline 
mUFC and LNSC will be summarized by visit, using descriptive statistics. Mean 
changes from Original Baseline and OLE Baseline will be assessed for nominal 
significance using paired t-test. For LNSC only, an analysis of covariance (ANCOVA) 
model will also be fitted with the change from the relevant Baseline in mean LNSC 
results at a post-baseline visit as the dependent variable, the result at the relevant 
Baseline as the independent variable, and the average collection time to midnight (in 
minutes) as covariate to assess the effect of collection time on the change from 
Baseline. Mean changes from each of the Original and OLE Baselines to each visit in 
mUFC will be compared between subjects with continuous exposure versus those with 
gaps between studies using unpaired t-test.  
Line plots of the mean +/- SE of actual and change from each of the Original and OLE 
Baselines by visit will be produced for mUFC and LNSC.  
mUFC Analysis on PP Population  
All the analyses of mUFC as described above will also be conducted on the PP 
population as supportive analyses if the PP population is < 90% of the ITT population.  
6.6.2 
Clinical Signs and Symptoms  
Clinical Signs and Symptoms Excluding Acne, Hirsutism and Peripheral 
Edema  
The Total Signs Score and the Menstrual Abnormalities Total Score (see Section 5.8 
for calculation detail) and changes from each of the Original and OLE Baselines will be 
summarized at each visit. Mean changes in the two total scores from each of the 
Original and OLE Baselines will be assessed for nominal significance using paired t-
test.  
Acne, Hirsutism and Peripheral Edema 
Acne, hirsutism (for females only) and peripheral edema total scores and changes 
from each of the Original and OLE Baselines will be summarized at each visit. Mean 
changes in total score from each of the Original and OLE Baselines will be assessed 
for nominal significance using paired t-test.  


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Shifts from each of the Original and OLE Baselines for acne, hirsutism and edema total 
scores will also be summarized using the following categories and will be analyzed 
using Bowker test of symmetry: 
 
Acne global score: 0, 1-18, 19-44 (Doshi 1997) = none, mild, moderate to 
severe 
 
Hirsutism total score: 0-7, 8-15, 16-36 (Hatch 1981) = none to mild, mild to 
moderate, moderate to severe 
 
Peripheral edema total score: 0-3, 4-6, 7-12 = none to mild, mild to 
moderate, moderate to severe 
Line plots of the mean +/- SE of actual and change from OLE Baseline values by visit 
will be presented. 
6.6.3 
  
Cushing QoL total score (see Section 5.7 for calculation detail), subscale scores and 
the changes from each of the Original and OLE Baselines will be summarized at each 
visit, using descriptive statistics. Mean changes in total score from each of the Original 
and OLE Baselines will be assessed for nominal significance using paired t-test. 
6.6.4 
BDI-II  
BDI-II total score and the changes from each of the Original and OLE Baselines will 
be summarized at each visit, using descriptive statistics. Mean changes in total score 
from each of the Original and OLE Baselines will be assessed for nominal significance 
using paired t-test.  
In addition, the number and percentage of subjects by category of severity (Minimal 
Depression: total score 0-13; Mild Depression: 14-19; Moderate Depression: 20-28; 
Severe Depression: 29-63) will be summarized by visit.  
6.6.5 
CS Comorbidity Biomarkers and HOMA-%B 
The observed value and the changes/percent changes from each of the Original and 
OLE Baselines in individual biochemical markers of CS comorbidities (fasting glucose, 
fasting insulin, HOMA-IR, HbA1c, blood pressure, total cholesterol, HDL-C, LDL-C, and 
hsCRP) will be summarized at each visit using descriptive statistics. Mean changes 
from each of the Original and OLE Baselines will be assessed for nominal significance 
using paired t-test. Mean changes from Original Baseline to each visit will also be 
compared between subjects with continuous exposure versus those with gaps 
between studies using unpaired t-test. 


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HOMA-IR is calculated by multiplying fasting plasma insulin (FPI, in microU/L)) by 
fasting plasma glucose (FPG, in nmol/L), 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 study will be excluded from fasting insulin and HOMA-IR 
summaries.  
Homeostatic Model Assessment-Beta Cell Function (HOMA-%B) is calculated as (20 x 
FPI)/(FPG - 3.5) and will also be summarized at each visit. HOMA-%B is only 
calculated whenever FPI and FPG are collected on the same day. FPI and FPG from 
different days cannot be combined to calculate HOMA-%B. Subjects who are using 
insulin during the study will be excluded from all HOMA-%B summaries. 
In addition, shifts from each of the Original and OLE Baselines (with regards to the 
laboratory reference ranges) in individual biochemical markers of CS comorbidities 
will be summarized at each visit, and analyzed using Bowker test of symmetry. Line 
plots of the mean +/- SE of actual and change from OLE Baseline values by visit will 
be presented. 
6.6.6 
Medication Changes  
The number and proportion of subjects with usage of each of the concomitant 
medication categories (anti-diabetic, anti-cholesterol, and anti-hypertensive) at OLE 
Baseline will be summarized. 
In addition, the number and proportion of subjects with medication changes from the 
OLE Baseline will be presented. Subjects whose usage is ongoing or started at the OLE 
Baseline will be categorized as follows: 
1) New and clinically significant medication  New medication is started during the 
study and its use was potentially clinically significant  
2) Medication dose increased  Dose is increased compared to the OLE Baseline 
AND the increase is considered potentially clinically significant  
3) Medication dose restarted after a gap  The medication is stopped after the OLE 
Baseline but is restarted during the study 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 changes from the OLE Baseline  
6) Medication dose decreased  Dose is decreased compared to the OLE Baseline 
AND the decrease is considered potentially clinically significant, or the dose is 
stopped after the OLE Baseline 


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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 database lock 
by a medical monitor. 
Subjects with no usage ongoing or started at the OLE Baseline will be categorized as 
follows: 
1) Medication added after OLE Baseline 
2) No medication used. 
If a subject has more than one medication in the same medication class that falls 
of these categories, i.e., the first applicable category that is listed above.  
6.6.7 
Subgroup Analyses 
Subgroup analyses for mUFC Categorization based on ULN, changes in mUFC from 
Baseline, and changes in CS comorbidities biomarkers from Baseline will be performed 
for the following subgroups of subjects (with a minimum subgroup size of at least 15 
subjects): 
Prior Therapy 
 
Subgroup displays will be generated for subjects who had prior surgery, radiotherapy, 
or medication therapy for the management of CS, versus those without.  
Baseline Glycemia Status  
Subgroup displays will be generated for subjects who enter the study as pre-diabetic 
(OLE 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 (OLE 
Baseline fasting glucose 
 126 mg/dL or receiving anti-diabetic medications at OLE 
baseline). 
If there are less than 15 subjects in the pre-diabetic subgroup, the pre-diabetic 
subjects and subjects with normal fasting glucose will be combined into one subgroup 
(non-diabetic) versus those in the diabetic subgroup. 
Age 
Subgroup displays will be generated for subjects with age < the median age (of the 
ITT population) versus those with age 
 the median age.  


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6.7 Safety 
Descriptive summaries of all safety endpoints, excluding AEs, will be presented by 
visit window (as defined in Section 5.3) for all subjects combined and where 
applicable, by dose level (as described in Section 6.1).  For continuous variables, 
summaries will be presented for the observed values and for the absolute and percent 
changes from each of the Original and OLE Baselines.  
The ITT population will be used for all safety analyses.  
6.7.1 
Adverse Events 
All 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 an 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 levoketoconazole 
dose in this study and up to 30 days after the last dose of levoketoconazole.  
TEAEs will be summarized by dose level (i.e., the last dose level on or before the AE 
onset date) and overall. 
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 experiences the same 
TEAE at more than one level of severity, or with more than one level of relationship 


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to levoketoconazole, the most severe rating or the stronger causal relationship to 
levoketoconazole will be used.  
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 levoketoconazole, 
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 levoketoconazole. 
 
For the overview summary of all levoketoconazole-related TEAEs  Same as in 
the previous bullet point. 
 
For the overview summary of all TEAEs, by time of first onset category (in 6-
month intervals, i.e., 0  6 months; > 6 months  12 months; > 12 months  
18 months; etc. Categories may be combined at the discretion of the sponsor 
depending on actual subject counts.) 
 
Number of subjects with TEAEs by MedDRA SOC and PT. 
 
Number of subjects with TEAEs by MedDRA SOC, PT, and closest relationship 
to levoketoconazole (Related/Not Related). Related events are defined as 
events that are definitely or probably related to levoketoconazole. 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. Worst severity is defined as first Death, then life-threatening followed 
by Severe, Moderate, and Mild in that order. 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 worst severity if the 
subject reported one or more events.  
 
Number of subjects with treatment-emergent SAEs by MedDRA SOC and PT. 
 
Number of most common TEAEs, i.e., unique events or episodes (frequency 
above 5% of all subjects) and incidence rate per subject-month (defined as the 
number of TEAEs divided by the total subject-months on levoketoconazole) by 
MedDRA SOC and PT. 


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Number of subjects with TEAEs, by time of first onset category (in 6-month 
intervals, i.e., 0  6 months; > 6 months  12 months; > 12 months  18 
months; etc. Categories may be combined at the discretion of the sponsor 
depending on actual subject counts.), MedDRA SOC and 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 serious TEAEs of special interest by AESI category, 
MedDRA SOC and PT. 
 
Number of subjects with TEAEs leading to levoketoconazole discontinuation by 
MedDRA SOC and PT. 
Listings of all AEs, SAEs, AESIs, AEs leading to discontinuation of levoketoconazole, 
AEs leading to withdrawal from the study, and AEs leading to death will be presented 
by subject, detailing verbatim term given by the Investigator or designee, SOC, PT, 
onset date, resolution date, severity, seriousness, AESI category, action taken, 
outcome, and levoketoconazole relatedness.  The event onset will also be shown 
relative (in number of days) to date of first dose.  
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), Lactate dehydrogenase (LDH), Direct and 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 Carbon Dioxide (CO2), Calcium, 
Magnesium, Phosphate, Uric Acid, Albumin, and Total Protein. 
Urinalysis: Specific gravity, pH, glucose, protein, blood, and ketones.  In addition, 
microscopic examination if blood or protein is > trace positive by dipstick.  


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Safety Hormones and Biomarkers: Thyroid-Stimulating Hormone (TSH)/Free T4, 
LDL-C:HDL-C ratio, Triglycerides 
Other Laboratory Tests:  Serum cortisol, ACTH 
Laboratory results will be summarized by SI units (see Section 6.1). Results will be 
summarized as received from the central laboratory. In the case that the results in SI 
units were not provided, data conversions will be performed. For serum cortisol only, 
an ANCOVA model will also be fitted with the change from the relevant Baseline in 
serum cortisol results at a post-baseline visit as the dependent variable, the result at 
the relevant Baseline as the independent variable, and the collection time since 8:00 
(in minutes) as covariate to assess the effect of collection time on the change from 
Baseline. 
Descriptive summaries by visit, including observed values and change from Original 
Baseline and OLE Baseline values, will be produced for each laboratory test.  
Shifts (low/normal/high) from baseline tables based on the reference ranges will be 
constructed. The shifts will be from each of the Original and OLE Baselines to each 
post-Baseline visit, and to the worst post-Baseline results during the study.  
For LFTs, tables will also be created to summarize the incidence at each visit and the 
shifts from Original Baseline and OLE 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 norma
  
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 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 being plotted: 
 
Baseline ALT (expressed as x ULN) x Maximum Post-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) 












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Radiologist assessment: Increase, Stable, Decrease, Unknown or Not Measurable, 
and Not Applicable (as collected on the CRF) 
Imputed categories based on maximum tumor diameter: Increase (increase of 
+2mm or more from OLE Baseline result); Decrease (decrease of -2mm or more from 
OLE Baseline result); Stable (less than 2mm change in either direction); Unknown or 
Not Measurable (results unknown, or the tumor is not measurable).  
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); Each of a), 
b), and c); No change; and Not applicable.   
6.7.6 
Physical Examinations  
Physical examination results will be presented in a listing only (i.e., no table).  
6.7.7 
Subgroup Analyses for Safety 
The following safety summaries will be produced for side-by-side comparison of 
subjects with continuous exposure versus those with gaps between studies: 
 
Overview summary of all TEAEs and summary of TEAEs by MedDRA SOC and 
PT (see Section 6.7.1) 
 
Mean changes from Original Baseline and OLE Baseline to each visit in LFTs, 
with between-group comparison using unpaired t-test 
 
Shift from the original Baseline and OLE Baseline in ALT, AST, and Total bilirubin 
using the categories defined in Section 6.7.2 
 
Mean changes from Original Baseline and OLE Baseline to each visit in ACTH, 
with between-group comparison using unpaired t-test 
 
Mean changes from Original Baseline and OLE Baseline to each visit in BMI and 
weight, with between-group comparison using unpaired t-test. 
 
Mean changes from Original Baseline and OLE Baseline in pituitary tumor size 
(in millimeters of maximum diameter) to each visit, with between-group 
comparison using unpaired t-test. 
The same set of summaries for TEAEs overview, TEAEs by SOC and PT, and QTc 
intervals will be produced for subgroups of subjects (with a minimum subgroup size 
of at least 15 subjects) based on the following: 
 
Baseline glycemia status (pre-diabetic, diabetic, normal, as defined in Section 
6.6.7)  


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Age (<median age of the ITT population versus 
 median age) 
Descriptive summaries by subgroup of interest will be produced for the following 
laboratory tests: ACTH by sex (for the subset of subjects with CD only). 
6.8 Interim Analysis 
No interim analysis is planned for this study. 
 


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7. Changes from Planned Analyses in the Protocol 
7.1 Imputation 
Protocol Section 12.4.1 stated 
Imputation may be performed for some 
endpoints as part of supportive or sensitivity analyses. Details of such imputations 
will be described in the SAP.
fine these 
imputations. Instead, it is 
endpoint value for a subject at a visit may be applied as part of supportive or 
sensitivity analyses. Any imputation used for these purposes will be reported in 
the 
 
7.2 UFC Adequacy 
Protocol Section 12.6.1 stated 
The mUFC will be calculated only if there are 
at least two adequate samples. The mUFC from the collections at each visit will 
be used in the analysis of UFC unless only one adequate sample is available, in 
which case the single sample will substitute for the mUFC.
we require at least two adequate samples in order for mUFC to be calculated, 
which is consistent with the analysis method in LOGICS. If there is only one 
adequate sample, the mUFC will be missing. 
7.3 Efficacy Analysis 
However, in this SAP we did not plan to calculate the 95% confidence interval 
for the difference in the paired proportions. 
7.4 Subgroup Analyses  
Protocol Section 12.7 stated that Subgroup analyses for selected exploratory 
efficacy endpoints and safety endpoints will be performed for a minimum subgroup 
size of at least 15 subjects. The subgroups of interest will include, but not be 
limited to, subgroups based on diagnosis of CD, prior therapy for CS, hypertension 
at Baseline, and prediabetes or diabetes at Baseline.  However, 
diagnosis of 
CD
, at least one of the subgroup  sizes is less 
than 15, thus the corresponding subgroup analyses are not planned to be 
performed. 


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7.5 Clinical Signs and Symptoms  
Protocol Section 12.6.2 stated that "Individual clinical signs and symptoms, ... will 
be summarized at each time point for assessment by number and percent of 
subjects." It is also stated that for signs and symptoms other than acne, hirsutism, 
and edema, Total severity score and changes from Baseline of the severity total 
score will be presented by visit. However, in Section 5.8 of this SAP, it is clarified 
that only acne, hirsutism, and edema will be summarized by each of their total 
scores. For other signs and symptoms, instead of being summarized by one total 
severity score, two total scores (The Total Signs Score and the Menstrual 
Abnormalities Total Score) are defined to distinguish signs that are common to 
both males and females from those that apply to females only (menstrual 
abnormalities). 
 
In the same section of the protocol, it is also stated that 
clinical signs and symptoms from each Baseline will be created to demonstrate 
based on the results 
from LOGICS, the sponsor found that the shift from Baseline analyses was not 
informative and will not be performed in this study.  
7.6 Medication Changes 
Protocol Section 12.6.6 stated that " The number and proportion of usage of each 
medication class of interest at Baseline and at all post-Baseline visits by treatment 
Since this is a single-
is an error in the protocol and should be ignored. In addition, the number and 
proportion of usage will be displayed for the OLE Baseline only. 
 
In addition, the number and proportion 
of subjects with medication changes during the study will be summarized by time 
" However, only medication change assessments from OLE Baseline to the 
worst change post-OLE Baseline were defined and planned in this SAP.  
7.7 Electrocardiograms  
Protocol Section 12.5.5 stated that "
descriptively by dose and time point." However, ECG results by dose level will be 
presented at the End of Study time point only, as stated in Section 6.1.  
 
This SAP also includes a PCS criterion for QTcF interval that is by sex: >450 msec 
for males; >470 msec for females, which is not mentioned in the protocol. 


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7.8 Interim Analysis 
Protocol Section 12.5 stated that " 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 analyses may include the 
worsening of any TEAEs relative to the original parent study and relative to the 
OLE Baseline. The effect of cumulative dose and levoketoconazole treatment 
exposure may be evaluated as risk factors for increased AE incidence and severity. 
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."  However, 
other than the periodic safety updates required by Competent Authorities and 
annual updates to the Investigator Brochure, no interim analysis of the data from 
this study will be performed. 
 
 
 


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8. References 
1 
Tiemensma J, Depaoli S, Felt J M. Using subscales when scoring the 
Eur. J. Endocrinol. 2016;174:33-40 
2 
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.  
3 
Hatch R, Rosenfield RL, Kim MH, Tredway D. Hirsutism: implications, 
etiology, and management. Am J Obstet Gynecol. 1981;140:815-830. 
4 
ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998. Available at 
https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-9-
statistical-principles-clinical-trials-step-5 en.pdf