Clinical trial NCT01838551
Conditions: Endogenous Cushing's Syndrome
Keywords: Cushing's disease ectopic ACTH adrenal Cushing's
Sponsor: Cortendo AB
Start date: 2014-08-01; Completion date: 2018-11-01
Enrollment: 94 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of this study are to evaluate the clinical responder rate, defined as the proportion of subjects with normal UFC after 6 months of treatment with COR-003 in the Maintenance Phase without dose increase, and to evaluate the range of effective doses in subjects with various levels of hypercortisolism.

Detailed description:
This is an open label, single arm study with a Screening Phase, a Dose Titration Phase, a 6-month Maintenance Phase, and a 6-month Extended Evaluation Phase designed to assess efficacy, safety, tolerability, and PK of COR-003 in subjects with endogenous CS.

Following an initial screening and washout period, as applicable, this study will be conducted in three treatment phases as follows:

* Dose Titration Phase: approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose). Dose titration will occur in increments of 150 mg with a starting dose of 150 mg twice daily (BID) over a period of approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose).
* Maintenance Phase: 6 months of treatment at the Therapeutic Dose following the Dose Titration Phase. Once the Therapeutic Dose has been reached and confirmed from the mean of a total of four adequately collected 24 hour urine collections for UFC measurements, subjects will enter into the Maintenance Phase of the study and will be asked to return to the clinic monthly for 6 months for assessment of efficacy and safety. During the Maintenance Phase, doses may not be increased to maintain UFC levels at or below ULN of the assay unless it is confirmed that a dose increase is deemed medically necessary at the discretion of the Investigator after discussion with the Medical Monitor. Prior to the End of Maintenance Phase Visit, four complete 24 hour urine collections will be obtained and subjects may enter the Extended Evaluation Phase.
* Extended Evaluation Phase: 6 months of continued treatment after the Maintenance Phase. In the 6-month Extended Evaluation Phase, subjects will return to the clinical site every 90 days (±14 days) for safety and efficacy evaluations.

Efficacy will be assessed primarily by measuring mean UFC concentrations at specified times as described in the clinical protocol. Safety will be assessed primarily by physical examinations with vital sign measurements, adverse events, clinical laboratory measures, electrocardiography, and pituitary MRI.

An independent Data Safety Monitoring Board (DSMB) will review the safety of the drug throughout the study. Membership of the DSMB is described in a Charter.

Arms: arm 1: Levoketoconazole Tablets Dose Level 0 Once Daily arm 2: Levoketoconazole Tablets Dose Level 1 Twice Daily arm 3: Levoketoconazole Tablets Dose Level 1 Twice Daily arm 4: Levoketoconazole Tablets Dose Level 3 Twice Daily arm 5: Levoketoconazole Tablets Dose Level 4 Twice Daily arm 6: Levoketoconazole Tablets Dose Level 5 Twice Daily arm 7: Levoketoconazole Tablets Dose Level 6 Twice Daily arm 8: Levoketoconazole Tablets Dose Level 7 Twice Daily
Interventions: intervention 1: Levoketoconazole
Intervention descriptions: intervention 1: Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole

Protocol documents:
Prot_000.pdf: 
 
AMENDMENT 6 
Page 1 of 119 
CONFIDENTIAL 
 
 
 
CLINICAL STUDY PROTOCOL 
An Open Label Study to Assess the Safety and Efficacy of COR-003 (2S, 4R-
Ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome 
Protocol Number 
COR-2012-01 
Compound 
COR-003 
IND No. 
115968 
EudraCT No. 
2013-002133-37 
Phase 
3 
Dates: 
 
Amendment 6 
25 October 2016 
Amendment 5 
16 April 2015 
Amendment 4 
28 August 2014 
Amendment 3 
26 February 2014 
Amendment 2 
20 October 2013 
Amendment 1 
09 September 2013 
Original 
10 April 2013 
 
 
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 
 
 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 2 of 119 
CONFIDENTIAL 
 
Revision Chronology 
10 April 2013 
Original 
09 September 2013 
Amendment 1: 
• Updated/clarified inclusion/exclusion criteria for 
the following:  prior irradiation, candidates for 
surgery, subjects with Cushing’s disease, prior 
treatment, history of prolonged QT syndrome, LFT 
thresholds, history of alcohol/drug use, 
concomitant medications. 
• Included analysis criteria for missing data to 
analyze restricted last observation carried over 
(RLOCF) and deleted modified ITT (mITT). 
• Clarified criteria for prolonged QTc observations 
and added more ECG assessments for subjects on 
doses >600 mg/day. 
• Updated Time and Events Table. 
• Editorial changes for clarity and consistency. 
20 October 2013 
Amendment 2: 
• Deleted upper end for BMI in Exclusion Criteria. 
• Late night salivary cortisol to be conducted in 
triplicate at certain time points. 
• Addition of ambulatory blood pressure monitoring 
based on feasibility. 
17 February 2014 
Amendment 3: 
• The PK sampling scheme now refers to planned 
sequences, instead of dose levels, including an 
explanation of the sample collection plan. 
• Use of acetaminophen >3 g/day was added to 
exclusion criteria and list of prohibited 
medications. 
• Pregnancy is no longer considered an SAE. 
• Subjects to complete diary cards for medication 
administration to measure compliance. 
• Dexamethasone suppression test to be conducted at 
12 months in the Extension Phase. 
• Dose Titration determined based on UFC results 
only and not serum cortisol levels. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 3 of 119 
CONFIDENTIAL 
 
• Ambulatory blood pressure to be evaluated 
throughout the study and formally analyzed. 
• Microalbuminuria assessments to be determined 
during Maintenance Phase ONLY if abnormal at 
Baseline. 
• Editorial changes for clarity and consistency. 
28 August 2014 
Amendment 4: 
• Medical Monitor and Sponsor signatory changed 
to Anthony DelConte, MD. 
• Description of DSMB responsibilities, including 
the use and role of an adjudication committee, was 
removed from the protocol, because those are 
defined in the DSMB charter. 
• The approximate time between dose adjustments 
was changed to 15 (±7) days from 15 (±2) days. 
• Inclusion Criterion #6 clarified to indicate that CS 
subjects with or without radiographically visible 
adenomas may be enrolled. 
• Exclusion Criterion #10 revised to provide more 
detail regarding contraceptive usage. 
• Exclusion Criterion #14 revised to allow screening 
assessments to occur following informed consent 
signature and discontinuation of prohibited 
medication(s). 
• Exclusion Criterion #15 clarified regarding 
diabetic subjects requiring hospitalization. 
• Screening Phase duration was changed to 
~12 weeks from 8. 
• Diabetic subjects will be allowed a small snack if 
intolerant of fasting when required for laboratory 
or ECG assessments. 
• Added new section: “Medications to be used with 
Caution”, which includes list of medications 
mainly mediated by CYP3A4.  This information 
was previously included as part of prohibited 
medication. 
• Revised Time and Events Table for further 
transparency. 
• Editorial changes for clarity and consistency. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 4 of 119 
CONFIDENTIAL 
 
16-April-2015 
Amendment 5 
• 
Removal of assessment of ambulatory blood 
pressure 
• Late night salivary cortisol samples will be 
measured over 2 nights instead of 3 nights, where 
applicable 
• The number of pharmacokinetic collection samples 
have been decreased as follows: 
o samples will be collected at 1.5 h and 2.5 h 
post dose during at least 2 visits at different 
dose levels from all subjects  
o a third sample will be collected between 6 to 
8h post dose in a subset of 10 to 15 subjects 
• The Targeted Signs and Symptom of Clinical 
Interest Form was revised and renamed 
“Assessment of Clinical Signs and Symptoms of 
Cushing’s Syndrome” 
• Added the Beck Depression Inventory (BDI-II) 
instrument to be administered at the same time as 
the Cushing’s QoL questionnaire 
• The Visual Analog Questionnaires for Physicians 
and Subjects was removed 
• Option for TID dosing was removed 
• Added a section on AEs of special interest and 
their analyses was included in secondary 
objectives 
• Added details on acceptable forms of 
contraception for men and women of childbearing 
potential 
• Objectives and endpoints were stated more 
precisely; Secondary Objectives were newly 
ordered and reworded for clarification; distinction 
between secondary and exploratory endpoints; 
clarification of “metabolic endpoints” to be 
changes in the biomarkers of CS comorbidities 
(diabetes, hypertension, hypercholesterolemia and 
obesity); a new exploratory composite endpoint of 
“Clinical benefit” was introduced; corresponding 
changes in the data analyses 
• Overall change in organization of the protocol and 
modifications to all sections of the protocol for 
clarity 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 5 of 119 
CONFIDENTIAL 
 
25-October-2016 
Amendment 6 
• Update Sponsor Approver information on 
Sponsor Approval Page. 
• Clarified and aligned the primary, secondary 
and exploratory objectives and endpoints 
(Section 2 and Section 3) 
• Clarified the pharmacokinetic and 
pharmacodynamics objectives and endpoints by 
moving them into a new section (Section 2.4 
and Section 3.4) 
• Added clarification to primary endpoint 
(Section 3.1) and the analysis (Section 12.5.2.1) 
to align with the primary objective to evaluate 
the range of effective doses. 
• Separated details about Screening Period and 
inserted a new section (Section 4.1). 
• Guidance regarding the option to re-screen 
subjects that have had a change in their medical 
condition that would increase their likelihood 
of eligibility for participation was added to new 
Section 4.1 and to Section 6. 
• The interval between dose level visits (if 
additional 24-hour urinary cortisol collections 
are not required) was clarified to be 
approximately 18 days (±4 days) in Section 4.2. 
• The collection of two adequate 24-hour urine 
specimens during the titration phase 
(Section 4.2.1) has been clarified to start 
collections on Day 10 (±1 day) after the start of 
each dose level, ideally on two consecutive 
days. 
• Section 4, Section 11.1, and Appendix A 
updated to include references to the expanded 
access program availability and the timing of 
the preparatory procedures, which might occur 
during their visits for COR-2012-01. 
• Information about the option to receive 
continued treatment through the expanded 
access protocol (COR-2015-EAP), where 
available, was added to Section 4, Section 4.5, 
and Section 4.7.  Subjects participating in 
expanded access do not need to complete the 
Follow-Up Visit for COR-2012-01, as they will 
be continuing treatment with COR-003. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 6 of 119 
CONFIDENTIAL 
 
• Section 4.2.2 and Appendix A clarified timing 
for additional safety visits to 1 safety visit 
occurring 7 (±3) days following each Dose 
Level titration. 
• Inserted new heading for the Dose Titration 
Phase (Section 4.2) and updated subheadings. 
• Wording in new Section 4.2 to specify timing 
and testing requirements for subjects through 
the Dose Titration Phase and to determine when 
to transition subjects to the Maintenance Phase. 
Timing and window for the visit after the two 
confirmatory 24-hour urine samples has been 
increased to 30 days (±7 days) for logistical 
reasons. 
• Included a footnote to Table 1 in new 
Section 4.2.1 and added Section 8.2.1 to 
specifically address dosage decreases to DL0. 
• The timing for additional safety visits for doses 
>600 mg total daily dose has been clarified 
with visit windows in Section 4.2.2. 
• Section 4.2.2 and Section 6.2.7.1 updated with 
additional safety monitoring to include ECG 
testing. 
• In Section 4.3 (previously Section 4.2) the 
timings for Maintenance Visits, to include visit 
windows, was added (every 30 days ± 7 days); 
clarification of documentation for dose 
adjustments during the Maintenance Phase. 
• In Section 4.4.1 description of steps for subjects 
that previously underwent radiation was 
clarified to include appropriate timing for entry 
into Extended Evaluation Phase if appropriate. 
• In Section 4.5 (previously Section 4.3) visit 
timing for Extended Evaluation Visits, 
including visit windows, was added (every 
90 days ± 14 days).  Information about the 
Follow-Up Visit, with its timing of at least 
14 days and within 30 days of completion of 
treatment was added. 
• Combined elements of prior Inclusion Criteria 
#3 and #4, which were errantly mutually 
exclusive, to reflect the spectrum of disease 
diagnoses required for inclusion. Inclusion 
criteria renumbered. 
• Updated Inclusion Criteria #6 (previously #7) 
to clarify that evidence of improvement should 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 7 of 119 
CONFIDENTIAL 
 
not be exhibited within the 6 months prior to 
the screening visit. 
• Clarified Inclusion Criteria #7 (previously #8) 
to indicate that a minimum of 6 weeks rather 
than 3 months should elapse before the subject 
can be deemed a surgical failure and subjects 
should have no significant post-operative 
sequelae. 
• Changed washout interval for pasireotide LAR 
to 12 weeks from 8 weeks (Inclusion 
Criteria #8). 
• Clarification of Inclusion Criteria #9 
(previously #10) to indicate that megestrol 
acetate and medroxyprogesterone acetate are 
different medications, which are both excluded 
for use during the study.  
• Section 5.3.2 hepatitis testing has been updated 
to clarify that the section addresses both 
Withdrawals and/or Re-Challenge.  The testing 
for causality has been clarified to include 
testing for Hepatitis [A, B, C, E], autoimmunity 
and imaging and clarified additional follow-up 
for liver-related AESIs. 
• Section 6 has been updated to include 
references to Appendix D, Appendix E and 
Appendix F for governance of study execution 
and reporting.  
• The evaluation of signs and symptoms of CS is 
not required as part of the additional safety 
evaluations required for each dose escalation 
beyond 600 mg/day.  The text in Section 6.2.1, 
which included this assessment, was not 
aligned with Section 4.2.1 and has been 
deleted. 
• Section 6.2.4.1 has been updated to include the 
collection of an additional PK sample as close 
to the time of the event as possible.  The 
definition of persistent and confirmed QTc 
prolongation was added with corresponding 
references to related sections and Appendices.  
The additional sample collection was also 
included in Section 6.2.8.1. 
• Section 6.2.4.2 has been updated to include 
timing of ECG evaluation following resumption 
of dosing as being within 1-2 hours of dosing. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 8 of 119 
CONFIDENTIAL 
 
• In Section 6.2.5 the testing for FSH was 
clarified to be for women only. 
• Table 2 (previously Table 3) has been updated 
to clarify that the values are minimum values 
for subjects ranging from 18 to 70 years and 
that adequate creatinine excretion rates for 
subjects over 70 years of age should be 
discussed on a case by case basis with the 
Medical Monitor. 
• Section 6.2.6.1 and Appendix A have been 
revised to remove the extra 24-hour urine 
collection at start of Maintenance Phase (M1 
visit), as this is collected at end of titration 
phase. 
• Section 6.2.7 and subsections were added to 
clarify situations where additional safety 
monitoring is required. 
• In Section 6.2.7.3 and Section 6.3.2, updated 
information about Adrenal Insufficiency and 
acute adrenal crisis. 
• Section 6.2.8.1 has been updated to clarify the 
timing of PK sampling. 
• Clarified section numbering and heading levels 
in Section 6.3. 
• Section 7 was clarified to indicate that the 
substances were to be avoided throughout the 
study, including a change from blood oranges 
to Seville oranges (i.e., sour orange bigarade 
orange, or marmalade orange). Clarifications 
were also made to indicate that licorice should 
be avoided throughout the study. 
• In Section 7, the restrictions associated with 
cortisol testing (urine and salivary) were 
aligned with the subject instructions and now 
include brushing teeth up to 2 hours prior to 
salivary testing, and any type of chewing, 
eating or drinking up to 1 hour prior to salivary 
testing. 
• Section 8.4 has been revised to reflect that a 
data restriction plan (DRP) will be used to 
govern the availability of efficacy data, rather 
than an SOP as originally stated. 
• Section 10.2 has been updated to advise that 
when no alternative medications are available, 
Investigators may seek permission from the 
Medical Monitor concerning subjects taking 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 9 of 119 
CONFIDENTIAL 
 
medications that cause QTc prolongation. This 
has also been clarified in Appendix J. 
• Section 10.3 has been updated to clarify those 
medications that should be used with caution. 
• Added wording in Section 11.1 and 
Appendix A clarifying the timing of the 
Follow-Up Visit approximately 2 weeks 
following termination of treatment with 
COR-003 (early withdrawal or M12 at the end 
of the Extended Evaluation Phase).  Updated 
Appendix references, including clarifying all 
Appendix references to ensure alignment with 
appropriate Appendix. 
• Sections 12.5.1.3, (clinical laboratory data) 
12.5.1.4 (vital signs) and 12.5.1.5 (ECG) have 
been revised to remove hypothesis tests. These 
data will be summarized but not tested. 
Additionally, QTc values of clinical importance 
have been added as Table 6 in Section 12.5.1.5. 
• Section 12.5.2.1 has been revised to clarify that 
the treatment estimate of the clinical response 
rate at the end of the Maintenance Phase and its 
associated two-sided 95% confidence interval 
(CI) will be obtained from a repeated measures 
generalized estimating equation (GEE) model 
with a logit link using SAS PROC GENMOD 
GLIMMMIX with LSMEANS statement.  Also 
that the longitudinal model will include visit, 
the concurrent CS medical conditions (diabetes, 
hypertension) as Baseline covariates as well as 
age (rounded median split), sex, disease 
duration, prior CS therapy, and prior radiation 
therapy, and subject will be included as a 
random effect.  The previous text regarding 
time trends has been deleted. 
• In Section 12.5.2.2 the analysis of Salivary and 
Serum Cortisol has been revised to clarify that 
change from Baseline, percent change from 
Baseline and at-visit values will be listed and 
summarized descriptively by visit, and a paired 
t-test will be used to compare post-baseline 
values with baseline values, for each visit. 
• In Section 12.5.2.2 for the analysis of CS 
Comorbidity Biomarkers, it has been clarified 
that the longitudinal model will include visit, 
the concurrent CS medical conditions (diabetes, 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 10 of 119 
CONFIDENTIAL 
 
hypertension) as Baseline covariates as well as 
age (rounded median split), sex, disease 
duration, prior CS therapy, and prior radiation 
therapy, and subject as a random effect.  The 
analysis of time trends and McNemar’s tests 
have been deleted. 
• In Section 12.5.2.2 for the analysis of the 
Glucose Tolerance Test and Spot Albumin, a 
paired t-test has been added for each 
assessment. 
• Section 12.5.2.3 it is no longer planned to 
perform the exact binomial test and 95% CI for 
and medication changes so these have been 
removed. Additionally, the text regarding 
additional exploratory analyses has been 
deleted as it is redundant. 
• Addition of cross-referencing throughout. 
• Reference was added (Schindler) for 
classification and pharmacology of progestins. 
• Added DL0 to Appendix A. 
• Appendix A, footnote 6 has been clarified to 
indicate that Spaulding ECGs are to be 
performed at each visit during Maintenance and 
Extended Evaluation phases monthly. 
• MRI at the Follow-Up Visit for subjects 
completing M12 was removed from the Time 
and Events Table in Appendix A to avoid 
magnetic resonance images (MRI) being taken 
within 2 weeks of each other. 
• Reformatted and expanded Appendix J to 
clarify Prohibited and Precautionary 
medications.  
• Overall minor modifications to wording have 
been included to increase clarity of protocol. 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 11 of 119 
CONFIDENTIAL 
 
Fredric Cohen, MD 
Senior Vice President, Global Research and Development 
 
 
 
Signature: ___________________________  
Date: ________________ 
SPONOSOR APPROVAL 
An Open Label Study to Assess the Safety and Efficacy of COR-003 (2S, 4R-
Ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome 
 
 
 
 
 
 
 
 
25 October 2016 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 12 of 119 
CONFIDENTIAL 
 
INVESTIGATOR AGREEMENT 
I have read this protocol and agree: 
• To conduct the study as outlined herein, in accordance with Good Clinical Practices 
(cGCPs), 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 IRB or 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: ________________ 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 13 of 119 
CONFIDENTIAL 
 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Cortendo AB 
Name of Investigational Product: 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] methoxyl]phenyl] piperazine} 
Title of Study:  An Open Label Study to Assess the Safety and Efficacy of COR-003 (2S, 
4R-Ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome 
Study center(s): A multicenter study in the US and Europe. 
Phase of development:  Phase 3 
Objectives:  
Primary:  
• 
To evaluate the clinical responder rate, defined as the proportion of subjects with 
normal urinary free cortisol (UFC) after 6 months of treatment with COR-003 in the 
Maintenance Phase without dose increase; and to evaluate the range of effective 
doses in subjects with various levels of hypercortisolism. 
Secondary:  
• 
To identify the proportion of subjects with clinical response, defined as reduction in 
mean 24-hour UFC levels to below or equal to the upper limit of normal (≤ ULN) 
after each month of treatment with COR-003 without a dose increase during the 
Maintenance Phase; 
• 
To identify the proportion of subjects with complete or partial response, defined as 
≥50% reduction of 24-hour UFC levels from Baseline after each of the 6 months of 
treatment with COR-003 without a dose increase in the Maintenance Phase; 
• 
To characterize changes in 24-hour UFC levels from Baseline during the 6 months of 
treatment with COR-003 in the Maintenance Phase regardless of dose increases; 
• 
To characterize shifts in normality for 24-hour UFC levels from Baseline during the 
6 months of treatment with COR-003 in the Maintenance Phase regardless of dose 
increases;  
• 
To characterize changes in serum and late night salivary cortisol concentrations 
during the 6 months of treatment with COR-003 in the Maintenance Phase; 
• 
To assess the effects on Clinical Signs and Symptoms of CS, the quality of life (QoL) 
measures obtained from the Cushing QoL questionnaire and the severity of 
depression obtained from the Beck’s Depression Inventory II in the Maintenance 
Phase; 
• 
To evaluate changes in the biomarkers of CS comorbidities (diabetes, hypertension, 
hypercholesterolemia and obesity) in the Maintenance Phase; 
• 
To assess the safety and tolerability of COR-003. 
Exploratory:  
• 
To assess the clinical responder rate (defined for the initial inference of efficacy as 
the proportion of subjects with normal 24-hour UFC levels after 6 months of 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 14 of 119 
CONFIDENTIAL 
 
treatment with COR-003 in the Maintenance Phase without dose increase) beyond 
6 months of treatment (Extended Evaluation Phase); 
• 
To assess the proportion of subjects with complete or partial response (defined for the 
initial inference of efficacy as ≥50% reduction of 24-hour UFC levels from Baseline 
after 6 months of treatment with COR-003 in the Maintenance Phase without dose 
increase) beyond 6 months of treatment (Extended Evaluation Phase); 
• 
To characterize changes in 24- hour UFC levels from Baseline beyond 6 months of 
treatment with COR-003 (Extended Evaluation Phase);  
• 
To characterize shifts in normality for 24-hour UFC levels from Baseline beyond 
6 months of treatment with COR-003 (Extended Evaluation Phase);  
• 
To characterize changes in serum and late night salivary cortisol concentrations 
beyond 6 months of treatment with COR-003 (Extended Evaluation Phase); 
• 
To assess the effects on Clinical Signs and Symptoms of CS, the QoL measures 
obtained from the Cushing QoL questionnaire and the severity of depression obtained 
from the Beck’s Depression Inventory II beyond 6 months of treatment with 
COR-003 (Extended Evaluation Phase); 
• 
To evaluate changes in the biomarkers of CS comorbidities (diabetes, hypertension, 
hypercholesterolemia and obesity) beyond 6 months of treatment with COR-003 
(Extended Evaluation Phase); 
• 
To describe the Clinical Benefit after 6 months of treatment with COR-003 in the 
Maintenance Phase, and after 9 and 12 months of treatment (Extended Evaluation 
Phase), defined as follows: 
o Clinical response as indicated by UFC ≤ upper limit of normal (ULN), and 
o No increase in COR-003 dose during Maintenance Phase, and 
o A clinically meaningful improvement in any one Baseline CS comorbidity 
(diabetes, hypertension, hypercholesterolemia, weight) as defined in the 
Statistical Analysis Plan (SAP), and  
o No study drug related treatment-emergent adverse event (TEAE) classified as 
severe or worse. 
• 
To assess changes in anti-diabetic, anti-cholesterol and antihypertensive therapies 
after 6 months of treatment with COR-003 in the Maintenance Phase, and after 9 and 
12 months of treatment (Extended Evaluation Phase); 
• 
To assess the change in clinical signs of hypercortisolism obtained from standardized 
photographs and rated by an adjudication committee after 3 and 6 months of 
treatment with COR-003 in the Maintenance Phase, and after 12 months of treatment 
(Extended Evaluation Phase). 
Pharmacokinetic/Pharmacodynamic:  
• 
To evaluate the pharmacokinetics (PK) of COR-003 in subjects with CS;  
• 
To explore the dose-response relationship for safety, including dose-response for 
adverse events of special interest (AESI) such as QTc if data allow; 
• 
To explore the dose-response relationship for reduction of UFC levels if data allow. 
Methodology:  This is a single arm, open label, dose titration study to assess efficacy, safety, 
tolerability, and PK of COR-003 in subjects with endogenous CS as illustrated below.  The 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 15 of 119 
CONFIDENTIAL 
 
range of effective doses for COR-003 in this CS population will also be established.  
Following an initial screening and washout period, as applicable, this study will be conducted 
in three treatment phases as follows: 
• 
Dose Titration Phase:  approximately 2 to 21 weeks to achieve an effective and 
tolerable maximum dose (the Therapeutic Dose); 
• 
Maintenance Phase:  6 months of treatment at the Therapeutic Dose following the 
Dose Titration Phase; 
• 
Extended Evaluation Phase: 6 months of continued treatment after the Maintenance 
Phase.  
 
After signing the informed consent, subjects will enter the Screening Phase. After the initial 
assessments, subjects on previous CS medical therapies or other prohibited medications must 
enter a washout period before completing all Screening assessments detailed in the Time and 
Events Table. Baseline measurements will be obtained as part of the Screening assessments 
after washout and completion of all initial Screening procedures.  If a subject does not meet 
the eligibility requirements, they might be eligible to re-screen but only if their underlying 
condition has changed in the interim such that they are now likely to meet study eligibility 
criteria. Such re-screenings will be exceptional circumstances, and all re-screenings require 
prior permission of the study Medical Monitor before they begin. 
After confirmation of eligibility at the Baseline Visit including confirmation of increased UFC 
levels as per eligibility requirements, subjects will enter into the Dose Titration Phase. Dose 
titration will occur in increments of 150 mg with a starting dose of 150 mg twice daily (BID) 
over a period of approximately 2 to 21 weeks to achieve an effective and tolerable maximum 
dose (the Therapeutic Dose). Decisions for dose increases will be based on each subject’s 
tolerability, assessment of UFC levels and safety data.  Dose decreases may also occur based 
on subject’s tolerability and safety data. 
Subjects that reach total daily doses of >600 mg/day will be monitored more closely and will 
be asked to return 7 days (±3 days) following each dose escalation visit at total daily doses 
>600 mg/day for an additional safety evaluation. Subjects will be advised to contact the 
Investigator immediately in the event of developing symptom-specific adverse events (AE), 
such as adrenal insufficiency or other AEs at any time.  
Once the Therapeutic Dose has been reached and confirmed from the mean of a total of four 
adequately collected 24-hour urine collections for UFC measurements, subjects will enter into 
the Maintenance Phase of the study and will be asked to return to the clinic monthly [every 
30 days (±7 days)] for 6 months for assessment of efficacy and safety.  During the 
Maintenance Phase, doses may not be increased to maintain UFC levels at or below ULN of 
the assay unless it is confirmed that a dose increase is deemed medically necessary at the 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 16 of 119 
CONFIDENTIAL 
 
discretion of the Investigator after discussion with the Medical Monitor. Prior to the End of 
Maintenance Phase Visit, four complete 24-hour urine collections will be obtained and 
subjects may enter the Extended Evaluation Phase.   
In the 6-month Extended Evaluation Phase, subjects will return to the clinical site every 
90 days (±14 days) for safety and efficacy evaluations.  
In order to exclude that a treatment effect is due to delayed onset of radiation therapy, 
previously irradiated subjects must stop treatment with COR-003 for at least 2 weeks after the 
end of the 6-month Maintenance Phase (End of Maintenance Phase Visit) and provide four 
complete 24-hour urine collections for UFC measurements at least 14 days following the End 
of Maintenance Phase Visit.  If the 24-hour UFC results indicate that UFC levels are elevated, 
the subject may subsequently restart therapy and continue into the Extended Evaluation 
Phase, at the discretion of the Investigator.  They should return for their next in-clinic visit for 
study assessments and resupply of study medication every 3 months [every 90 days (± 14 
days)] from the End of Maintenance Visit. 
Throughout the study, safety data will be collected at specified times.  Adequate medical 
coverage will be provided at all times during the course of the study to ensure that prompt 
safety decisions can be made and appropriate medical interventions are provided.  The 
Investigator will provide subjects with instructions on how to access the medical staff 
regardless of day and time in order to obtain medical care. An independent Data Safety 
Monitoring Board (DSMB) will review the safety of the drug throughout the study  
After completion of treatment in this study, subjects who do not extend treatment through the 
expanded access program, will have a Follow-Up Visit (a minimum of 2 weeks and no longer 
than 30 days following the completion of treatment).  Once all study assessments have been 
completed, subjects will be promptly referred back to their endocrinologist (if not the 
Investigator) for further management according to the local standard of care, and based on 
their preceding medical history.  [NOTE: The Follow-Up Visit is not required for subjects 
continuing into expanded access treatment.] 
Number of subjects (planned):  A sufficient number of subjects (estimated at approximately 
90) will be enrolled into the Dose Titration Phase of the study to ensure that at least 
70 subjects complete the 6-month Maintenance Phase.   
Inclusion Criteria:  
Subjects will be eligible for the study if all of the following criteria are met: 
1. Male or female ≥18 years of age 
2. 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. 
3. Confirmed diagnosis of newly diagnosed, persistent or recurrent Cushing’s disease (CD) 
or endogenous CS of other etiology if subjects are not candidates for surgery or 
radiotherapy within the 18 months after enrollment. 
Previous medical records will be collected and used to support the diagnosis of CD or 
endogenous CS of other etiology, including the following etiologies:   
- 
Ectopic adrenocorticotropic hormone (ACTH) secretion, i.e. ACTH not of pituitary 
origin 
- 
Ectopic corticotropin-releasing hormone (CRH) secretion 
- 
Adrenal-dependent CS (i.e. adrenal adenoma (NOT carcinoma), adrenal hyperplasia, 
etc.) 
- 
Etiology unknown. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 17 of 119 
CONFIDENTIAL 
 
In the absence of pathological or post-surgical confirmation of the diagnosis of CD (i.e. 
documented adrenal insufficiency post-adenomectomy or hypophysectomy, which will be 
considered diagnostic). The following historical evidence will be considered satisfactory 
to establish the diagnosis of CD: 
Plasma corticotropin (ACTH) level >20 pg/mL (4.5 pmol/L) or greater (Note: ACTH 
≥5 pg/mL (1.1 pmol/L) and ≤20 pg/mL will generally suffice only if accompanied by 
either a positive CRH stimulation test or Dexamethasone Suppression Test (DST) or 
combined CRH-DST) PLUS one of the diagnostic strategies described below based on 
pituitary magnetic resonance imaging (MRI)/computed tomography (CT) findings (Note: 
pituitary imaging preceding the original diagnosis is a requirement for eligibility): 
For tumors ≥6 mm by imaging: 
- 
Inferior petrosal sinus sampled (IPSS) ACTH central:plasma gradient ≥2 before 
CRH or ≥3 after CRH, OR if IPSS was not done then: 
- 
Positive ACTH and/or cortisol response to CRH/desmopressin or combined 
CRH-desmopressin stimulation plus high-dose (8 mg) dexamethasone 
suppression of plasma cortisol, ideally on more than one occasion, performed and 
interpreted according to internationally recognized standards of diagnosis 
- 
In the absence of IPSS and the combination of tests described, an individual 
might be eligible if CD was otherwise confirmed via adequate testing. Such cases 
must be discussed with and explicitly approved by the Medical Monitor, and the 
specific diagnostic criteria used to establish the diagnosis of CD must be 
documented. 
For tumors <6 mm or not visible by MRI: 
- 
IPSS with ACTH central:plasma gradient ≥2 before CRH or ≥3 after CRH 
- 
In the absence of IPSS, an individual might be eligible if CD was otherwise 
confirmed via adequate testing. Such cases must be discussed with and explicitly 
approved by the Medical Monitor, and the specific diagnostic criteria used to 
establish the diagnosis of CD must be documented. 
4. Regardless of the etiology of endogenous CS, subjects MUST have elevated mean 
24-hour UFC levels ≥1.5X ULN based on the normative range of the central lab assay 
and on a minimum of four measurements from adequately collected urine.  Urine will 
ideally be collected on sequential days.   
5. In addition to elevated mean UFC, presence of abnormal values from one of the 
following tests: 
• 
Abnormal DST: Elevated 8 AM serum cortisol ≥1.8 µg/dL (50 nmol/L) after 1 mg 
dexamethasone orally at 11 PM the evening prior (if not conducted already in the 
diagnostic workup of the subject within the previous 2 months before start of 
Screening Phase; in that case previous test results and details of conduct will need 
to be available by the Baseline Visit) 
• 
Elevated late night salivary cortisol concentrations (at least two measurements) 
>ULN  
NOTE: For subjects with estimated glomerular filtration rate (eGFR as determined by 
Modified Diet in Renal Disease MDRD equation) >40 and <60 mL/min/1.73 m2 in 
addition to meeting the UFC criteria, late night salivary cortisol test results 
(≥2 measurements) MUST also demonstrate evidence of CS.  
6. Previously irradiated subjects with CD or endogenous CS of other etiology will be 
allowed as long as the radiation treatment occurred > 4 years ago and subjects have not 
exhibited evidence for improvement in their underlying CD for 6 months prior to the 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 18 of 119 
CONFIDENTIAL 
 
Screening visit. The total number of previously irradiated subjects enrolled in this study 
will not exceed 10. 
7. Subjects with CD or CS of other etiology who are not candidates for surgery, refuse 
surgery, or in whom surgery will be delayed for at least 18 months following enrollment. 
Subjects may be allowed to participate in the trial while awaiting surgery, but must agree 
to complete this study prior to surgery. For subjects who have already undergone surgery, 
a minimum of 6 weeks should have elapsed before the subject can be deemed a surgical 
failure.  Subjects who have undergone surgery should be stable post-surgery (i.e., no 
significant post-operative sequelae remain and the risk of such sequelae is considered 
negligible). 
8. Subjects on treatment for CD or endogenous CS of other etiology for whom treatment has 
been inadequate or not well tolerated must agree to the following minimum washout 
periods prior to the Baseline Visit: 
• 
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 
9. Subjects on megestrol acetate or medroxyprogesterone acetate (and selected other 
synthetic progestins) must agree to a washout period of at least 6 weeks prior to the 
Baseline Visit   
10. A female is eligible to enter and participate in the study if she is of:  
Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, 
including any female who is post-menopausal or surgically sterile). Surgically sterile 
females are defined as those with a documented hysterectomy and/or bilateral 
oophorectomy or tubal ligation.  
Post-menopausal females are defined as being amenorrheic for greater than 1 year 
with an appropriate clinical profile, e.g. age > 45 years, in the absence of hormone 
replacement therapy. However, in questionable cases, a blood sample with follicle 
stimulating hormone (FSH) > 40MIU/ml and estradiol < 40pg/ml (<140 pmol/L) is 
confirmatory.  
OR  
Child-bearing potential and agrees to use highly effective methods of birth control 
while participating in the study and for 2 weeks after the study is completed. 
11. Fertile men must also agree to use a medically acceptable form of birth control while on 
study drug and up to 2 weeks after the study is completed. 
12. Able to comprehend and comply with procedures. 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following criteria are met: 
1. Subjects with Pseudo-Cushing’s syndrome based on assessment of the Investigator.   
2. Subjects with cyclic CS based on assessment of the Investigator 
3. Subjects with a non-endogenous source of hypercortisolism such as exogenous source of 
glucocorticoids or therapeutic use of ACTH. 
4. Known inherited syndrome as the cause of hypercortisolism, including but not limited to 
multiple endocrine neoplasia Type 1, McCune Albright Syndrome and Carney Complex 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 19 of 119 
CONFIDENTIAL 
 
5. Subjects with adrenal carcinoma  
6. History of malignancy, other than thyroid, early stage prostate, squamous cell and basal 
cell carcinoma, within 3 years prior to the Screening Phase. Subjects with history of such 
allowed carcinoma must have a life expectancy of >18 months and must be considered 
medically stable. Subjects with early stage prostate cancer undergoing no treatment due to 
low grade potential may be enrolled.  
7. Clinical or radiological signs of compression of the optic chiasm. 
8. Major surgery within 1 month prior to enrollment (informed consent form signing)  
9. Subjects with clinically significant abnormality in 12-lead ECGs during the Screening 
Phase needing medical intervention. 
10. Subjects with QTc interval of >470 msec during the Screening Phase. 
11. Subjects with a history of Torsades des Pointes, or ventricular tachycardia, or ventricular 
fibrillation, or history of prolonged QT syndrome (including family history), or use of 
medications resulting in QT/QTc prolongation, or hypokalemia <3.0 meq/L. 
12. Pre-existing hepatic disease; subjects with mild to moderate hepatic steatosis consistent 
with fatty infiltration (non-alcoholic fatty liver disease [NAFLD] are allowed).  
13. Positive for hepatitis B surface antigen (HbsAg) or positive hepatitis C test. 
14. History or symptoms of recurrent symptomatic cholelithiasis or pancreatitis. 
15. Liver function tests (LFT) must not be above the following cut-offs during the Screening 
Phase:  
• 
Alanine transaminase (ALT) and/or aspartate transaminase (AST) >3 X ULN  
• 
Total bilirubin (TBN) >2 X ULN 
If all LFTs are within normal limits (WNL) and TBN is elevated, examination of direct 
and indirect bilirubin may be conducted. Subjects with isolated indirect TBN up to 3X 
ULN are presumed to have Gilbert’s syndrome and may be enrolled if all other LFTs are 
within normal levels. 
16. History of documented or suspected drug-induced liver injury requiring drug 
discontinuation of ketoconazole or any azole antifungals.  
17. Pregnant or lactating women 
18. Human immunodeficiency virus (HIV)-positive. 
19. History of persistent uncontrolled hypertension (>180/120 mmHg) despite medical 
intervention. 
20. Subjects with hypercholesterolemia who are currently treated with atorvastatin, lovastatin 
or simvastatin and not willing or unable to change to alternative therapies, i.e. pravastatin, 
fluvastatin, or rosuvastatin within 2 weeks of start of the Screening Phase.  
21. Body habitus preventing repeated venipuncture as required by protocol. 
22. Subject is currently in another study or has received any investigational treatment (drug, 
biological agent or device) within 30 days or five half-lives of treatment, whichever is 
longer. 
23. Repeated hospitalization for hyperglycemia or for any complication of hyperglycemia and 
diabetes during the last 12 months  
24. Subjects with decreased renal function as defined by eGFR <40 mL/min/1.73 m2, using 
MDRD equation. 
25. Any other clinically significant medical condition, as determined by the Investigator that 
precludes enrollment and participation in the study through completion, including 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 20 of 119 
CONFIDENTIAL 
 
conditions that would preclude the subject from being able to follow instructions or to 
perform the necessary procedures (for example, psychiatric instability or severe 
disability).  
26. Abnormal free thyroxine (T4). Subjects with thyroid stimulating hormone (TSH) < lower 
limit of normal (LLN) and normal free T4 are permitted to participate in the study.  
27. Subjects who have a history of alcohol or drug abuse in the 6-month period prior to 
enrollment. 
28. Subjects who have been treated with mitotane within 6 months of the Screening Phase. 
29. Subjects who are currently taking any H2 receptor antagonists, proton-pump inhibitors, or 
sucralfate (all of which inhibit absorption of COR-003).  A list of orally acceptable 
antacids (for example, Mylanta and Maalox) will be provided, and can only be taken a 
minimum of 2 hours after dosing of COR-003.  
30. Subjects who receive any prohibited concomitant medication and cannot discontinue it 
safely prior to the Baseline Visit, including but not limited to the following: 
• 
Weight loss medications (prescription or over the counter); 
• 
Acetaminophen (paracetamol) >3 g total daily dose; 
• 
Strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with 
the metabolism of COR-003 and cannot be discontinued prior to first dose; 
• 
Herbal preparations: St John’s Wort, echinacea, gingko, goldenseal, yohimbe, red 
rice yeast, danshen, silybum marianum, Asian ginseng, schissandra sphenanther, 
shankhapushi, and Asian herb mixture (Xiao chai hu tang and Salboku-to); 
• 
Topical or inhaled corticosteroids; 
• 
Carbamazepine, fenofibrate, carbenoxolone; 
• 
Drugs that might pose unacceptable risks due to overlapping toxicities (e.g. QT 
prolongation, liver toxicity); 
• 
Genuine licorice. 
Investigational product, dosage and mode of administration:  
COR-003 (2S,4R ketoconazole); 150 mg immediate release tablets for oral BID dosing; total 
daily dose will be titrated in 150 mg increments from a starting dose of 300 mg up to a 
maximal daily dose of 1200 mg (Doses can be reduced and can be as low as 150 mg daily.) 
Duration of treatment:  
Subjects will undergo dose titration over approximately 2 to 21 weeks until achieving efficacy 
at their individual therapeutic dose, followed by 6 months of dosing at that dose level 
(Maintenance Phase). All subjects completing the Maintenance Phase will be eligible to be 
rolled over into an Extended Evaluation Phase for another 6 months of follow-up, for a total 
treatment duration of approximately 1 year (exclusive of the dose titration period).  
Reference therapy, dosage and mode of administration:  
None; this will be a single arm, uncontrolled study of oral administration of COR-003 
(2S,4R-ketoconazole). 
Analysis Populations: 
Intent-to-Treat (ITT) Population: The ITT population will include all subjects who receive at 
least one dose of COR-003.  This population will be used for the evaluation of efficacy and 
all safety analyses. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 21 of 119 
CONFIDENTIAL 
 
Maintenance (M) Population: The M population will consist of all subjects who enter the 
Maintenance Phase of the study. This population will be used for the supportive evaluation of 
all the primary and secondary efficacy endpoints. 
Per Protocol (PP) Population:  The PP population will consist of all subjects who enter the 
Maintenance Phase of the study and have no major protocol deviations that may affect 
efficacy. This population will be as supportive analysis for the analysis of the primary 
endpoint. 
Criteria for evaluation: 
Primary endpoint:  
• 
Proportion of subjects with response to COR-003, defined as reduction in mean 
24-hour UFC levels to ≤ ULN following 6 months of Maintenance Phase therapy 
without a dose increase during that phase, summarized by Maintenance Phase dose 
level and overall.  
Secondary endpoints: 
• 
Proportion of subjects with clinical response to COR-003, defined as mean UFC level 
≤ ULN, to be determined after 1, 2, 3, 4, and 5 months of dosing without a dose 
increase in the Maintenance Phase;  
• 
Proportion of subjects with complete or partial response to COR-003, defined as 
mean UFC level ≥ 50% reduction from Baseline after 1, 2, 3, 4, 5 and 6 months of 
dosing without a dose increase in the Maintenance Phase; 
• 
Change and percentage change from Baseline in mean 24-hour UFC levels after 1, 2, 
3, 4, 5 and 6 months of dosing in the Maintenance Phase regardless of dose increases; 
• 
Shift in UFC normality categories from Baseline to 1, 2, 3, 4, 5 and 6 months of 
dosing in the Maintenance Phase regardless of dose increases; 
• 
Change and percentage change from Baseline in serum and late night salivary cortisol 
levels after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; 
• 
Changes from Baseline in Clinical Signs and Symptoms of CS after 1, 2, 3, 4, 5 and 6 
months of dosing in the Maintenance Phase;  
• 
Changes from Baseline in the QoL measures obtained from the Cushing QoL 
questionnaire and the severity of depression obtained from the Beck’s Depression 
Inventory II after 3 and 6 months of dosing in the Maintenance Phase; 
• 
Change from Baseline in CS comorbidities biomarkers (fasting glucose, hemoglobin 
A1C [HbA1c], systolic blood pressure [SBP], diastolic blood pressure [DBP], total 
cholesterol, low and high density lipoproteins [LDL, HDL, respectively], and body 
weight) after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; 
• 
Changes from Baseline for oral glucose tolerance test (OGTT) (pre-diabetics only) 
and spot albumin/creatinine ratio as a measure of microalbuminuria (only if abnormal 
at Baseline) after 3 and 6 months of dosing in the Maintenance Phase; 
• 
Changes from Baseline for C-reactive protein (CRP) after 1, 2, 3, 4, 5 and 6 months 
of dosing in the Maintenance Phase; 
• 
Safety evaluations will include clinical observations and AE reporting, vital signs 
(SBP, DBP, body weight, body mass index [BMI]), electrocardiograms (ECGs), 
hematology, chemistry panels (inclusive of expanded markers of liver function, 
ACTH, Insulin-like Growth Factor-1 [IGF-1] and testosterone concentrations), 
dipstick urinalysis (microscopic evaluation, if dipstick positive), tumor size by MRI 
as applicable. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 22 of 119 
CONFIDENTIAL 
 
Exploratory endpoints: 
• 
Proportion of subjects with long-term clinical response to COR-003, defined as mean 
UFC level ≤ ULN, after 9 and 12 months (Extended Evaluation Phase); 
• 
Proportion of subjects with long-term complete or partial response to COR-003, 
defined as mean UFC level ≥ 50% reduction from Baseline after 9 and 12 months 
(Extended Evaluation Phase); 
• 
Change and percentage change from Baseline in mean 24-hour UFC levels after 9 and 
12 months (Extended Evaluation Phase); 
• 
Shift in UFC normality categories from Baseline at 9 and 12 months (Extended 
Evaluation Phase); 
• 
Change and percentage change from Baseline in serum and late night salivary cortisol 
levels after 9 and 12 months (Extended Evaluation Phase); 
• 
Changes from Baseline in Clinical Signs and Symptoms of CS, on the QoL measures 
obtained from the Cushing QoL questionnaire, and on the severity of depression 
obtained from the Beck’s Depression Inventory II after 9 and 12 months of dosing 
(Extended Evaluation Phase); 
• 
Change from Baseline in CS comorbidities biomarkers (HbA1c, SBP, DBP, total 
cholesterol, LDL, HDL and body weight) after 9 and 12 months of dosing (Extended 
Evaluation Phase); 
• 
Changes from Baseline for OGTT (pre-diabetics only) and spot albumin/creatinine 
ratio as a measure of microalbuminuria (only if abnormal at Baseline) after 9 and 
12 months of dosing (Extended Evaluation Phase);  
• 
Changes from Baseline for CRP after 9 and 12 months of dosing (Extended 
Evaluation Phase); 
• 
Clinical benefit rate determined after 1, 2, 3, 4, 5 and 6 months of dosing in the 
Maintenance Phase and at 9 and 12 months (Extended Evaluation Phase). Clinical 
benefit is defined as follows: 
o Clinical response as indicated by UFC ≤ ULN, and 
o No increase in COR-003 dose during Maintenance Phase, and 
o A clinically meaningful improvement in any one Baseline CS comorbidity 
(diabetes, hypertension, hypercholesterolemia, weight) as defined in the SAP 
and  
o No study drug related TEAE classified as severe or worse; 
• 
Changes in the doses of concomitant medications and in particular anti-diabetic, 
anti-cholesterol and antihypertensive medications after 6 months of dosing with 
COR-003 during the Maintenance Phase and during the Extended Evaluation Phase 
relative to Baseline doses of such medications; 
• 
Changes in the severity score for clinical signs of hypercortisolism obtained from 
standardized photographs and rated by an adjudication committee after 3 and 
6 months of dosing with COR-003 during the Maintenance Phase at 12 months in the 
Extended Evaluation Phase. 
Pharmacokinetic Endpoints and Pharmacokinetic/Pharmacodynamic Modeling: 
• 
Estimate the following parameters using population PK modeling: clearance (CL/F), 
volume of distribution (V/F), absorption rate constant (Ka) with associated between 
subject variability where feasible. These parameters will be used to calculate half-life 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 23 of 119 
CONFIDENTIAL 
 
(t½), area under the concentration-time curve (AUC) and peak concentration (Cmax) 
if feasible.   
• 
Estimate the following pharmacodynamic parameters: COR-003 concentration 
producing half-maximal UFC suppression (IC50), the maximal suppression of UFC 
(Imax) and associated estimates of between subject variability, if feasible. The range 
of UFC reduction by dose will be explored.  
• 
Other safety and efficacy endpoints will also be explored graphically by dose or 
summary metrics of exposure. 
• 
The relationship of AESI including QTc interval to dose of COR-003 will be 
evaluated if data allow. 
• 
The relationship of UFC reduction to dose of COR-003 will be evaluated if data 
allow. 
Statistical methods: 
Primary Efficacy Endpoint:  The treatment estimate of the clinical response rate at the end of 
the Maintenance Phase and its associated two-sided 95% confidence interval (CI) will be 
obtained from a repeated measures GEE model with logit link using SAS PROC GLIMMIX 
with LSMEANS statement.  The primary analysis will be the ITT population and analysis will 
be repeated in the Maintenance population and Per Protocol population. 
Secondary Efficacy Endpoints:  Analyses of response rates will be analyzed as described for 
the primary endpoint. 
Calculations for the biomarkers of CS comorbidity (fasting glucose, HbA1c, SBP, DBP, total 
cholesterol, LDL, HDL, and body weight) will be performed using SAS PROC MIXED to 
account for all post-Dose Titration Phase outcomes per subject with changes from Baseline 
and two-sided 99% lower confidence bounds calculated using LSMEANS. 
Changes from Baseline in serum and late night salivary cortisol, and scores from the 
Cushing’s QoL and Beck’s Depression questionnaires, will be summarized by time point 
using descriptive statistics and analyzed using paired t-test.   
Safety Analyses:  Safety assessments, including AEs, vital signs, ECGs (inclusive of QTc), 
laboratory parameters, and physical examinations will be summarized using descriptive 
statistics by time point. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 24 of 119 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................................27 
1 
INTRODUCTION ..................................................................................................................30 
1.1 DISEASE BACKGROUND ...................................................................................................................30 
1.2 RATIONALE FOR STUDY DESIGN ......................................................................................................31 
2 
OBJECTIVES ........................................................................................................................32 
2.1 PRIMARY OBJECTIVE .......................................................................................................................32 
2.2 SECONDARY OBJECTIVES .................................................................................................................32 
2.3 EXPLORATORY OBJECTIVES .............................................................................................................33 
2.4 PHARMACOKINETIC/PHARMACODYNAMIC OBJECTIVES ...................................................................34 
3 
ENDPOINTS ..........................................................................................................................34 
3.1 PRIMARY ENDPOINT ........................................................................................................................34 
3.2 SECONDARY ENDPOINTS ..................................................................................................................34 
3.3 EXPLORATORY ENDPOINTS ..............................................................................................................35 
3.4 PHARMACOKINETIC ENDPOINTS AND PHARMACOKINETIC/PHARMACODYNAMIC MODELING ..........36 
4 
STUDY DESIGN ....................................................................................................................37 
4.1 SCREENING PERIOD ..........................................................................................................................38 
4.2 DOSE TITRATION PHASE ..................................................................................................................38 
4.2.1 
Dose Titration and Adjustment Criteria ................................................................................39 
4.2.1.1 
Determination of the Effective and Tolerable Dose of COR-003 (Therapeutic Dose) .................... 40 
4.2.1.2 
Dose Titration to the Therapeutic Dose ........................................................................................... 41 
4.2.2 
Dose Titration Above 600 Mg Total Daily Dose ...................................................................42 
4.3 MAINTENANCE PHASE .....................................................................................................................42 
4.4 TRANSITION FROM MAINTENANCE PHASE TO EXTENDED EVALUATION PHASE ...............................43 
4.4.1 
Exclusion of Treatment Effect Due to Delayed Onset of Radiation Therapy .........................43 
4.5 EXTENDED EVALUATION PHASE ......................................................................................................43 
4.6 STOPPING CRITERIA .........................................................................................................................44 
4.7 OPTIONAL EXPANDED ACCESS PROGRAM .......................................................................................44 
5 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ...........................................45 
5.1 INCLUSION CRITERIA .......................................................................................................................45 
5.2 EXCLUSION CRITERIA ......................................................................................................................47 
5.3 WITHDRAWAL CRITERIA ..................................................................................................................50 
5.3.1 
Withdrawal due QTc Interval Prolongation ..........................................................................50 
5.3.2 
Withdrawal and/or Re-Challenge due to Liver Function Tests (LFTs) .................................51 
6 
STUDY ASSESSMENTS AND PROCEDURES .................................................................52 
6.1 DEMOGRAPHIC/MEDICAL HISTORY ASSESSMENTS ..........................................................................53 
6.2 SAFETY AND EFFICACY ASSESSMENTS ............................................................................................54 
6.2.1 
Physical Examination and Assessment of Clinical Signs and Symptoms of CS .....................54 
6.2.2 
Standard Photographs ...........................................................................................................54 
6.2.3 
Vital Signs ..............................................................................................................................54 
6.2.4 
12-Lead Electrocardiograms (ECG) .....................................................................................55 
6.2.4.1 
Prolongation of QTc Interval > 500 Msec or > 60 Msec Above Baseline ....................................... 56 
6.2.4.2 
Resuming Treatment After Resolution of QTc Prolongation .......................................................... 58 
6.2.5 
Clinical Laboratory Tests ......................................................................................................58 
6.2.5.1 
Pregnancy ........................................................................................................................................ 59 
6.2.5.2 
Action to be Taken if Pregnancy Occurs ......................................................................................... 60 
6.2.6 
Disease-Related Assessments ................................................................................................60 
6.2.6.1 
Urinary Sample Collections ............................................................................................................ 60 
6.2.6.2 
Urinary Sample Analysis ................................................................................................................. 61 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 25 of 119 
CONFIDENTIAL 
 
6.2.6.3 
Late Night Salivary Cortisol ............................................................................................................ 62 
6.2.6.4 
Dexamethasone Suppression Test (DST) ........................................................................................ 62 
6.2.6.5 
ACTH .............................................................................................................................................. 62 
6.2.6.6 
Pituitary Magnetic Resonance Imaging (MRI) ................................................................................ 62 
6.2.6.7 
Oral Glucose Tolerance Test ........................................................................................................... 63 
6.2.6.8 
Quality of Life Measures ................................................................................................................. 63 
6.2.7 
Situations Requiring Additional Safety Monitoring ...............................................................63 
6.2.7.1 
Dose Titration Higher than 600mg/day ........................................................................................... 63 
6.2.7.2 
QTc Prolongation ............................................................................................................................ 63 
6.2.7.3 
Adrenal Insufficiency ...................................................................................................................... 63 
6.2.8 
Pharmacokinetics ..................................................................................................................64 
6.2.8.1 
Pharmacokinetics Sample Collection .............................................................................................. 64 
6.2.8.2 
Pharmacokinetics Sample Analysis ................................................................................................. 64 
6.3 ADDITIONAL CONSIDERATIONS FOR RISK MANAGEMENT ...............................................................64 
6.3.1 
Instructions for Subjects ........................................................................................................64 
6.3.2 
Considerations for Investigator .............................................................................................65 
6.3.3 
Adrenal Insufficiency .............................................................................................................65 
7 
LIFESTYLE AND DIETARY RESTRICTIONS ...............................................................66 
8 
INVESTIGATIONAL PRODUCTS .....................................................................................67 
8.1 DESCRIPTION OF INVESTIGATIONAL PRODUCT .................................................................................67 
8.2 DOSAGE AND ADMINISTRATION.......................................................................................................67 
8.2.1 
Dosage Reduction and use of Dose Level 0 ...........................................................................67 
8.3 DOSE RATIONALE ............................................................................................................................68 
8.4 BLINDING .........................................................................................................................................68 
8.5 RANDOMIZATION AND TREATMENT ASSIGNMENT ...........................................................................68 
9 
DRUG SUPPLIES, DISPENSING, STORAGE AND ACCOUNTING ............................69 
9.1 PRODUCT ACCOUNTABILITY ............................................................................................................69 
9.2 COMPLIANCE ASSESSMENT ..............................................................................................................69 
9.3 TREATMENT OF INVESTIGATIONAL PRODUCT OVERDOSE ................................................................69 
10 
CONCOMITANT MEDICATIONS ....................................................................................69 
10.1 PERMITTED MEDICATIONS ...............................................................................................................69 
10.2 PROHIBITED MEDICATIONS ..............................................................................................................69 
10.3 MEDICATIONS TO BE USED WITH CAUTION ......................................................................................70 
11 
SUBJECT COMPLETION AND WITHDRAWAL ...........................................................71 
11.1 SUBJECT COMPLETION .....................................................................................................................71 
11.2 SUBJECT WITHDRAWAL CRITERIA AND PROCEDURES .....................................................................71 
12 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .......................................71 
12.1 POPULATION FOR ANALYSIS ............................................................................................................71 
12.2 HYPOTHESIS.....................................................................................................................................72 
12.3 SAMPLE SIZE DETERMINATION ........................................................................................................72 
12.4 GENERAL CONSIDERATIONS FOR DATA ANALYSIS ..........................................................................73 
12.4.1 
Premature Withdrawal and Missing Data .............................................................................73 
12.5 FINAL ANALYSES .............................................................................................................................74 
12.5.1 
Safety Analyses ......................................................................................................................74 
12.5.1.1 Extent of Exposure .......................................................................................................................... 74 
12.5.1.2 Adverse Events (AEs) ..................................................................................................................... 74 
12.5.1.3 Clinical Laboratory Evaluations ...................................................................................................... 75 
12.5.1.4 Vital Signs ....................................................................................................................................... 75 
12.5.1.5 Electrocardiograms (ECGs)............................................................................................................. 76 
12.5.1.6 Other Safety Measures .................................................................................................................... 77 
12.5.2 
Efficacy Analyses ...................................................................................................................77 
12.5.2.1 Primary Efficacy Analysis ............................................................................................................... 77 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 26 of 119 
CONFIDENTIAL 
 
12.5.2.2 Secondary Efficacy ......................................................................................................................... 78 
12.5.2.3 Exploratory Efficacy ....................................................................................................................... 80 
12.5.3 
Pharmacokinetics Analysis ....................................................................................................81 
12.5.4 
Pharmacodynamics Analysis .................................................................................................81 
12.5.5 
Subgroup Analyses ................................................................................................................82 
12.5.5.1 Prior Therapy for Cushing’s Syndrome ........................................................................................... 82 
12.5.5.2 Prior Radiation Therapy .................................................................................................................. 82 
12.5.5.3 Hypertensive Subjects ..................................................................................................................... 82 
12.5.5.4 Pre-diabetic/Diabetic Subjects ......................................................................................................... 82 
13 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ........................83 
13.1 DEFINITION OF AN AE ......................................................................................................................83 
13.2 DEFINITION OF A SAE ......................................................................................................................83 
13.2.1 
Disease-Related Events .........................................................................................................84 
13.2.2 
Adverse Events of Special Interest (AESI) .............................................................................84 
13.3 TIME PERIOD, FREQUENCY, AND METHOD OF DETECTING AES AND SAES .....................................85 
13.4 RECORDING OF AES AND SAES .......................................................................................................86 
13.5 EVALUATING AES AND SAES ..........................................................................................................86 
13.5.1 
Severity Rating .......................................................................................................................86 
13.5.2 
Relationship to Study Drug ....................................................................................................86 
13.6 FOLLOW-UP OF AES AND SAES ......................................................................................................87 
13.7 PROMPT REPORTING OF SAES TO SPONSOR .....................................................................................87 
14 
REFERENCES .......................................................................................................................89 
APPENDIX A 
TIME AND EVENTS SCHEDULE ..........................................................................92 
APPENDIX B 
LABORATORY ANALYTES ..................................................................................95 
APPENDIX C 
STUDY MANAGEMENT AND MATERIALS ......................................................96 
APPENDIX D 
ADMINSTRATION AND REGULATORY POLICIES ........................................97 
APPENDIX E 
PUBLICATION POLICY .........................................................................................99 
APPENDIX F 
PROTOCOL AMENDMENT(S) ............................................................................100 
APPENDIX G 
CONDITIONS ASSOCIATED WITH PSEUDO-CUSHING’S SYNDROME ..101 
APPENDIX H 
CRITERIA FOR DIAGNOSES OF PREDIABETES AND DIABETES ............102 
APPENDIX I 
GUIDELINES FOR HYPERTENSION ................................................................103 
APPENDIX J 
CONCOMITANT MEDICATIONS PROHIBITED OR TO BE USED ONLY 
WITH PRIOR PERMISSION ................................................................................104 
APPENDIX K 
SIGNS AND SYMPTOMS OF CONDITIONS TO BE CONSIDERED FOR 
RISK MANAGEMENT ...........................................................................................112 
APPENDIX L 
QUALITY OF LIFE QUESTIONNAIRE .............................................................113 
APPENDIX M 
ASSESSMENT OF CLINICAL SIGNS AND SYMPTOMS OF CUSHING’S 
SYNDROME ............................................................................................................116 
APPENDIX N 
BECK DEPRESSION INVENTORY (BDI-II)......................................................117 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 27 of 119 
CONFIDENTIAL 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACTH 
Adrenocorticotropic hormone 
ADA 
American Diabetes Association 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
βhCG 
Beta human chorionic gonadotropin 
BDI-II 
Beck Depression Inventory  
BID 
Twice daily 
BIPSS 
Bilateral inferior petrosal sinus sampling 
BMI 
Body mass index 
CBG 
Cortisol-binding globulin 
CFR 
Code of Federal Regulations 
CD 
Cushing’s disease 
CI 
Confidence Interval 
CL/F 
Apparent clearance following oral administration 
Cmax 
Peak concentration 
CRF 
Case Report Form 
CRH 
Corticotropin-releasing hormone 
CRP 
C-reactive protein 
CS 
Cushing´s syndrome 
CT 
Computed tomography 
CYP 
Cytochrome P450 
GCP 
Good Clinical Practice 
DBP 
Diastolic blood pressure 
DCCT 
Diabetes Control and Complications Trial 
DILI 
Drug-induced liver injury 
DL 
Dose level 
DRP 
Data restriction plan 
DSMB 
Data Safety Monitoring Board 
DST 
Dexamethasone Suppression Test 
EAP 
Expanded Access Program 
E/T 
Early termination 
ECG 
Electrocardiogram/electrocardiograph 
eGFR 
Estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GEE 
Generalizing estimating equation 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
GR 
Glucocorticoid receptor 
GTT 
Glucose tolerance test 
HbsAg 
Hepatitis B surface antigen 
HbA1c 
Hemoglobin A1C 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 28 of 119 
CONFIDENTIAL 
 
HDL 
High density lipoprotein 
HDPE 
High Densitiy polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human immunodeficiency virus 
HPLC/MS/MS 
High pressure liquid chromatography tandem mass spectroscopy 
HR 
Heart rate 
IC50 
Half-maximal suppression 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IGF-1 
Insulin-like Growth Factor-1 
Imax 
Maximal suppression of UFC 
IPSS 
Inferior petrosal sinus sampling 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IU 
International Unit 
IUD 
Intrauterine device 
Ka 
Absorption rate constant 
LDL 
Low density lipoprotein 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LOCF 
Last observation carried forward 
LSMEAN 
Least Squares Mean 
M 
Maintenance 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDRD 
Modified Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
MR 
Mineralocorticoid receptor 
MRI 
Magnetic Resonance Imaging 
NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Non-alcoholic steatohepatitis 
NCI-CTCAEv4 
National Cancer Institute Common Terminology for Adverse Events, 
Version 4.0 
NGSP 
National Glycohemoglobin Standardization Program 
OGTT 
Oral glucose tolerance test 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per protocol 
PR 
Progesterone receptor 
PT 
Prothrombin time 
PTT 
Prothromboplastin time 
QD 
Once daily 
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 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 29 of 119 
CONFIDENTIAL 
 
RBC 
Red blood cell 
RLOCF 
Restricted last observation carried forward 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOP 
Standard operating proceure 
SPM 
Study procedures manual 
t½ 
Half-life 
T4 
Thyroxine 
T2DM 
Type 2 diabetes mellitus 
TBN 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TKI 
Tyrosine kinase inhibitors 
TSH 
Thyroid stimulating hormone 
UFC 
Urinary free cortisol  
ULN 
Upper limit of normal 
V/F 
Apparent volume of distribution following oral administration 
WBC 
White blood cell 
WNL 
Within normal limits 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 30 of 119 
CONFIDENTIAL 
 
1 
INTRODUCTION  
1.1 Disease Background 
Endogenous Cushing´s syndrome (CS) is a rare, serious and potentially lethal endocrine 
disease caused by chronic elevated cortisol exposure to human organs. The incidence of 
CS has been estimated to be 2-3 cases per million per year [Lindholm 2001, Steffensen 
2010]. The prevalence of CS has been reported to be 30-60 cases per million [Dalton 
1974, Kreutzer 2009, Pivonello 2005, Sharma 2011]. Patients with incompletely 
controlled disease are seriously ill and have a 4 to 5-fold higher mortality rate than age-
and gender matched controls, mainly due to metabolic and cardiovascular complications 
[Lindholm 2001, Mancini 2004, Pivonello 2005]. 
Treatment options for CS include surgery, radiation therapy and medical treatment.  
Medical treatment is used to suppress excessive cortisol production or activity and 
ameliorate its clinical manifestations, prior to surgery, in patients awaiting the effects of 
radiation therapy [Nieman 2002], or in cases when surgery is delayed, contraindicated, or 
unsuccessful.  As such, normalization of 24-hour urinary free cortisol (UFC) and normal 
serum or plasma cortisol levels from a low-dose overnight dexamethasone suppression test 
(DST) are considered adequate markers of disease remission [Bochicchio 1995].  More 
recently, measurement of late night salivary cortisol levels is gaining clinical importance.  
Conversely, the persistence of high or only modestly reduced UFC levels argues for 
treatment failure.  
Ketoconazole (Nizoral®, comprised of two enantiomers: 2S,4R- and 2R,4S-ketoconazole) 
is an antifungal agent that, at higher dosages, reduces adrenal steroid production via 
inhibition of multiple steroidogenic enzymes, e.g. 11β-hydroxylase, 17α-hydroxylase and 
aldosterone synthase [Engelhardt 1991, Sonino 1987, Nizoral 2002]. One publication has 
reported a direct effect on ectopic adrenocorticotropic hormone (ACTH) secretion by 
ketoconazole. [Steen 1991]. Because of these properties of ketoconazole, it is a commonly 
used off-label drug for treatment of CS in the US and is approved for the treatment of CS 
in Europe and elsewhere [DeMartin 2006, Daniel 2015, Castinetti 2014, Nizoral 2013 
Product Insert, Ketoconazole 2014 HRA Assessment Report]. 
When patients are treated with ketoconazole, adrenal insufficiency is avoided by 
adjusting the dose to allow normal cortisol levels.  The most frequent adverse effects of 
ketoconazole are nausea, vomiting, abdominal pain and pruritus.  Abnormal liver 
function tests (LFTs), primarily of the hepatocellular type, can occur.  Rarely does severe 
hepatotoxicity occur.  Early markers for these side effects are elevations in serum alkaline 
phosphatase (AP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and bilirubin, which are monitored at regular intervals during treatment [Ketoconazole 
2014 HRA Assessment Report, Nizoral 2013 Product Insert, Lake-Bakaar 1987; Lewis 
1984]. 
Cortendo AB is developing COR-003, also known as levoketoconazole, the 2S,4R 
enantiomer of ketoconazole, as an investigational new drug for the treatment of cortisol 
hypersecretion in CS.  It is hypothesized that COR-003 may prove to be both safer and 
more efficacious than ketoconazole.  


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 31 of 119 
CONFIDENTIAL 
 
COR-003 has a significantly lower IC50 (50% inhibitory concentration) towards key 
enzymes in cortisol synthesis (11β -hydroxylase, IC50 = 150 nM; 17-α-hydroxylase 
[CYP17], IC50 = 48 nM) than the 2R,4S enantiomer of ketoconazole (IC50 = 680 nM 
and 1800 nM, respectively, thus potentially allowing a lower dose of drug to achieve the 
same efficacy [Rotstein 1992, unpublished results from Moulder Center for Drug 
Discovery Research, Temple University School of Pharmacy, 2012]. In rats, COR-003 
was more potent with respect to reducing corticosterone (the major glucocorticoid in 
rodents) than either the 2R, 4S-enantiomer or ketoconazole [Cortendo Report Number 
2002-02-21]. 
Although elevations in LFTs associated with ketoconazole [Daneshmend 1988, Kucers 
1997, Whitehouse 1994] are generally modest in nature and reversible following 
cessation of treatment, in rare cases (1 in 10,000 to 15,000 patients) severe hepatotoxicity 
may occur [Lewis 1984], and in extremely rare cases this adverse reaction may be 
irreversible and life-threatening. Preclinical data suggest that COR-003 may pose less 
risk to impair hepatic function than ketoconazole. 2S,4R-ketoconazole has 12-fold higher 
IC50 towards CYP7A (IC50 = 2.4 μM) than does 2R,4S-ketoconazole 
(IC50 = 0.195 μM) [Rotstein 1992]. CYP7A is the first and rate-limiting enzyme in the 
major (classical) liver pathway for production of bile acids, catalyzing 7α-hydroxylation 
of cholesterol and other oxysterols. Inhibition of this enzyme can lead to functional 
cholestasis and consequent accumulation of potentially toxic metabolites such as bilirubin 
and xenobiotics such as ketoconazole itself. 
Another property that suggests potentially improved safety of 2S,4R-ketoconazole 
compared to ketoconazole relates to the pharmacokinetics (PK) of the 2S,4R and 2R,4S 
enantiomers, which have been studied in humans after oral administration of 
ketoconazole or COR-003 [Gerber 2003, Schindler 2003, Schwartz 2008]. The 
enantiomers in ketoconazole are present in equal amounts, but following ketoconazole 
oral administration blood concentrations of the 2S,4R enantiomer exceed those of the 
2R,4S enantiomer by approximately 3-fold [Gerber 2003], suggesting preferred 
extraction of the 2R,4S enantiomer by the liver. Reduced hepatic exposure to the 2S,4R 
enantiomer (COR-003) may be of value in reducing the liver function abnormalities 
observed following administration of racemic ketoconazole. 
COR-003 has been previously administered to healthy volunteers and human subjects 
with Type 2 Diabetes Mellitus (T2DM).  Doses of COR-003 over the range of 200 mg to 
600 mg once daily (QD) for up to 14 days and 150 mg to 450 mg for up to 4 months were 
shown to be generally well tolerated in all of these studies, with an adverse effect profile 
similar to that of ketoconazole.  Please refer to the Investigator’s Brochure for a detailed 
description of all prior preclinical and clinical studies conducted with COR-003. 
1.2 Rationale for Study Design 
This study is the first and pivotal clinical trial investigating the safety and efficacy of 
COR-003 in subjects with endogenous CS.  This is an open label, single arm study with a 
Screening Phase, a Dose Titration Phase, a 6-month Maintenance Phase, and a 6-month 
Extended Evaluation Phase. An open label, single arm design was chosen, since a 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 32 of 119 
CONFIDENTIAL 
 
concurrent placebo control as monotherapy was deemed unethical, and an approved drug 
to serve as active control (monotherapy) or as background therapy (adjunctive therapy) 
suitable for an international study population was unavailable. Pasireotide, which is 
approved in the EU and US, has a different mode of action at the tumor level and 
therefore an indication for Cushing’s disease (CD) only, and is an injectable with a 
different safety profile, including hyperglycemia, which would preclude blinding and 
confound evaluation of efficacy and safety signals. 
The chosen design has considered the reported experience treating CS patients with 
ketoconazole [Castinetti 2014].  Like ketoconazole, dosing of COR-003 needs to be 
individualized, since therapeutic need varies considerably among patients.  Response to 
therapy (i.e. normalization of UFC and clinical signs and symptoms) is equally variable 
and results in a wide range of effective doses, each tailored to an individual patient.  As 
such, the design of this study includes an initial Dose Titration Phase that will identify a 
tolerable and effective dose for each subject, which will then be administered during the 
subsequent Maintenance Phase of the study, intended to be without further dose 
increases. The Maintenance Phase was designed to demonstrate durability of the 
therapeutic response and, together with the Extended Evaluation Phase, provides 
long-term efficacy and safety data.  
2 
OBJECTIVES 
2.1 Primary Objective 
• To evaluate the clinical responder rate, defined as the proportion of subjects with 
normal UFC after 6 months of treatment with COR-003 in the Maintenance Phase 
without dose increase, and to evaluate the range of effective doses in subjects with 
various levels of hypercortisolism. 
2.2 Secondary Objectives 
• To identify the proportion of subjects with clinical response, defined as reduction 
in mean 24-hour UFC levels to below or equal to the upper limit of normal 
(≤ ULN) after each month of treatment with COR-003 without a dose increase 
during the Maintenance Phase; 
• To identify the proportion of subjects with complete or partial response, defined 
as ≥50% reduction of 24-hour UFC levels from Baseline after each of the 
6 months of treatment with COR-003 without a dose increase during the 
Maintenance Phase; 
• To characterize changes in 24-hour UFC levels from Baseline during the 
6 months of treatment with COR-003 in the Maintenance Phase regardless of dose 
increases; 
• To characterize shifts in normality for 24-hour UFC levels from Baseline during 
the 6 months of treatment with COR-003 in the Maintenance Phase regardless of 
dose increases;  
• To characterize changes in serum and late night salivary cortisol concentrations 
during the 6 months of treatment with COR-003 in the Maintenance Phase; 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 33 of 119 
CONFIDENTIAL 
 
• To assess the effects on Clinical Signs and Symptoms of CS, the quality of life 
(QoL) measures obtained from the Cushing QoL questionnaire and the severity of 
depression obtained from the Beck’s Depression Inventory II in the Maintenance 
Phase; 
• To evaluate changes in the biomarkers of CS comorbidities (diabetes, 
hypertension, hypercholesterolemia and obesity) in the Maintenance Phase; 
• To assess the safety and tolerability of COR-003. 
2.3 Exploratory Objectives 
• To assess the clinical responder rate (defined for the initial inference of efficacy 
as the proportion of subjects with normal 24-hour UFC levels after 6 months of 
treatment with COR-003 in the Maintenance Phase without dose increase) beyond 
6 months of treatment (Extended Evaluation Phase); 
• To assess the proportion of subjects with complete or partial response (defined for 
the initial inference of efficacy as ≥50% reduction of 24-hour UFC levels from 
Baseline after 6 months of treatment with COR-003 in the Maintenance Phase 
without dose increase) beyond 6 months of treatment (Extended Evaluation 
Phase); 
• To characterize changes in 24-hour UFC levels from Baseline beyond 6 months of 
treatment with COR-003 (Extended Evaluation Phase); 
• To characterize shifts in normality for 24-hour UFC levels from Baseline beyond 
6 months of treatment with COR-003 (Extended Evaluation Phase);  
• To characterize changes in serum and late night salivary cortisol concentrations 
beyond 6 months of treatment with COR-003 (Extended Evaluation Phase); 
• To assess the effects on Clinical Signs and Symptoms of CS, the QoL measures 
obtained from the Cushing QoL questionnaire and the severity of depression 
obtained from the Beck’s Depression Inventory II beyond 6 months of treatment 
with COR-003 (Extended Evaluation Phase); 
• To evaluate changes in the biomarkers of CS comorbidities (diabetes, 
hypertension, hypercholesterolemia and obesity) beyond 6 months of treatment 
with COR-003 (Extended Evaluation Phase); 
• To describe the Clinical Benefit after 6 months of treatment with COR-003 in the 
Maintenance Phase, and after 9 and 12 months of treatment (Extended Evaluation 
Phase) as defined in Section 3.3; 
• To assess changes in anti-diabetic, anti-cholesterol and antihypertensive therapies 
after 6 months of treatment with COR-003 in the Maintenance Phase, and after 9 
and 12 months of treatment (Extended Evaluation Phase); 
• To assess the change in clinical signs of hypercortisolism obtained from 
standardized photographs and rated by an adjudication committee after 3 and 
6 months of treatment with COR-003 in the Maintenance Phase, and after 
12 months of treatment (Extended Evaluation Phase). 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 34 of 119 
CONFIDENTIAL 
 
2.4 Pharmacokinetic/Pharmacodynamic Objectives  
• To evaluate the PK of COR-003 in subjects with CS; 
• To explore the dose-response relationship for safety, including dose-response for 
adverse events of special interest (AESI) such as QTc, if data allow; 
• To explore the dose-response relationship for reduction of UFC levels, if data 
allow. 
3 
ENDPOINTS 
3.1 Primary Endpoint 
• Proportion of subjects with response to COR-003, defined as reduction in mean 
24-hour UFC levels to below or equal to the upper limit of normal (≤ ULN) 
following 6 months of Maintenance Phase therapy without a dose increase during 
that phase, summarized by Maintenance Phase dose level and overall. 
3.2 Secondary Endpoints 
• Proportion of subjects with clinical response to COR-003, defined as mean UFC 
level ≤ ULN, to be determined after 1, 2, 3, 4 and 5 months of dosing without a 
dose increase in the Maintenance Phase;  
• Proportion of subjects with complete or partial response to COR-003, defined as 
mean UFC level ≥ 50% reduction from Baseline after 1, 2, 3, 4, 5 and 6 months of 
dosing without a dose increase in the Maintenance Phase; 
• Change and percentage change from Baseline in mean 24-hour UFC levels after 
1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase regardless of dose 
increases; 
• Shift in UFC normality categories from Baseline to 1, 2, 3, 4, 5 and 6 months of 
dosing in the Maintenance Phase regardless of dose increases; 
• Change and percentage change from Baseline in serum and late night salivary 
cortisol levels after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; 
• Changes from Baseline in Clinical Signs and Symptoms of CS after 1, 2, 3, 4, 5 
and 6 months of dosing in the Maintenance Phase;  
• Changes from Baseline in the QoL measures obtained from the Cushing QoL 
questionnaire and the severity of depression obtained from the Beck’s Depression 
Inventory II after 3 and 6 months of dosing in the Maintenance Phase; 
• Change from Baseline in CS comorbidities biomarkers (fasting glucose, 
hemoglobin A1C [HbA1c], systolic blood pressure [SBP], diastolic blood 
pressure [DBP], total cholesterol, low and high density lipoproteins [LDL, HDL, 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 35 of 119 
CONFIDENTIAL 
 
respectively], and body weight) after 1, 2, 3, 4, 5 and 6 months of dosing in the 
Maintenance Phase; 
• Changes from Baseline for oral glucose tolerance test (OGTT) (pre-diabetics 
only) and spot albumin/creatinine ratio as a measure of microalbuminuria (only if 
abnormal at Baseline) after 3 and 6 months of dosing in the Maintenance Phase; 
• Changes from Baseline for C-reactive protein (CRP) after 1, 2, 3, 4, 5 and 
6 months of dosing in the Maintenance Phase; 
• Safety evaluations will include clinical observations and adverse event (AE) 
reporting, vital signs (SBP, DBP, body weight, body mass index [BMI]), 
electrocardiograms (ECGs), hematology, chemistry panels (inclusive of expanded 
markers of liver function, ACTH, Insulin-like Growth Factor-1 (IGF-1) and 
testosterone concentrations), dipstick urinalysis (microscopic evaluation, if 
dipstick positive), tumor size by magnetic resonance imaging (MRI) as 
applicable. 
3.3 Exploratory Endpoints 
• Proportion of subjects with long-term clinical response to COR-003, defined as 
mean UFC level ≤ ULN, after 9 and 12 months (Extended Evaluation Phase); 
• Proportion of subjects with long-term complete or partial response to COR-003, 
defined as mean UFC level ≥ 50% reduction from Baseline after 9 and 12 months 
(Extended Evaluation Phase); 
• Change and percentage change from Baseline in mean 24-hour UFC levels after 
9 and 12 months (Extended Evaluation Phase); 
• Shift in UFC normality categories from Baseline at 9 and 12 months (Extended 
Evaluation Phase); 
• Change and percentage change from Baseline in serum and late night salivary 
cortisol levels after 9 and 12 months (Extended Evaluation Phase); 
• Changes from Baseline in Clinical Signs and Symptoms of CS, on the QoL 
measures obtained from the Cushing QoL questionnaire, and on the severity of 
depression obtained from the Beck’s Depression Inventory II after 9 and 
12 months of dosing (Extended Evaluation Phase); 
• Change from Baseline in CS comorbidities biomarkers (HbA1c, SBP, DBP, total 
cholesterol, LDL, HDL and body weight) after 9 and 12 months of dosing 
(Extended Evaluation Phase); 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 36 of 119 
CONFIDENTIAL 
 
• Changes from Baseline for OGTT (pre-diabetics only) and spot 
albumin/creatinine ratio as a measure of microalbuminuria (only if abnormal at 
Baseline) after 9 and 12 months of dosing (Extended Evaluation Phase);  
• Changes from Baseline for CRP after 9 and 12 months of dosing (Extended 
Evaluation Phase); 
• Clinical benefit rate determined after 1, 2, 3, 4, 5 and 6 months of dosing in the 
Maintenance Phase and at 9 and 12 months (Extended Evaluation Phase). Clinical 
benefit is defined as follows: 
1. Clinical response as indicated by UFC ≤ ULN, and 
2. No increase in COR-003 dose during Maintenance Phase, and 
3. A clinically meaningful improvement in any one Baseline CS comorbidity 
(diabetes, hypertension, hypercholesterolemia, weight) as defined in the 
Statistical Analysis Plan (SAP), and  
4. No study drug related treatment-emergent adverse event (TEAE) classified as 
severe or worse. 
• Changes in the doses of concomitant medications and in particular anti-diabetic, 
anti-cholesterol and antihypertensive medications after 6 months of dosing with 
COR-003 during the Maintenance Phase and during the Extended Evaluation 
Phase relative to Baseline doses of such medications; 
• Changes in the severity score for clinical signs of hypercortisolism obtained from 
standardized photographs and rated by an adjudication committee after 3 and 
6 months of dosing with COR-003 during the Maintenance Phase and at 
12 months in the Extended Evaluation Phase. 
3.4 Pharmacokinetic Endpoints and Pharmacokinetic/Pharmacodynamic 
Modeling 
• Estimate the following parameters using population PK modeling: clearance 
(CL/F), volume of distribution (V/F), absorption rate constant (Ka) with 
associated between subject variability where feasible. These parameters will be 
used to calculate half-life (t½), area under the concentration-time curve (AUC) 
and peak concentration (Cmax) if feasible.  Because the PK of ketoconazole are 
reported to change over time, time dependent changes in CL/F, AUC and t½ will 
be investigated, and if identified, will be incorporated into the model.   
• Estimate the following pharmacodynamic (PD) parameters: COR-003 
concentration producing half-maximal UFC suppression (IC50), the maximal 
suppression of UFC (Imax) and associated estimates of between subject 
variability, if feasible. The range of UFC reduction by dose will be explored.  
• Other safety and efficacy endpoints will also be explored graphically by dose or 
summary metrics of exposure. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 37 of 119 
CONFIDENTIAL 
 
• The relationship of AESI including QTc interval to dose of COR-003 will be 
evaluated if data allow. 
• The relationship of UFC reduction to dose of COR-003 will be evaluated if data 
allow. 
4 
STUDY DESIGN 
This is a single arm, open label, dose titration study to assess efficacy, safety, tolerability, 
and PK of COR-003 in subjects with endogenous CS as illustrated in Figure 1.  The range 
of effective doses for COR-003 in this CS population will also be established.  Following 
an initial screening and washout period, as applicable, this study will be conducted in 
3 treatment phases as follows: 
• Dose Titration Phase:  approximately 2 to 21 weeks to achieve an effective and 
tolerable maximum dose (the Therapeutic Dose)—see Section 4.2 for details; 
• Maintenance Phase:  6 months of treatment at the Therapeutic Dose following 
the Dose Titration Phase; 
• Extended Evaluation Phase: 6 months of continued treatment after the 
Maintenance Phase. 
Figure 1 
Study Design 
 
 
Efficacy will be assessed by measuring UFC levels and other endpoints at the times 
indicated in the Time and Events Table (Appendix A). 
Blood samples for PK determination will be collected as described in Section 6.2.8.1.  
Note that the times indicated in the Time and Events Table (Appendix A) are indicative 
of potential collection times and do not apply to each subject. 
Safety data will be collected at the times indicated in the Time and Events Table and as 
described in Section 6.2.  Adequate medical coverage will be provided by the 
Investigator at all times during the course of the study (including nights, weekends and 
holidays) to ensure that prompt safety decisions can be made and appropriate medical 
interventions provided.  The Investigator should provide all subjects with instructions on 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 38 of 119 
CONFIDENTIAL 
 
how to access the medical staff regardless of day and time in order to obtain medical 
care.  An independent Data Safety Monitoring Board (DSMB) will review the safety of 
the drug throughout the study.  At a minimum, the DSMB membership will consist of an 
endocrinologist with expertise in the treatment and clinical investigation of CS; a 
gastroenterologist/hepatologist with expertise in the assessment of abnormal LFTs and 
hepatotoxicity during clinical study conduct; and an expert in the evaluation of QTc 
interval during clinical study conduct/clinical pharmacologist. The full extent of 
responsibilities by the DSMB is defined in its charter. 
Subjects completing the 6-month Maintenance Phase of the study with COR-003 will 
remain in the study for an additional 6 months for extended evaluations of safety and 
efficacy of COR-003 treatment (Extended Evaluation Phase).   
At the completion of the 6-month Extended Evaluation Phase, subjects may be eligible to 
enter an expanded access program and receive continued treatment with COR-003 in 
accordance with local regulations.  If the program is not available at their location, or 
they are not eligible to participate or do not wish to consent to the program, after 
completion of the Follow-Up Visit they will be promptly referred back to their 
endocrinologist (if not the Investigator) for further management according to the local 
standard of care, and based on their preceding medical history.  (Note: As subjects 
entering the expanded access program for COR-003 will not be discontinuing treatment 
with COR-003, they will not be required to complete the Follow-Up Visit for this study.) 
4.1 Screening Period 
After signing the informed consent, subjects will enter the Screening Period.  After 
performing initial Screening assessments, subjects on previous CS medical therapies or 
other prohibited medications must enter a washout period, as applicable (see Section 5) 
before completing all Screening assessments detailed in the Time and Events Table 
(Appendix A).  Baseline measurements will be obtained as part of the Screening 
assessments, after washout and completion of all initial Screening procedures. 
If a subject does not initially meet the eligibility requirements described in Section 5, 
they might be eligible to re-screen but only if their underlying condition has changed in 
the interim such that they are now likely to meet study eligibility criteria. Such 
re-screenings will be exceptional circumstances, and all re-screenings require prior 
permission of the study Medical Monitor before they begin. 
4.2 Dose Titration Phase 
After confirmation of eligibility at the Baseline Visit, including confirmation of increased 
UFC levels as per eligibility requirements, each subject will return to the investigational 
site to receive study medication and will begin dosing at dose level 1 (DL1) with an 
initial dose of 150 mg twice daily (BID), taken as one tablet in the morning and one tablet 
in the evening.  Decisions for subsequent dose increases will be based on an assessment 
of each subject’s UFC levels and safety data (i.e. tolerability of therapy) and will be made 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 39 of 119 
CONFIDENTIAL 
 
by the Investigator.  The interval between dose adjustments will be approximately 
18 days (±4 days) 
4.2.1 Dose Titration and Adjustment Criteria 
COR-003 will be administered BID according to the titration scheme in Table 1 until one 
of the following criteria has been met:  
• Mean 24-hour UFC levels ≤ULN as established for the assay being used at a central 
laboratory 
• Highest protocol-specified dose reached 
• Highest tolerated dose reached (in the opinion of the Investigator) 
Table 1 
Dosing Titration Scheme 
Dose Level (DL)* 
Morning dosing 
Evening Dosing 
DL1 
150 mg 
150 mg 
DL2 
150 mg 
300 mg 
DL3 
300 mg 
300 mg 
DL4 
300 mg 
450 mg 
DL5 
450 mg 
450 mg 
DL6 
450 mg 
600 mg 
DL7 
600 mg 
600 mg 
*DL0, permitted for dose reductions, is a dose of 150 mg once daily administered in the evening, 
except on the day of the in-clinic procedures, when the dose should be administered in the clinic 
(see Section 8.2.1). 
All subjects will be asked to collect two adequate 24-hour urine specimens starting at 
Day 10 (±1 day) after the start of each dose level, ideally on two consecutive days.  The 
subjects are asked to bring or ship per courier service their two urine collections to the 
clinic, as soon as possible (approximately Day 12) for measurement of 24-hour UFC 
levels from each sample.  Urine volume and creatinine will be measured as markers of 
the adequacy of each collection (see Section 6.2.6.1 for definition).  Subjects will 
continue on their current dose of COR-003 until the UFC results have been obtained from 
the central laboratory (within approximately 2-4 days of shipment).  Based on their UFC 
results and tolerability, subjects will be asked to do one of the following:  
• Return to the clinic for scheduled assessments and receive the first dose of drug 
for the next Dose Titration interval; 
• Have a confirmatory UFC evaluation (e.g. two additional UFC measurements to 
determine if the Therapeutic Dose of COR-003 has been reached; 
Section 4.2.1.1); or 
• Enter the Maintenance Phase (if an alternative determination of Therapeutic Dose 
of COR-003 has been made; Section 4.2.1.1) as applicable.  


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 40 of 119 
CONFIDENTIAL 
 
4.2.1.1 Determination of the Effective and Tolerable Dose of COR-003 
(Therapeutic Dose) 
When a subject achieves normalized UFC results (≤ULN for UFC) from the mean of the 
first two adequately collected 24-hour urine samples, two additional 24-hour urine 
samples will be collected and returned to the clinic for submission to the central 
laboratory.  Subjects should be contacted as soon as the results from the first two 24-hour 
urine samples are received to ask them to begin the next two 24-hour urine collections.   
A Therapeutic Dose for a subject will be considered established when mean UFC levels 
(determined from a total of four adequate 24-hour urine collections) are ≤ULN of the 
assay, or the maximum dose allowed has been reached, or a clinically meaningful partial 
response and the maximal tolerated dose has been reached.  Once the Therapeutic Dose 
has been reached the subject can begin the Maintenance Phase of the study. 
Steps for Determination of Therapeutic Dose 
• If the mean value for the first two UFC test levels is ≤ULN of the assay of two 
adequate 24-hour urine collections, the subject should be notified immediately and 
asked to begin the next two 24-hour urine collections, for the purpose of confirming a 
biochemical response.  The two additional urine collections should be completed and 
returned to the clinic, as soon as practical (for example, if samples were provided to 
site on Day 12 following the dose escalation visit and results were received on Day 15, 
the subject should ideally begin collection the following day (Day 16) and return the 
two additional samples to the site immediately upon completion of collection (Day 
18).  The next visit for the subject should be scheduled to coincide with receipt of the 
results (Day 30 [±7 days]) and the mean of the four UFC test values is available to 
make the determination of whether or not the Therapeutic Dose has been achieved. 
• When confirmatory urine sample collection is required, in order to allow for adequate 
time for urine sample collection and analysis between visits, the subject should return 
no later than 37 days after the prior dose escalation visit for either the next dose 
escalation visit or start of the Maintenance Phase (based on the mean of the four UFC 
values) [NOTE: Always ensure that the subject has an adequate supply of COR-003 to 
cover the duration between visits.] 
• If the mean value of four adequate 24-hour urine collections is ≤ULN of the assay, the 
subject may enter the Maintenance Phase at the current dose level (i.e. Therapeutic 
Dose level) [Section 4.3].  The total duration of the Titration Phase should not be any 
longer than approximately 21 Weeks; assuming approximately 3 weeks of treatment 
for each dose level. 
• If the mean value of four adequate 24-hour urine collections is >ULN of the assay of 
four adequate 24-hour urine collections, the subject should proceed to the next Dose 
Level. 
Alternative Determination of Therapeutic Dose 
• If the subject has reached the highest allowed dose level and UFC levels remain 
>ULN of the assay for the mean of two adequate 24-hour urine collections, yet there is 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 41 of 119 
CONFIDENTIAL 
 
a clinically meaningful partial response from Baseline, the subject may enter the 
Maintenance Phase at that dose level. 
• If the subject has reached the highest tolerated dose and UFC levels remain >ULN of 
the assay for the mean of two adequate 24-hour urine collections, yet there is a 
clinically meaningful partial response from Baseline, the subject may enter the 
Maintenance Phase at that dose level at the discretion of the Investigator. 
• If UFC is >ULN and LFTs are elevated, the Investigator may maintain the dose in the 
Dose Titration Phase in consultation with the Medical Monitor before a decision is 
made to progress to the next dose level or into Maintenance Phase.  
NOTE:  If UFC levels remain >ULN of the assay for the mean of two adequate 24-hour 
urine collections, and there is no clinically meaningful partial response from Baseline 
upon reaching the highest allowed dose or the highest tolerated dose, discontinuation 
should be considered. Consultation with the Medical Monitor is encouraged. 
4.2.1.2 Dose Titration to the Therapeutic Dose 
Subjects will continue the process of dose titration until the Therapeutic Dose has been 
reached (Section 4.2.1.1).  
• If UFC levels are >ULN of the assay for the mean of two adequate 24-hour urine 
collections, the dose should be increased to the next dose level, unless the highest 
tolerable dose or the highest protocol-specified dose has already been reached. 
• If UFC levels are >ULN of the assay for the mean of two adequate 24-hour urine 
collections, the subject should return no later than 22 days (18 days ± 4 days) after 
the prior dose escalation visit for the next dose escalation visit. 
Other factors that are to be considered during the Dose Titration Phase: 
• Subjects will have ECG evaluations at Baseline and within approximately 1 to 
2 hours after drug administration (i.e., at ~ Cmax) during the Dose Titration Phase at 
each dose level), monthly (at the Therapeutic Dose) during the Maintenance Phase 
and at each visit during the Extended Evaluation Phase using the Spaulding ECG 
device for collection of up to 5 minutes of continuous ECG (Section 6.2.4).  The dose 
of study medication will be reduced if the confirmed COR-003-related QTc interval 
persistently increases to >500 msec or >60 msec from Baseline. Please refer to 
Section 5.3.1 where guidance to the Investigator on the assessment of the prolonged 
QTc interval is provided in detail.  
• If the subject develops signs and/or symptoms of adrenal insufficiency (e.g., 
orthostatic hypotension, nausea, vomiting, abdominal pain), based on further 
investigation (see Section 6.3.3) and clinical judgment, the Investigator may 
temporarily stop dosing of the study medication to allow resolution of these 
symptoms.  In such cases, at the discretion of the Investigator, the dose will be 
reduced and restarted at a preceding dose level (see Section 6.2.4.2).  In the event that 
this observation is made at DL1, the subjects may receive a lower dose of 150 mg 
once daily (DL0) based on the medical discretion of the Investigator and agreement 
with the Sponsor.  Subjects may resume the Dose Titration scheme after a dose 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 42 of 119 
CONFIDENTIAL 
 
reduction at the discretion of the Investigator and agreement with the Sponsor.  See 
Section 6.3.3 for details on assessment of signs and symptoms of adrenal 
insufficiency.  
4.2.2 Dose Titration Above 600 Mg Total Daily Dose 
COR-003 has only been dosed up to 600 mg/day in diabetic subjects. The safety in 
subjects at doses beyond 600 mg/day is unknown. For this reason, subjects that reach 
total daily doses of > 600 mg/day (i.e., doses of 750, 900, 1050, and 1200 mg/day) must 
be monitored more closely in order to ensure proper evaluation of the safety of doses at 
these levels.  In addition to the assessments that will be carried out during dose escalation 
for doses ≤600 mg/day, for each dose escalation beyond 600 mg/day, subjects will be 
asked to return for one additional safety evaluation 7 days (±3 days) after each dose 
escalation to include the following assessments:  AEs, vital signs, routine safety 
laboratory assessments (including LFTs), ECGs, and morning serum cortisol levels as 
outlined in Time and Events Table (Appendix A).  Subjects will be advised to contact the 
Investigator immediately in the event of developing adrenal insufficiency (see 
Section 6.3) or other AEs at any time. 
• Return 7 days (±3 days) after each dose level escalation visit for DL4 through DL7 for 
additional safety assessment (see Section 6.2.7.1);  
• Start the collection of two adequate 24-hour urine samples 10 days (±1 day) after the 
dose level escalation visit for DL4 through DL7 - provide containers to sites as soon as 
possible after completion (approximately 12 days after dose level escalation); 
• If the mean value for the first two adequate 24-hour urine collections is >ULN of the 
assay, the subject should return no later than 22 days (18 days ± 4 days) after the prior 
dose escalation visit for next dose escalation visit;  
• If the mean value for the first two adequate 24-hour urine collections is ≤ULN of the 
assay and additional UFC tests are needed to confirm the mean value of ≤ULN, the 
subject should be notified to collect an additional two 24-hour urine samples and 
return them to the site, as soon as possible after completion (see timing details in 
Section 4.2.1.1).  
 
The results of relevant assessments should be available promptly in order for the 
Investigator to make decisions for the safety of the subject.  Reports of Serious Adverse 
Events (SAEs) experienced at these higher doses will be shared with all Investigators 
regularly during the study.  
4.3 Maintenance Phase 
By convention, the very first visit during the Maintenance Phase will be called “Month 1” 
and will take place on the first day of Month 1 of the Maintenance Phase. After the 
Month 1 visit, subjects will be asked to return to the clinic monthly (every 30 ± 7 days) 
for approximately 6 months for assessment of efficacy and safety (as outlined in the Time 
and Events Table [Appendix A]).   


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 43 of 119 
CONFIDENTIAL 
 
During the Maintenance Phase, doses may not be increased to maintain UFC levels at or 
below ULN of the assay unless it is confirmed that a dose increase is deemed medically 
necessary, based on a totality of evidence including other disease markers or symptoms, 
at the discretion of the Investigator after discussion with the Medical Monitor.  The 
reason for this restriction is that some variability in mean UFC levels from two urine 
collections is expected, and such variability in and of itself is not considered a sufficient 
reason for further dosage adjustment. If it is deemed medically necessary, prior to 
increasing the dose during the Maintenance Phase, two additional adequate 24-hour urine 
collections should be obtained within 2 weeks of the first UFC samples to provide a total 
of four UFC samples for analysis.  If confirmed hypercortisolemia is present, the COR-
003 dose may be increased by 150-mg increments as medically indicated up to the 
maximally allowed dose of 1200 mg/day, and the subject may stay in the study through 
completion. 
During the Maintenance Phase the COR-003 dose may also be reduced temporarily or 
permanently for safety reasons, including but not limited to LFT elevation (see 
Section 5.3.2, instructions for re-challenge), QTc prolongation (Section 5.3.1) and 
adrenal insufficiency (Section 6.3.3). If medically indicated, the dose should be resumed 
at the individual’s Therapeutic Dose.  All dose adjustments during the Maintenance 
Phase must be documented.  
4.4 Transition from Maintenance Phase to Extended Evaluation Phase 
Prior to the End of Maintenance Phase Visit, four complete 24-hour urine collections will 
be obtained and subjects may enter the Extended Evaluation Phase (Section 4.5).   
4.4.1 Exclusion of Treatment Effect Due to Delayed Onset of Radiation 
Therapy 
Previously irradiated subjects must stop treatment with COR-003 for at least 
2 weeks after the end of the 6-month Maintenance Phase (End of Maintenance 
Phase Visit) and provide four complete 24-hour urine collections for UFC 
measurements collected at least 14 days following the End of Maintenance Phase 
Visit.  If the 24-hour UFC results indicate that UFC levels are elevated, the subject may 
subsequently restart therapy and continue into the Extended Evaluation Phase, at the 
discretion of the Investigator (Section 4.5).  [NOTE: Subjects restarting therapy should 
initiate therapy as soon as the need is identified and should return for their next in-clinic 
visit (M9) for study assessments and resupply of study medication 90 days (±14 days) 
from the End of Maintenance Visit.] 
4.5 Extended Evaluation Phase 
The end of the Maintenance Phase visit will be the start of the Extended Evaluation 
Phase. In the 6-month Extended Evaluation Phase, subjects will return to the clinical site 
every 3 months (every 90 days ± 14 days) for assessments, (i.e., at the end of Months 9 
and 12), and will have safety and efficacy evaluations as indicated in the Time and 
Events Table (Appendix A).   


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 44 of 119 
CONFIDENTIAL 
 
After completion of treatment in this study, if subjects do not extend treatment through 
the expanded access program (Section 4.7), they will return for a Follow-Up Visit as 
indicated in the Time and Events Table (Appendix A).  The Follow-Up Visit should be a 
minimum of 2 weeks (14 days) and no longer than 30 days following the completion of 
treatment. [NOTE: The Follow-Up Visit is not required for subjects continuing into 
expanded access treatment (see Section 4.7)]. 
4.6 Stopping Criteria 
Dosing with the study medication will cease due to any of the following observations: 
• Intolerability to the study medication based on the subjects’ signs or symptoms in 
accordance with the Investigator’s medical judgment 
• Lack of any clinically relevant response at the maximally tolerated dose, in the 
opinion of the Investigator 
• QTc prolongation as specified in Section 5.3.1 at 150 mg/day 
• LFT abnormalities as specified in Section 5.3.2 
• Adrenal insufficiency at the lowest dose of COR-003 (150 mg daily)—See also 
Section 6.3.3 for more details 
• Any withdrawal criteria specified in Section 5.3. 
 
Subjects who are withdrawn early will complete the Follow-Up Visit (see Appendix A) 
and provide two adequate 24-hour urine collections within approximately 2 weeks of 
termination of treatment with COR-003. 
The cause for withdrawal will be documented and appropriately captured in the database. 
Withdrawn subjects, due to any of the above criteria, must receive appropriate follow-up 
medical care. The Investigator will explain all other treatment options available to them 
in their country of residence and subjects will be promptly referred back to their 
endocrinologist (if not the Investigator) for further management according to the local 
standard of care and based on their preceding medical history.   
4.7 Optional Expanded Access Program 
An expanded access program (COR-2015-EAP) will be made available, as local 
regulations allow, to sites participating in this study.  Subject interest and eligibility for 
participating in the expanded access program will be evaluated at the M9 visit, including 
the informed consent process.  If eligible, they will begin participation in the 
COR-2015-EAP program upon completion of the M12 visit.  Subjects continuing into 
expanded access program will NOT be required to complete the Follow-Up Visit for 
COR-2012-01.  
If a subject completing COR-2012-01 at a site that does not have regulatory approval to 
provide access to COR-003 under the expanded access program wishes to continue 
COR-003 treatment after completing this study, Cortendo will make a reasonable effort 
to provide continued access to the medication through another access option that meets 
all applicable local and national regulatory requirements. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 45 of 119 
CONFIDENTIAL 
 
In the event that continued access to COR-003 is anticipated but delayed for any reason, 
and dosing with COR-003 will be interrupted for more than 2 weeks, the Follow-Up Visit 
should occur according to the Time and Event Schedule (see Appendix A). 
5 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
Cortendo will review each subject’s enrollment criteria to ensure that subjects meet the 
eligibility criteria. 
5.1 Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
1. Male or female ≥18 years of age 
2. 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. 
3. Confirmed diagnosis of newly diagnosed, persistent or recurrent CD or endogenous 
CS of other etiology if subjects are not candidates for surgery or radiotherapy within 
the 18 months after enrollment. 
Previous medical records will be collected and used to support the diagnosis of CD or 
endogenous CS of other etiology, including the following etiologies:   
• Ectopic ACTH secretion, i.e. ACTH not of pituitary origin 
• Ectopic corticotropin-releasing hormone (CRH) secretion 
• Adrenal-dependent CS (i.e. adrenal adenoma (NOT carcinoma), adrenal 
hyperplasia, etc.) 
• Etiology unknown 
 
In the absence of pathological or post-surgical confirmation of the diagnosis of CD 
(i.e. documented adrenal insufficiency post-adenomectomy or hypophysectomy, 
which will be considered diagnostic). The following historical evidence will be 
considered satisfactory to establish the diagnosis of CD: 
• Plasma corticotropin (ACTH) level >20 pg/mL (4.5 pmol/L) or greater 
(Note: ACTH ≥5 pg/mL (1.1 pmol/L) and ≤20 pg/mL will generally suffice 
only if accompanied by either a positive CRH stimulation test or DST or 
combined CRH-DST) PLUS one of the diagnostic strategies described below 
based on pituitary MRI/computed tomography (CT) findings (Note: pituitary 
imaging preceding the original diagnosis is a requirement for eligibility): 
• For tumors ≥6 mm by imaging: 
− Inferior petrosal sinus sampled (IPSS) ACTH central:plasma gradient ≥2 
before CRH or ≥3 after CRH, OR if IPSS was not done then: 
− Positive ACTH and/or cortisol response to CRH/desmopressin or 
combined CRH-desmopressin stimulation plus high-dose (8 mg) 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 46 of 119 
CONFIDENTIAL 
 
dexamethasone suppression of plasma cortisol, ideally on more than one 
occasion, performed and interpreted according to internationally 
recognized standards of diagnosis 
− In the absence of IPPS and the combination of tests described, an 
individual might be eligible if CD was otherwise confirmed via adequate 
testing. Such cases must be discussed with and explicitly approved by the 
Medical Monitor, and the specific diagnostic criteria used to establish the 
diagnosis of CD must be documented. 
• For tumors <6 mm or not visible by MRI: 
− IPSS with ACTH central:plasma gradient ≥2 before CRH or ≥3 after CRH 
− In the absence of IPSS, an individual might be eligible if CD was 
otherwise confirmed via adequate testing. Such cases must be discussed 
with and explicitly approved by the Medical Monitor, and the specific 
diagnostic criteria used to establish the diagnosis of CD must be 
documented. 
4. Regardless of the etiology of endogenous CS, subjects MUST have elevated mean 
24-hour UFC levels ≥1.5X ULN based on the normative range of the central lab assay 
and on a minimum of four measurements from adequately collected urine.  Urine will 
ideally be collected on sequential days.   
5. In addition to elevated mean UFC, presence of abnormal values from one of the 
following tests: 
• 
Abnormal DST: Elevated 8 AM serum cortisol ≥1.8 µg/dL (50 nmol/L) after 
1 mg dexamethasone orally at 11 PM the evening prior (if not conducted 
already in the diagnostic workup of the subject within the previous 2 months 
before start of Screening Phase; in that case previous test results and details 
of conduct will need to be available by the Baseline Visit) 
• 
Elevated late night salivary cortisol concentrations (at least two 
measurements) >ULN  
NOTE: For subjects with estimated glomerular filtration rate (eGFR as 
determined by Modified Diet in Renal Disease MDRD equation) >40 and 
<60 mL/min/1.73 m2 in addition to meeting the UFC criteria, late night salivary 
cortisol test results (≥2 measurements) MUST also demonstrate evidence of CS.  
6. Previously irradiated subjects with CD or endogenous CS of other etiology will be 
allowed as long as the radiation treatment occurred >4 years ago and subjects have 
not exhibited evidence for improvement in their underlying CD for 6 months prior to 
the Screening visit. The total number of previously irradiated subjects enrolled in this 
study will not exceed 10. 
7. Subjects with CD or CS of other etiology who are not candidates for surgery, refuse 
surgery, or in whom surgery will be delayed for at least 18 months following 
enrollment. Subjects may be allowed to participate in the trial while awaiting surgery, 
but must agree to complete this study prior to surgery. For subjects who have already 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 47 of 119 
CONFIDENTIAL 
 
undergone surgery, a minimum of 6 weeks should have elapsed before the subject can 
be deemed a surgical failure.  Subjects who have undergone surgery should be stable 
post-surgery (i.e., no significant post-operative sequelae remain and the risk of such 
sequelae is considered negligible). 
8. Subjects on treatment for CD or endogenous CS of other etiology for whom treatment 
has been inadequate or not well tolerated must agree to the following minimum 
washout periods prior to the Baseline Visit: 
• 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 
9. Subjects on megestrol acetate or medroxyprogesterone acetate (and selected other 
synthetic progestins) must agree to a washout period of at least 6 weeks prior to the 
Baseline Visit   
10. A female is eligible to enter and participate in the study if she is of:  
Non-child bearing potential (i.e. physiologically incapable of becoming 
pregnant, including any female who is post-menopausal or surgically sterile). 
Surgically sterile females are defined as those with a documented hysterectomy 
and/or bilateral oophorectomy or tubal ligation.  
Post-menopausal females are defined as being amenorrheic for greater than 
1 year with an appropriate clinical profile, e.g. age > 45 years, in the absence of 
hormone replacement therapy. However, in questionable cases, a blood sample 
with follicle stimulating hormone (FSH) > 40MIU/ml and estradiol < 40pg/ml 
(<140 pmol/L) is confirmatory.  
OR  
Child-bearing potential and agrees to use highly effective methods of birth 
control while participating in the study and for 2 weeks after the study is 
completed (see Section 6.2.5.1). 
11. Fertile men must also agree to use a medically acceptable form of birth control while 
on study drug and up to 2 weeks after the study is completed (see Section 6.2.5.1). 
12. Able to comprehend and comply with procedures. 
5.2 Exclusion Criteria 
Subjects will be excluded from the study if any of the following criteria are met: 
1. Subjects with Pseudo-Cushing’s syndrome based on assessment of the Investigator.  
Appendix G describes a number of conditions in which elevated cortisol levels may be 
observed in the absence of CS, sometimes referred to as Pseudo-Cushing’s syndrome 
2. Subjects with cyclic CS based on assessment of the Investigator 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 48 of 119 
CONFIDENTIAL 
 
3. Subjects with a non-endogenous source of hypercortisolism such as exogenous source 
of glucocorticoids or therapeutic use of ACTH. 
4. Known inherited syndrome as the cause of hypercortisolism, including but not limited 
to multiple endocrine neoplasia Type 1, McCune Albright Syndrome and Carney 
Complex 
5. Subjects with adrenal carcinoma  
6. History of malignancy, other than thyroid, early stage prostate, squamous cell and 
basal cell carcinoma, within 3 years prior to the Screening Phase. Subjects with 
history of such allowed carcinoma must have a life expectancy of >18 months and 
must be considered medically stable. Subjects with early stage prostate cancer 
undergoing no treatment due to low grade potential may be enrolled.  
7. Clinical or radiological signs of compression of the optic chiasm. 
8. Major surgery within 1 month prior to enrollment (informed consent form signing).  
9. Subjects with clinically significant abnormality in 12-lead ECGs during the Screening 
Phase needing medical intervention. 
10. Subjects with QTc interval of >470 msec during the Screening Phase. 
11. Subjects with a history of Torsades des Pointes, or ventricular tachycardia, or 
ventricular fibrillation, or history of prolonged QT syndrome (including family 
history), or use of medications resulting in QT/QTc prolongation, or hypokalemia 
<3.0 meq/L. 
12. Pre-existing hepatic disease; subjects with mild to moderate hepatic steatosis 
consistent with fatty infiltration (non-alcoholic fatty liver disease [NAFLD] are 
allowed).  
13. Positive for hepatitis B surface antigen (HbsAg) or positive hepatitis C test. 
14. History or symptoms of recurrent symptomatic cholelithiasis or pancreatitis. 
15. LFTs must not be above the following cut-offs during the Screening Phase:  
• ALT and/or AST >3 X ULN  
• Total bilirubin (TBN) >2 X ULN 
If all LFTs are within normal limits (WNL) and TBN is elevated, examination of 
direct and indirect bilirubin may be conducted. Subjects with isolated indirect TBN 
up to 3X ULN are presumed to have Gilbert’s syndrome and may be enrolled if all 
other LFTs are within normal levels. 
16. History of documented or suspected drug-induced liver injury requiring drug 
discontinuation of ketoconazole or any azole antifungals.  
17. Pregnant or lactating women 
18. Human immunodeficiency virus (HIV)-positive. 
19. History of persistent uncontrolled hypertension (>180/120 mmHg) despite medical 
intervention. 
20. Subjects with hypercholesterolemia who are currently treated with atorvastatin, 
lovastatin or simvastatin and not willing or unable to change to alternative therapies, 
i.e. pravastatin, fluvastatin, or rosuvastatin within 2 weeks of start of the Screening 
Phase.  


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 49 of 119 
CONFIDENTIAL 
 
21. Body habitus preventing repeated venipuncture as required by protocol. 
22. Subject is currently in another study or has received any investigational treatment 
(drug, biological agent or device) within 30 days or five half-lives of treatment, 
whichever is longer. 
23. Repeated hospitalization for hyperglycemia or for any complication of hyperglycemia 
and diabetes during the last 12 months  
24. Subjects with decreased renal function as defined by eGFR <40 mL/min/1.73 m2, 
using MDRD equation. 
25. Any other clinically significant medical condition, as determined by the Investigator 
that precludes enrollment and participation in the study through completion, including 
conditions that would preclude the subject from being able to follow instructions or to 
perform the necessary procedures (for example, psychiatric instability or severe 
disability).  
26. Abnormal free thyroxine (T4). Subjects with thyroid stimulation hormone (TSH) 
below the lower limit of normal (<LLN) and normal free T4 are permitted to 
participate in the study.  
27. Subjects who have a history of alcohol or drug abuse in the 6-month period prior to 
enrollment. 
28. Subjects who have been treated with mitotane within 6 months of the Screening 
Phase. 
29. Subjects who are currently taking any H2 receptor antagonists, proton-pump 
inhibitors, or sucralfate (all of which inhibit absorption of COR-003).  A list of orally 
acceptable antacids (for example, Mylanta and Maalox) will be provided, and can 
only be taken a minimum of 2 hours after dosing of COR-003.  
30. Subjects who receive any prohibited concomitant medication and cannot discontinue 
it safely prior to the Baseline Visit. Section 10 and Appendix J provide more 
complete lists of specific medications that are not permitted to be used during this 
study. Below is a partial listing of prohibited medications: 
• Weight loss medications (prescription or over the counter); 
• Acetaminophen (paracetamol) >3 g total daily dose; 
• Strong inducers or inhibitors of CYP3A4 enzyme system that may interfere 
with the metabolism of COR-003 and cannot be discontinued prior to first dose; 
• Herbal preparations: St John’s Wort, echinacea, gingko, goldenseal, yohimbe, 
red rice yeast, danshen, silybum marianum, Asian ginseng, schissandra 
sphenanther, shankhapushi, and Asian herb mixture (Xiao chai hu tang and 
Salboku-to); 
• Topical or inhaled corticosteroids; 
• Carbamazepine, fenofibrate, carbenoxolone; 
• Drugs that might pose unacceptable risks due to overlapping toxicities (e.g. QT 
prolongation, liver toxicity); 
• Genuine licorice. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 50 of 119 
CONFIDENTIAL 
 
5.3 Withdrawal Criteria 
Subjects have the right to discontinue participation in the study at any time. Reasons for 
withdrawal during the study may include, but are not limited, to the following: 
• Withdrawal of informed consent. 
• Safety reasons, as stipulated in Sections 5.3.1 and 5.3.2, either at the discretion of 
the Investigator or at the subject’s request (see also Section 4.6, Stopping 
Criteria). 
• Protocol violations at the discretion of the Sponsor. 
• Concomitant therapy that could interfere with the results of the study (the 
Investigator will report all such information on the case report forms [CRFs] and 
decide, in accordance with the Sponsor, whether the subject is to be withdrawn).  
All premature discontinuations and their causes must be carefully documented by the 
Investigator on the CRF, and, if need be, on the AE page.   
If, for any reason, a subject is withdrawn before completing the study, the reason for 
termination will be entered in the CRF.  All data gathered on the subject prior to 
termination will be made available to the Sponsor.  All withdrawn subjects will be asked 
to report to the clinic for a Follow-Up Visit at approximately 2 weeks after receiving their 
last dose of the study medication.  All assessments at the Follow-Up Visit are listed in the 
Time and Events Table (Appendix A). All AEs will be followed until resolution or at a 
minimum of 30 days after the last dose of the study medication.   
5.3.1 Withdrawal due QTc Interval Prolongation 
If a persistent and confirmed COR-003-related QTc interval prolongation >500 msec or a 
change from Baseline of >60 msec as defined below is identified, an attempt should be 
made to manage such QTc prolongations by dose reduction. If a persistent and confirmed 
COR-003-related QTc interval prolongation >500 msec or a change from Baseline of 
>60 msec is observed at the lowest COR-003 dose (150 mg/day), administration of the 
study drug will cease and the subject will be withdrawn.   
In order to decide whether a QTc prolongation is persistent and confirmed to be related to 
COR-003, QTc will be evaluated using the Spaulding ECG device or a local ECG device 
with central reading of the ECG by Spaulding. The Investigator should consider 
alternative possibilities as causative or contributory to QTc prolongation prior to 
discontinuation of COR-003, including concomitant medications that may result in 
prolongation of the QTc interval either directly or through interference with the 
metabolism of COR-003, 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 COR-003 and must be stopped (Section 10.2). Please also see 
Section 6.2.4.1 for guidance on the assessment of QTc interval prolongation. Regardless 
of seriousness or causality, instances of persistent QTc prolongation should be reported to 
the Sponsor’s designated Pharmacovigilance group within 24 hours from the time the 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 51 of 119 
CONFIDENTIAL 
 
persistent prolongation has been confirmed, in the same manner as SAEs (see 
Section 13.2.2).  
If persistent and confirmed QTc prolongation, as defined above, is observed, an 
additional PK sample should be collected as close to the time of the event as possible, 
ideally within several hours of dosing. 
5.3.2 Withdrawal and/or Re-Challenge due to Liver Function Tests (LFTs) 
The recommendations within the Food and Drug Administration (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 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.  Other testing including laboratory assessments to 
assess causality (such as, hepatitis [A, B, C, E], autoimmunity), imaging and consultation 
with a liver specialist should be obtained prior to a planned withdrawal of the subject due 
to elevated LFTs.  Appropriate medical evaluations and interventions should be 
implemented based on the clinical presentation of the subject, including appropriate 
diagnostic imaging procedures.  All such medical interventions will be recorded in the 
CRF. While LFTs may be assayed at a local lab for immediate medical intervention, 
simultaneous samples must be sent to the central laboratory to ensure consistency of 
assay and interpretation. 
Subjects withdrawn due to LFT abnormalities must be followed until LFT normalization 
or until near Baseline values and stable.  Subjects not withdrawn from the study may be 
re-challenged after resolution of LFT abnormalities, at the discretion of the Investigator 
AND with approval by the Cortendo Medical Monitor.  
In agreement with FDA Guidance of 2009, discontinuation of therapy should be 
considered if: 
• ALT or AST >8X ULN 
• ALT or AST rises to >5X ULN in <4 weeks or persists for >2 weeks 
• ALT or AST >3X ULN and TBN >2X ULN or International Normalized Ratio 
(INR) >1.5 not explained by any other cause such as viral hepatitis, and without 
evidence of cholestasis  
• ALT or AST >3X ULN with new onset of or worsening of fatigue, nausea, 
vomiting, fever, rash or eosinophilia, in the absence of other evident cause 
• Signs and /or symptoms suggestive of hepatic dysfunction (any of the following: 
nausea, anorexia, fever, fatigue, right upper quadrant discomfort, pruritus, dark 
urine or acholic stool) coupled with ALT and/or AST >3X ULN and/or AP >2X 
ULN, and/or TBN >2X ULN in the absence of evidence for obstruction or Gilbert 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 52 of 119 
CONFIDENTIAL 
 
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. 
  
Subjects with ALT and/or AST >3X ULN or AP >2X ULN (in the absence of evidence 
for cholestasis) or TBN >2X ULN (in the absence of evidence for cholestasis and except 
for subjects enrolled with presumed Gilbert’s syndrome) at any visit will undergo serial 
repeat LFT and INR evaluations. The first repeat LFT should occur as soon as possible 
after initial determination to confirm the observation and thereafter at 3 to 4 day intervals 
or as the clinical situation dictates.  Appropriate medical evaluations and interventions 
should be implemented based on the clinical presentation of the subject.   
If the LFTs return towards Baseline, serial measurements can be discontinued at the 
discretion of the Investigator, and the subject will continue for the remainder of the trial.  
If therapy has been interrupted and LFTs have normalized, subjects may be re-challenged 
at the discretion of the Investigator AND with approval by the Cortendo Medical 
Monitor.  If 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 will continue to be followed after withdrawal 
until resolution or normalization of the laboratory abnormality that resulted in the 
withdrawal. 
If on serial measurements and in the absence of clinical signs or symptoms, the ALT 
and/or AST continue to rise (but TBN do not exceed the cut-offs for study drug 
cessation/early termination), subjects will continue on study drug and protocol unless the 
ALT and/or AST levels are >8X or are persistently higher than 5X ULN. If the ALT 
and/or AST levels exceed these levels, the subject should stop taking the study 
medication immediately. 
6 
STUDY ASSESSMENTS AND PROCEDURES 
The exact timings of each assessment are provided in the Time and Events Table 
(Appendix A).  Detailed procedures are provided in the Study Procedures Manual.  The 
study is being conducted and reported in accordance with the guidelines presented in 
Appendix D and Appendix E.  Any changes to the study design are managed in 
accordance with Appendix F. 
In addition to the protocol-specified procedures, at any time during the study 
appropriate medical evaluations and safety interventions should be implemented, as 
necessary, based on the clinical presentation of the subject according to 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 CRFs as unscheduled visits. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 53 of 119 
CONFIDENTIAL 
 
The study will consist of the following phases with approximate timings: 
• Screening Phase (up to approximately 12 weeks’ duration, prior to first dose) 
• Dose Titration Phase (approximately 2-21 weeks’ duration) 
• Maintenance Phase (6 months’ duration) 
• Extended Evaluation Phase (6 months’ duration) 
After signing the informed consent, subjects will enter the Screening Phase.  After 
performing the initial Screening assessments, subjects on previous CS therapies must 
enter a washout period, as applicable (see Section 5.1) before completing all Screening 
assessments detailed in the Time and Events Table (Appendix A).  Baseline evaluations 
will be obtained as part of the Screening assessments and should be conducted AFTER 
completion of all initial Screening procedures and after subjects have undergone a 
sufficient washout period from previous CS therapies (see Section 5.1), if applicable. 
Results from the Baseline assessments are necessary in order to determine if the subject 
remains eligible for participation in the study.  Please see the Study Procedure Manual 
(SPM) for details on urine collections.  
All subjects must meet all eligibility criteria prior to the first dosing.   
A screen failure subject is one from whom a signed informed consent is obtained but who 
has not started on treatment and failed to meet some or all eligibility criteria at Baseline.  
With approval by the Sponsor Medical Monitor, subjects may have repeated assessments 
of laboratory values for screening purposes to confirm eligibility if the condition limiting 
their participation has changed and is no longer limiting.  Re-screening is allowed for 
subjects with changes in their medical condition that alters their potential to meet the 
eligibility criteria. All re-screenings are considered exceptional and require prior 
permission of the Medical Monitor. 
6.1 Demographic/Medical History Assessments 
The following demographic parameters will be captured at Screening:   
• Date of birth 
• Gender 
• Race and ethnicity 
Medical and medication history will be assessed and collected as related to the Eligibility 
Criteria in Section 5.1 and will include the following, as available: 
• An effort will be made to collect the following information for documentation of 
medical history as part of this study: 
 Documentation of diagnosis of CS, including but not limited to 
evaluations for CS for the previous 6 months, e.g., levels of UFC, late 
night salivary and/or serum cortisol, DST results, IPSS results and 
diagnostic imaging results 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 54 of 119 
CONFIDENTIAL 
 
 Documentation of associated metabolic complications (e.g., diabetes, 
hypertension, osteoporosis, and reproductive dysfunction) 
 Documentation of prior management of CS for the previous 3 months, 
including medications (capturing doses, duration of treatment, time of 
discontinuation and reason for discontinuation of medication) and any 
surgical or radiation therapies 
• Available clinical laboratory data for the previous 3 months; specifically: LFTs 
(ALT, AST, AP, direct and TBN), HbA1c, fasting serum glucose, OGTT, serum 
lipid panel (LDL-C, HDL-C, total cholesterol, triglycerides), CRP, urinary 
albumin/creatinine ratio, testosterone and IGF-1 concentrations 
• Available blood pressure data for the previous 3 months 
• Medication history (all medications, including any non-prescription medications, 
other than those to treat CS specifically) taken within 3 months prior to Screening 
with particular attention to blood pressure, anti-diabetic and cholesterol lowering 
drugs 
• History of drug and alcohol use. 
6.2 Safety and Efficacy Assessments 
6.2.1 Physical Examination and Assessment of Clinical Signs and Symptoms 
of CS 
Full physical examinations will be performed by a physician at the times indicated in the 
Time and Events Table (Appendix A).  The physical examinations will be inclusive of all 
body systems, and should include height (cm) and weight (kg). Abdominal girth will be 
measured in triplicate at the times indicated in the Time and Events Table and as 
described in the SPM.  BMI will be calculated based on data entered into the CRF during 
that visit.   
The examining physician will be asked to complete a questionnaire related to the 
assessment of Clinical Signs and Symptoms of CS (see Appendix M).  The results will be 
used to quantify changes in Clinical Signs and Symptoms of CS.  Details regarding these 
assessments will be provided in the SPM.  
6.2.2 Standard Photographs 
Standard photographs will be taken for consenting subjects to document visible signs of 
hypercortisolism at the times indicated in the Time and Events Table (Appendix A) as 
described in the COR-2012-01 Photography Manual.   
6.2.3 Vital Signs 
Vital sign measurements will include temperature, sitting SBP, DBP and heart rate (HR) 
at Baseline and at each visit throughout the study (see Time and Events Table in 
Appendix A).   
For proper measurement of blood pressure, the following procedures should be followed: 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 55 of 119 
CONFIDENTIAL 
 
• Use of an appropriately sized cuff for the size of the subject’s arm circumference 
should be utilized to minimize inaccurate readings.  The sites may use available 
cuffs on site for these measurements. 
• No smoking or exercise for at least 30 minutes before a blood pressure 
measurement. 
• Subjects should sit in a chair with a back support and the arm supported at heart 
level with feet flat on the floor. The subject should void prior to the measurement. 
• Blood pressure measurements will be measured 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 each be recorded in the CRF and a 
mean value for that visit will be calculated for reporting. 
Vital sign measurements must be repeated if clinically significant or machine/equipment 
errors occur.  Out of range blood pressure or HR measurements will be repeated at the 
Investigator’s discretion.  Any confirmed, clinically significant change from Baseline 
vital sign measurements must be recorded as AEs. 
Guidelines for classification for blood pressure levels and recommendations for follow-
up are provided in Appendix I. 
6.2.4 12-Lead Electrocardiograms (ECG) 
Male patients with CS have been reported to have prolongation of the QT interval 
[Giraldi 2011].  Thus, the inclusion criteria have allowed for this possibility and both 
males and females with QTc prolongation will be allowed into the study with Baseline 
QTc ≤470 msec.  
QTc interval is highly variable during the course of a day. Food intake can increase QTc 
intervals. Nausea, vomiting, upset stomach, and dizziness can also cause prolongation in 
the QTc interval, as well as electrolyte abnormalities (low serum magnesium, calcium 
and potassium levels).  
Many drugs can prolong the QTc interval directly, or in the case of COR-003, through 
interference with the metabolism of COR-003 causing levels of the drug to increase, thus 
resulting in a prolongation of the QTc. 
In this study, ECG monitoring is being performed at the designated times (as in the Time 
and Events Table in Appendix A), ideally using the Spaulding ECG device continuously 
for a maximum of 5 minutes.  
It will be upon this integrated summary result that QTc prolongation will initially be 
identified. The integrated summary of the ECG assessments (including arrhythmia 
analysis) will be done centrally after electronic transmission of the data, along with real-
time results provided to the Investigator.  
NOTE:  ECGs during the Screening Visit (single ECGs) are not required to be performed 
using the Spaulding ECG device. The Spaulding ECG device should be used at the 
Baseline Visit and for all subsequent assessments during the study.  In the event that the 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 56 of 119 
CONFIDENTIAL 
 
Spaulding ECG device is not available, a local ECG may be performed (following the 
below guidance) and transmitted to Spaulding via a paper printout of the recording. 
ECGs will be obtained within approximately 1 to 2 hours after drug administration (i.e., 
at approximately Cmax of COR-003). ECGs will be obtained after the subject has rested 
in a supine position for at least 5 minutes, and should be conducted after the subject has 
not eaten for at least 2 hours. A small snack will be allowed for diabetic subjects and 
subjects who are intolerant of fasting since food intake can prolong QTc intervals. Food 
intake has to be recorded in the CRF.  The recording from the continuous ECG 
(maximum of 5 minutes) reading with the Spaulding device will be uploaded 
electronically to a computer and subsequently transmitted over the internet for centralized 
analysis and archiving.  The system will provide automated measurements of HR, 
respiratory rate (RR), PR, QRS, QT, QTcF and QTcB and ECG diagnostic statements to 
the investigative site within a short time following the completion and uploading of the 
recording.  A central reader cardiologist, not involved in the conduct of the study, will 
subsequently evaluate the ECGs.  It is imperative that the transmission of all ECGs to 
the central reader takes place as soon as possible after the completion of the test to 
allow for the proper medical evaluation of the subject should QTc prolongations 
occur.  
6.2.4.1 Prolongation of QTc Interval > 500 Msec or > 60 Msec Above 
Baseline 
The potential risk of protracted, drug-induced prolongation of the QTc interval is the 
development of an arrhythmia called Torsade de Pointes. The development of Torsade de 
Pointes in the face of QTc interval prolongation is rare, and appears to occur primarily 
when the QTc interval is particularly prolonged and generally at least >500 msec or 
>60 msec above Baseline.  
Subjects with prolonged QTc intervals >500 msec or >60 msec increase over the QTc 
interval at the Baseline Visit based on the assessment ideally using the Spaulding ECG 
device or local ECG must be medically observed until the QTc has returned to a value 
≤500 msec or ≤60 msec change from Baseline.  
The following need to be considered in cases of QTc prolongation: 
• If the integrated ECG reading demonstrates a QTc prolongation >60 msec from 
Baseline or an absolute QTc >500 msec, the subject should be questioned about 
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.  
• The subject should also be questioned about the use of any other medications that 
may have increased QTc interval, either directly because of their direct effect on the 
QTc interval or indirectly as a result of a drug interaction that may have increased the 
concentrations of COR-003. If such a drug is identified, it should be stopped 
immediately.  


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 57 of 119 
CONFIDENTIAL 
 
• The subject should be evaluated for symptoms of nausea or recent vomiting prior to 
the ECG assessment, lightheadedness or other symptoms that may influence the QTc 
interval. In such cases, the ECG evaluation should be conducted once the subject's 
symptoms have abated. COR-003 dosing may have to be withheld if the symptoms 
are protracted and the QTc interval prolongation remains evident. The Investigator 
should ensure that the symptoms as well as the ECG results are not due to a 
cardiovascular event, such as a myocardial infarction. 
• If the subject has not eaten, has no confounding medical symptoms/events, does not 
have a concomitant medication that may be increasing the QTc interval, and there are 
no other significant abnormalities on the ECG warranting immediate medical 
intervention, 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 QTc prolongation >60 msec 
above Baseline or an absolute value of >500 msec, a blood sample should be obtained 
from the subject for evaluation of electrolyte abnormalities, including potassium, 
magnesium and calcium concentrations in addition to routine electrolytes and for a 
PK evaluation. If electrolyte abnormalities are identified, these should be corrected 
before re-evaluation of the ECG. COR-003 may be temporarily withheld until 
electrolytes can be normalized. 
If electrolytes are normal and no other cause can be identified to account for the absolute 
QTc interval >500 msec (or >60 msec above Baseline), and the ECG evaluation on repeat 
determination demonstrated persistent QTc prolongation, causal relationship to COR-003 
should be assumed and COR-003 should be withheld. The ECG should be monitored per 
discretion of the Investigator until resolution of the QTc prolongation.  In all cases, 
abnormal morphology of the ECG (especially T wave changes), if present, will be 
recorded in the CRF.  
If the subject is on the lowest possible dose of COR-003 (150 mg/day) and has persistent 
and COR-003-related QTc interval prolongation >500 msec or a change from Baseline of 
>60 msec, administration of the study drug will cease permanently and the subject will be 
withdrawn.  
At higher doses, an attempt should be made to manage persistent QTc prolongations that 
are deemed to be related to COR-003 by resuming treatment at a lower dose after 
resolution of QTc prolongation as described below.  If persistent and confirmed QTc 
prolongation is observed, an additional PK sample should be collected as close to the 
time of the event as possible, ideally within several hours of dosing. 
Persistent and confirmed QTc prolongation are defined as follows: 
• Persistence:  The 12-lead ECG should be repeated within 30 minutes of the first 
ECG revealing a QTc prolongation to confirm the persistent reading. 
• Confirmation:  The Investigator should consider alternative possibilities as 
causative or contributory to the QTc prolongation prior to discontinuation of the 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 58 of 119 
CONFIDENTIAL 
 
study drug and/or study withdrawal.  Such contributing factors include 
nausea/vomiting, concomitant medications that may result in prolongation of the 
QTc interval either directly or through interference with the metabolism of 
COR-003, recent food ingestion (temporary QTc elevation), and electrolyte 
abnormalities (particularly serum calcium, magnesium and potassium).  
Supplementing potassium to raise serum potassium into the high-normal range 
can shorten the QTc interval in many cases.  Interfering concomitant medications 
with this potential are contraindicated in co-administration with the study drug 
and must be stopped (Appendix J). 
Regardless of seriousness or causality, instances of persistent QTc prolongation should be 
reported to the Sponsor’s designated Pharmacovigilance group as an AESI within 
24 hours from the time the persistent prolongation has been confirmed, similar to the 
reporting for SAEs (see Section 13.7). 
6.2.4.2 Resuming Treatment After Resolution of QTc Prolongation 
COR-003 at a lower dose can be restarted after a washout period of 2 days and resolution 
of the QTc prolongation (absolute QTc interval ≤500 msec or is ≤60 msec above 
Baseline). After restart, ECG evaluation should occur within 1 to 2 hours of resumption 
of dosing and be continued according to the visit schedule for increased safety 
monitoring.   
Abnormal morphology of the ECG (especially T wave changes), if present, will be 
recorded in the CRF.  If the absolute QTc interval remains ≤500 msec, or remains 
≤60 msec below the Baseline value, administration of COR-003 may be continued at the 
discretion of the Investigator and with approval by the Cortendo Medical Monitor. 
If persistent QTc prolongation deemed related to COR-003 is observed after 
reintroduction at a lower dose, COR-003 should be permanently discontinued (see 
Withdrawal criteria in Section 5.3.1), an additional PK sample should be collected as 
close to the time of the event as possible and repeat ECG evaluation should occur until 
QTc interval remains ≤500 msec, or ≤60 msec below the Baseline value. 
6.2.5 Clinical Laboratory Tests 
Samples for clinical laboratory testing will be collected at the times indicated in the Time 
and Events Table (Appendix A).  A complete list of all the analytes, including an entire 
battery of LFTs, is provided in Appendix B.  In addition to biochemistry, hematology and 
urinalysis, laboratory parameters will also include the following: serum cortisol, ACTH, 
FSH (women only), TSH, free T4, serum free and total testosterone, IGF-1, coagulation 
parameters (prothrombin time [PT], partial thromboplastin time [PTT], INR), 
triglycerides, serum lipid panel, HbA1c, CRP, and spot urine for albumin/creatinine ratio 
to determine microalbuminuria.  Screening safety laboratory tests will also include the 
following:  HIV, as well as antibody for hepatitis B and C. All testing will be conducted 
in a fasting state and in the morning unless stated differently in the Time and Events 
Table (Appendix A).   


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 59 of 119 
CONFIDENTIAL 
 
TSH and free T4 will be measured during the Screening Phase, DL4 during the Dose 
Titration Phase, then every 2 months during the Maintenance Phase and both Extended 
Evaluation Phase visits.  If subjects achieve their maximum COR-003 dose prior to DL4, 
their TSH and free T4 levels must be measured at Month 1 of the Maintenance Phase 
(time = 0), every 2 months during the Maintenance Phase and every 3 months during the 
Extended Evaluation Phase. 
6.2.5.1 Pregnancy 
Regardless of post-menopausal status, all female participants must have a negative 
pregnancy test at screening and at study visits indicated in the Time and Events Table 
(Appendix A).  A urine βhCG will be performed at the first Screening visit and all other 
subsequent visits.  Results of the test must be available before dosing can begin. 
Post-menopausal females will be defined as having amenorrhea for a minimum of 
24 consecutive months and an elevated FSH level during the Screening Phase.   
Women of child-bearing potential must agree to use an effective form of contraception 
for up to 2 weeks after study completion.  Acceptable methods include the following: 
• Male partner is sterile prior to female subject entry into the study, and 
this male partner is the sole partner for that subject; or  
• Implants of levonorgestrol inserted for at least 1 month prior to the study 
medication administration but not beyond the third successive year 
following insertion; or  
• Oral contraceptive (combined or progestogen only) administered for at 
least one monthly cycle prior to study medication administration; or  
• Double barrier method: condom or occlusive cap (diaphragm or 
cervical/vault caps) plus spermicidal agent 
(foam/gel/film/cream/suppository); or  
• An intrauterine device (IUD); or  
• Estrogenic vaginal ring; or  
• Percutaneous contraceptive patches; or 
• If medical contraceptives and barrier methods are not feasible for medical or 
religious reasons, an assurance of abstinence will be deemed an acceptable 
form of contraception for as long as the subject remains abstinent. 
Fertile men must agree to use a double barrier method of contraception (condom plus 
spermicide or diaphragm plus spermicide) while participating in the study and for 
2 weeks after the last dose of study drug OR, the male subject or his female partner must 
be surgically sterile (e.g. vasectomy, tubal ligation) or the female partner must be post-
menopausal. 
Reports of pregnancies in female subjects (or in female partners of male subjects) will be 
collected after the start of dosing and until the Follow-Up Visit.  Female subjects found to 
be pregnant will be withdrawn from the study.  


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 60 of 119 
CONFIDENTIAL 
 
6.2.5.2 Action to be Taken if Pregnancy Occurs 
The Investigator will collect pregnancy information on any female subject or partner of a 
male subject who becomes pregnant while participating in this study.  The Investigator 
will record pregnancy information on the appropriate form and submit it to the Sponsor 
within 24 hours of learning of the pregnancy.  The subject will also be followed to 
determine the outcome of the pregnancy.  Generally, follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported. 
All pregnancies will be reported from the site and documented according to the same 
procedures as SAE.  While a pregnancy will not be considered as an SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE. 
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and which is 
considered reasonably related to the investigational product by the Investigator, will be 
reported to the Sponsor. While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.  Subjects will be asked to contact the clinic in these situations. 
6.2.6 Disease-Related Assessments 
6.2.6.1 Urinary Sample Collections 
Urine will be collected in the containers provided.  Subjects will be asked to provide 
either two or four adequate 24-hour urine collections (ideally collected on sequential 
days) at the times indicated in the Time and Events Table (Appendix A).  The total 
volume of urine and urine creatinine excretion rates will be measured from the 24-hour 
collections as a marker of the adequacy of the collection as detailed below in this section. 
Collections judged to be inadequate may be repeated at discretion of the 
Investigator.  
Subjects should be instructed to avoid consuming ≥4 L/day of liquids on the day of urine 
collection. Subjects must also follow all of the lifestyle and dietary restrictions listed in 
Section 7. 
At Baseline, subjects will be asked to provide four adequate 24-hour urine collections.   
During the Dose Titration Phase, after the start of each dose and in order to assess the 
need for further dose titration, subjects will be asked to provide two adequately collected 
24-hour urine specimens starting at Day 10 (±1 day) after the start of each dose level, 
ideally on two consecutive days.  The two urine collections will be returned to the clinic 
on approximately Day 12. Urine volume will be measured at the clinic and samples will 
then be shipped frozen to the designated laboratory for measurement of UFC levels from 
each collection, as soon as possible upon receipt of the collections.  Section 4.2.1 
includes additional details of the dose titration process and determination of the 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 61 of 119 
CONFIDENTIAL 
 
Therapeutic Dose.  As part of this process, two additional adequate 24-hour urine 
collections will be obtained to confirm a Therapeutic Dose has been reached, prior to 
entry into the Maintenance Phase. 
Four adequate 24-hour urine collections will be obtained just prior to the End of the 
Maintenance Phase visit. These urine collections are absolutely critical to the 
interpretation of the study results and the subject should be made fully aware of the 
need for their compliance with this collection.  Prior to each monthly visit after 
entering the Maintenance Phase and prior to the Month 9 and 12 visit of the Extended 
Evaluation Phase, two adequate 24-hour collections will be obtained, ideally on two 
consecutive days. 
Urine collections will begin after the first morning void (collection Day 1) and will be 
collected over 24 hours until the next morning, including the first void on the morning of 
collection Day 2.  Careful instructions must be provided to the subject on the process 
for proper urine collection and storage of samples over 24 hours. 
The total volume of urine and urine creatinine excretion rates will be measured from the 
24-hour collections as a marker of the adequacy of the collection.  Total urine volume 
should be 400 to 4000 mL/day.  
Minimum expected values for normal 24-hour creatinine excretion rates up to age 70 are 
provided in Table 2. 
Table 2 
Minimum 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. 
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 in the lower end of the ranges 
reported in Table 2 [Petersenn 2013].  
6.2.6.2 Urinary Sample Analysis 
UFC levels from the 24-hour urine collection will be assayed at a central laboratory 
according to the current validated methodology high pressure liquid chromatography 
tandem mass spectroscopy (HPLC/MS/MS). Details for handling of 24-hour UFC 
measurements and urine creatinine excretion rates will be provided in the SPM. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 62 of 119 
CONFIDENTIAL 
 
6.2.6.3 Late Night Salivary Cortisol 
Late night salivary cortisol samples will be collected by each subject at the times 
indicated in the Time and Events Table (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 two hours of collecting the 
saliva sample.  Late night samples from two nights, will be collected at Baseline, at the 
beginning of Maintenance Phase (Month 1) and just prior to the End of Maintenance 
Phase. Late night samples from one night will be collected at all other times indicated in 
Time and Events Table (Appendix A). All samples will be analyzed at a central 
laboratory with experience in salivary cortisol measurements.  All details for collection 
and handling of samples are provided in the SPM. 
6.2.6.4 Dexamethasone Suppression Test (DST) 
A DST (1 mg overnight test as described below) will need to be available at Baseline if 
not previously performed within the 2 months prior to start of Screening Phase, to 
confirm eligibility for participation in the study. In order to be fully interpretable, 
adherence to the timing requirement of the test will be important.  
Overnight DST 
• 1 mg dose of dexamethasone will be self-administered orally between 11 PM and 
midnight 
• Blood sample to measure serum cortisol must be obtained at approximately 8 AM 
the next morning; the exact time to be recorded in the CRF 
• Subjects will have nothing to drink or eat for at least 10 hours before the blood 
test. 
The following medications may affect the DST results: barbiturates, corticosteroids, 
phenytoin, and tetracyclines. 
Details of the assay are described in the SPM. 
6.2.6.5 ACTH 
ACTH levels will be measured in all subjects at all study visits starting with the Baseline 
Visit as listed in the Time and Events Table in Appendix A.  Details of the assay are 
described in the SPM. 
6.2.6.6 Pituitary Magnetic Resonance Imaging (MRI) 
Pituitary MRIs will be obtained for subjects with a diagnosis of CD at Baseline, if not 
done within 6 months of administration of the first dose of the study drug, just prior to the 
End of the Maintenance Phase, and at the end of the Extension Phase. The results of 
MRIs obtained during the study will be evaluated by a central reader (neuroradiologist). 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 63 of 119 
CONFIDENTIAL 
 
6.2.6.7 Oral Glucose Tolerance Test 
All pre-diabetic subjects with screening fasting glucose concentrations >100 mg/dL but 
<126 mg/dL will have an OGTT at Baseline and at the times indicated in the Time and 
Events Table (Appendix A).  After an overnight fast of at least 12 hours, subjects will be 
asked to drink 75 g of glucose.  Blood samples for the determination of glucose 
concentrations will be drawn before glucose administration and 30, 60, 90, and 
120 minutes after administration.  Subjects with diabetes, as defined in Appendix H will 
be excluded from the OGTT. 
6.2.6.8 Quality of Life Measures 
The Cushing QoL questionnaire [Webb 2008] [Appendix L] and the Beck Depression 
Inventory (BDI-II) [Appendix N] instrument will be administered at the times indicated 
in the Time and Events Table (Appendix A). 
6.2.7 Situations Requiring Additional Safety Monitoring 
Additional safety monitoring will be required for the following situations. 
6.2.7.1 Dose Titration Higher than 600mg/day 
If titration levels go beyond 600 mg/day, subjects are required to return once 7 days 
(± 3 days) after each dose level escalation visit for DL4 through DL7 for additional safety 
evaluations which will include the following assessments: AEs, vital signs, routine safety 
laboratory assessments (LFTs), ECGs, and morning serum cortisol levels (see 
Section 4.2.2). 
6.2.7.2 QTc Prolongation 
In the event QTc prolongation occurs (as defined in Section 6.2.4.1), additional safety 
monitoring is required, including medical observation of the subject until the QTc has 
returned to a value ≤500 msec or ≤60 msec change from Baseline.  Additional evaluation 
of the subject, as described in Section 6.2.4.1, will include the potential requirement for 
additional ECGs, laboratory assessments and PK samples. 
6.2.7.3 Adrenal Insufficiency 
Subjects with suspected adrenal insufficiency should be assessed for signs and symptoms 
of adrenal insufficiency and cortisol levels as described in Section 6.3.3.  Should adrenal 
insufficiency be deemed present, study drug should be temporarily discontinued for mild 
symptoms/signs.  For moderate or severe symptoms/signs, study drug will be temporarily 
discontinued and rescue glucocorticoids administered as indicated. In addition, an 
additional PK sample should be collected as close to the time of the event as possible, 
ideally within several hours of dosing. 
Study drug at an appropriately lower dose can be restarted once the medical situation is 
deemed sufficiently resolved by the Investigator. Cases of suspected adrenal 
insufficiency should be reported to Cmed Pharmacovigilance as AESIs (Section 13.7). 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 64 of 119 
CONFIDENTIAL 
 
6.2.8 Pharmacokinetics 
6.2.8.1 Pharmacokinetics Sample Collection 
Blood samples (1 mL minimum) for the determination of plasma concentrations of 
COR-003 will be collected at the times indicated in the Time and Events Table 
(Appendix A). 
The chosen dose level for PK sampling might vary from subject to subject. It is important 
to collect PK samples from subjects at higher dose levels.  Samples will be collected from 
different subjects at different dose levels. 
Subjects will be asked to provide the time of the last dose on the day prior to the PK 
sampling visit and to forego taking their medication on the day of the scheduled visit. All 
subjects will have a blood sample taken for PK immediately pre-dose and between 
1.5 and 2.5 hours post-dose.  PK samples for at least two different dose levels will be 
collected unless the Therapeutic Dose is reached at DL1.  The chosen dose levels for PK 
sampling might vary from subject to subject. It is important to collect PK samples 
from subjects at higher dose levels. A subset of at least 10 to 15 subjects will be asked 
to provide a third sample around 6 to 8 hours after dosing, for at least two different dose 
levels. 
In addition, if persistent and confirmed QTc prolongation is observed, an additional PK 
sample should be collected as close to the time of the event as possible, ideally within 
several hours of dosing (see Section 6.2.4).  Additional PK samples may also be collected 
in association with other AESIs as close to the time of the event as possible 
(Section 13.2.2). 
The actual PK times may vary from the nominal times; the actual dose administered, time 
of dose administration, and actual times of PK sample collection MUST be recorded. See 
SPM for further details. 
6.2.8.2 Pharmacokinetics Sample Analysis 
Sample analysis will be performed by Alturas Analytics (Moscow, Indiana USA) under 
the direction of Cortendo AB.  Concentrations of COR-003 (2S,4R-ketoconazole) in 
plasma will be determined using current validated methodology. See SPM for further 
details. 
6.3 Additional Considerations for Risk Management 
6.3.1 Instructions for Subjects 
Subjects will be instructed to carry a card at all times identifying the potential risk for 
adrenal insufficiency. This card will include subject’s information, contact information 
for the Investigator, and the potential need for glucocorticoids in cases of shock, surgery, 
and other conditions, as appropriate.  


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 65 of 119 
CONFIDENTIAL 
 
Subjects will be advised 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 access the 
medical staff at the investigational site regardless of day or time of day. 
In addition, subjects will also be asked to carry an emergency kit containing 
hydrocortisone or another appropriate glucocorticoid, according to local medical 
practice, that can be administered immediately in case of adrenal insufficiency.  
6.3.2 Considerations for Investigator 
Subjects will be contacted (method by subject preference) approximately 1 week after 
taking the first dose and approximately 1 week after each dose adjustment to check on 
subject status and ensure compliance with medication administration.   
Throughout the study, subjects must be monitored and managed by the Investigator for 
the following diseases associated with CS or its treatment, according to recommended 
guidelines for diagnosis and standard of care: 
• Diabetes and impaired glucose tolerance:  See Appendix H for testing 
recommendations. 
• Hypertension:  See Appendix I for guidelines for classification of blood pressure 
levels and follow-up recommendations.  
• Hypocortisolemia:  See Appendix K for evaluations of signs and symptoms. 
• Hypomineralocorticoidism:  See Appendix K for evaluations of signs and 
symptoms. 
• Hypogonadism:  See Appendix K for evaluations of changes in sexual function as 
reported by the subject. 
• Acute adrenal crisis:  Acute adrenal crisis is a life-threatening condition that 
often occurs primarily because of mineralocorticoid deficiency (Appendix K).  In 
such cases, the major clinical problem is hypotension (low blood pressure or 
shock).  Adrenal crisis can result in seizures, shock, coma or death.  In patients 
treated for CS, adrenal crisis typically occurs in the setting of acute stress or 
pituitary infarction.  With pituitary infarction, glucocorticoid deficiency can 
predominate.  
• Adrenal insufficiency:  See the following section (Section 6.3.3) for assessment of 
signs and symptoms of adrenal insufficiency and Appendix K for evaluation of 
signs and symptoms of adrenal insufficiency. 
6.3.3 Adrenal Insufficiency 
All medical care providers identified by the subject, in addition to the Investigator, 
MUST be given sufficient written instructions about potential risks of adrenal 
insufficiency in subjects in this study. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 66 of 119 
CONFIDENTIAL 
 
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 (non-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 evident. Furthermore, subjects 
may have adrenal insufficiency without abnormal cortisol concentrations, but the 
concentrations, while within or above the normal range, are inappropriately low for the 
degree of physiological stress being experienced by the subject. These symptoms include: 
nausea, vomiting, abdominal pain, anorexia, malaise, fatigue, headache, 
arthralgias/myalgias, gastrointestinal discomfort, dizziness (particularly upon standing), 
irritability, depression, sweating, and fever. Subjects may have hypoglycemia as well. 
Therefore, subjects should be assessed for signs and symptoms AND cortisol levels as 
follows: 
• Full review of symptoms. 
• Lying and standing blood pressure measurements and pulse to evaluate postural 
changes.  
• Laboratory evidence of hypoadrenalism is defined as morning serum cortisol level 
< 3 μg/dL (LLN or the lower limit of the assay being used for clinical testing). 
Even if the serum cortisol and/or the UFC are within the normal range, the 
possibility of adrenal insufficiency should be considered, based on postural 
(orthostatic) vital sign changes and clinical signs and symptoms. Please see 
Appendix K for a list of clinical signs and symptoms.  
• Should adrenal insufficiency be deemed present, COR-003 should be temporarily 
discontinued for mild symptoms/signs. 
• For moderate or severe symptoms/signs, COR-003 will be temporarily 
discontinued and rescue glucocorticoids temporarily administered.  
• COR-003 at an appropriately lower dose can be restarted once the medical 
situation is deemed resolved. If the dose that caused adrenal insufficiency is 
150 mg/day, COR-003 should be completely discontinued, and the subject 
withdrawn from the study. 
All cases of suspected adrenal insufficiency should be reported as AESIs to Cmed 
Pharmacovigilance (Section 13.7). 
7 
LIFESTYLE AND DIETARY RESTRICTIONS 
Subjects must follow the following lifestyle and dietary restrictions throughout the study. 
• Consumption of grapefruit, lime juice and Seville oranges and products (i.e. sour 
orange, bigarade orange, or marmalade orange) should be avoided; 
• Genuine licorice should be avoided;  
• Consumption of excessive alcohol should be avoided; 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 67 of 119 
CONFIDENTIAL 
 
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 ≥4 L/day of fluids (which equals a little less than a gallon) 
o Use of medicines or products with glucocorticoids, such as hemorrhoid or 
steroid skin creams  
• On the nights that samples are collected for salivary cortisol test, subjects must 
refrain from the following: 
o Within 2 hours of the collection: 
 Brushing or flossing teeth or doing anything that could induce 
bleeding of the gums  
 Sleeping and subsequently awakening 
o Within 1 hour of the collection: 
 Eating or drinking or chewing anything (including tobacco) 
 Using any creams or lotions 
 Smoking cigarettes, pipe, cigar or any other substance. 
 
Information on subject’s job related to working shift hours will be collected by the site 
personnel. 
8 
INVESTIGATIONAL PRODUCTS 
8.1 Description of Investigational Product 
COR-003 (2S,4R-ketoconazole, also known as levoketoconazole) will be provided as 
150 mg tablets.  The tablets will be 3/8” round, biconvex, and unmarked with a pink film 
coat and supplied in foil induction sealed High Density polyethylene (HDPE) 
bottles. Refer to the Pharmacy Manual for details of labeling of the investigational 
product. 
8.2 Dosage and Administration 
COR-003 will be administered BID, approximately every 12 hours, according to the 
titration scheme described in Section 4.2.  Subjects will receive an adequate number of 
the investigational product at each visit prepared by the study pharmacist. 
8.2.1 Dosage Reduction and use of Dose Level 0 
In accordance with the guidance in Section 6.3.3 if the subject develops signs and/or 
symptoms of adrenal insufficiency (e.g., orthostatic hypotension, nausea, vomiting, 
abdominal pain), based on further investigation and clinical judgment, the Investigator 
may opt to stop dosing of the study medication to allow resolution of these symptoms. 
Similarly, dosage reductions following temporary drug interruption might be used to 
manage possibly drug-associated toxicities, including LFT elevations (Section 5.3.2) or 
QTC prolongation (Section 6.2.7.2).  In such cases, when the study medication is 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 68 of 119 
CONFIDENTIAL 
 
restarted it should be reduced to the preceding dose level (as described in 
Section 6.2.4.2).  In the event that an observation is made at DL1 necessitating dose 
reduction, the subject may receive a lower dose of 150 mg once daily (DL0) at the 
discretion of the Investigator and agreement with agreement of the Medical Monitor.  
Subjects may subsequently resume the Dose Titration scheme, if appropriate at the 
discretion of the Investigator and agreement with the Medical Monitor. 
The 150 mg dose for DL0 may be administered in the evening except on the day of the 
in-clinic procedures, when the dose should be administered in the clinic to allow for post-
dosing ECG and PK assessments. 
8.3 Dose Rationale 
The effects of treating CS with any therapeutic agent is not generally predictable a priori. 
Ketoconazole a commonly used therapeutic agent has variable PK and is titrated to effect 
up to levels as high as 1800 mg to control severely ill CS patients. In most patients 
responsive to ketoconazole, doses average approximately 600 to 800 mg/day with the 
range of 200 to 1800 mg having been utilized to achieve normalization of cortisol levels 
[Nieman 2002; Pozza 2012]. 
Like ketoconazole, COR-003 is not expected to be administered at a fixed dose but will 
be titrated to effect in each subject.  COR-003 has been used in clinical trials up to a dose 
of 600 mg. The highest dose of 600 mg BID COR-003 (1200 mg total daily dose) is 
indicated during this trial, because some CS subjects may require higher levels of cortisol 
suppression to achieve control in this severe disease.  Any titration to a dose of COR-003 
higher than 300 mg BID (600 mg total daily dose and higher) will be guided by enhanced 
tolerability and safety monitoring as described in Section 4.2.2.  It is expected that 
titration to this highest dose will be the exception rather than the norm, based on the 
experience with ketoconazole and the potentially higher in vitro potency of COR-003 to 
inhibit key enzymes controlling adrenal cortisol synthesis.  A detailed description of 
preclinical and prior clinical data with COR-003 and rationale for dose selection is 
provided in the Investigator’s Brochure. 
8.4 Blinding 
This will be an open label study.  However, a study-specific data restriction plan (DRP) 
has been crafted to govern the availability of efficacy data, such that the Sponsor will not 
be able to discern the emerging efficacy profile of the drug during study conduct, thus 
reducing the possibility of introduced bias. 
8.5 Randomization and Treatment Assignment 
This is a non-randomized study.  All subjects that sign informed consent and meet 
eligibility criteria at Baseline will begin treatment on 150 mg BID. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 69 of 119 
CONFIDENTIAL 
 
9 
DRUG SUPPLIES, DISPENSING, STORAGE AND ACCOUNTING 
9.1 Product Accountability 
The Investigator is responsible for investigational product accountability, reconciliation, 
and record maintenance.  In accordance with all applicable regulatory requirements, the 
Investigator or designated site staff must maintain investigational product accountability 
records throughout the course of the study.  The responsible person(s) will document the 
amount of investigational product received from and returned to Cortendo (when 
applicable), the amount supplied and/or administered to and returned by subjects, if 
applicable. 
9.2 Compliance Assessment 
Subjects will be asked to maintain a patient diary to record medication administration, 
urine sample collection, saliva sample collection, concomitant medications, and changes 
in condition. In addition, subjects should bring all empty medication bottles and unused 
medication with them to all visits except for the additional safety visit required in the 
Titration Phase for DL4 through DL7 (where empty medication bottles and unused 
medication will not be collected and accountability will not be performed). 
Accountability to determine compliance will be performed at all other visits. 
9.3 Treatment of Investigational Product Overdose 
There is no known antidote to COR-003.  Subjects should be medically managed 
according to their clinical condition, as appropriate.  Refer to Section 4.2.2 for 
administration of doses >600 mg/day.   
10 CONCOMITANT MEDICATIONS 
10.1 Permitted Medications 
Over the counter liquid and tablet antacids are allowed, but must be used in moderation 
and taken ≥2 hours after dosing with COR-003. A list will be provided.  
10.2 Prohibited Medications 
During the study, subjects are not allowed to take the following medications, a more 
complete list categorized by primary reason for prohibition is found in Appendix J. The 
Investigator is encouraged to contact the Medical Monitor for any questions. 
• Total daily dose of acetaminophen (paracetamol) >3g (increased liver toxicity 
risk); 
• Prescription or over the counter H2 receptor antagonists or proton-pump 
inhibitors or sucralfate (inhibition of drug absorption); 
• Statins other than pravastatin, fluvastatin and rosuvastatin; potentially eligible 
subjects should be switched to an allowed statin several weeks prior to the 
Baseline Visit whenever feasible to allow equilibration of blood lipids; 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 70 of 119 
CONFIDENTIAL 
 
• Carbamazepine, fenofibrate (assay interference), carbenoxolone; 
• Genuine licorice (mineralocorticoid effects);  
• Steroidogenesis inhibitors or dopamine agonists (interference with drug effect, 
Appendix J, Table 9 and Table 10); 
• Megestrol acetate or medroxyprogesterone acetate and selected other synthetic 
progestins (see Appendix J, Table 11) [Schindler 2003]; 
• Any other drug treatments used to lower cortisol in CS that are subject to washout 
(Section 5.1 and Appendix J, Table 12) are prohibited throughout the study; 
• Weight loss medications (either prescription or over the counter, Appendix J, 
Table 13); 
• Drugs whose systemic exposure is potentially increased significantly by 
concomitant use of COR-003 (Appendix J, Table 15); 
• Medications that are strong CYP3A4 inhibitors or CYP3A4 inducers as they may 
interfere with the metabolism of COR-003. As examples, rifampicin, rifabutin, 
isoniazid, nevirapine and phenytoin may significantly reduce COR-003 
concentrations via CYP3A4 induction, and ritonavir may increase COR-003 
concentrations via CYP3A4 inhibition, and are therefore prohibited (Appendix J, 
Table 16); 
• Medications resulting in QTc prolongation as a direct effect or as a result of 
interaction with COR-003, examples include: cisapride, dofetilide, pimozide, 
quinidine. (Appendix J, Table 17).  However, in selected cases where no 
alternative medications are available, permission from the Medical Monitor may 
be sought; 
• Topical or inhaled corticosteroid preparations (interference with drug effect, 
Appendix J, Table 9);  
• The following herbal medicines: St John’s Wort, echinacea, gingko, goldenseal, 
yohimbe, red rice yeast, danshen, silybum marianum, Asian ginseng, schissandra 
sphenanther, shankhapushi, and Asian herb mixture (Xiao chai hu tang and 
Salboku-to); 
10.3 Medications to be Used with Caution 
• There are some medications that are often considered contraindicated when used 
with ketoconazole, due to an increased risk of AEs (Appendix J, Table 20). 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 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 increases 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 that case, careful monitoring, with 
possible adjustments in doses, is recommended (see Appendix J, Table 18). 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 71 of 119 
CONFIDENTIAL 
 
11 SUBJECT COMPLETION AND WITHDRAWAL 
11.1 Subject Completion 
Subjects who complete the End of Maintenance Phase Visit of the study, regardless of 
their response status, will be considered to have completed the study and are eligible for 
inclusion into the Extended Evaluation Phase. 
Subjects who complete the Extended Evaluation Phase (M12 Visit) and are not 
progressing into an expanded access program should return approximately 2 weeks after 
completion of treatment with COR-003 for the Follow-Up Visit (see Appendix A). 
11.2 Subject Withdrawal Criteria and Procedures 
Reasons for premature study withdrawal (i.e. do not return for all study visits), include, 
but are not limited, to the following (see also Section 5.3): 
• Safety reasons, either at the discretion of the Investigator or at the subject’s 
request 
• Protocol violations at the discretion of the Sponsor 
• Permanent study medication discontinuation 
• Concomitant therapy that could interfere with the results of the study, (the 
Investigator will report all such information on the CRFs and decide, in 
accordance with the Sponsor, whether the subject is to be withdrawn).  
All study withdrawals and their causes must be carefully documented by the Investigator 
on the CRF, and, if need be, on the AE form.   
If the subject chooses to withdraw or is otherwise withdrawn before completing the 
study, the Investigator should make every attempt to have the subject return to the clinic 
to complete all safety and PK assessments as outlined for the Follow-Up Visit in 
Appendix A (approximately 2 weeks following end of treatment with COR-003). If a 
subject is withdrawn before completing the Maintenance or Extended Evaluation Phases 
of the study, the reason for termination will be recorded.  All data gathered on the subject 
prior to termination will be made available to the Sponsor.   
12 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
12.1 Population for Analysis 
Intent-to-Treat (ITT) Population: The ITT population will include all subjects who 
receive at least one dose of COR-003.  This population will be used for the evaluation of 
efficacy and all safety analyses. 
Maintenance (M) Population: The M population will consist of all subjects who enter 
the Maintenance Phase of the study. This population will be used for the supportive 
evaluation of all the primary and secondary efficacy endpoints.   


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 72 of 119 
CONFIDENTIAL 
 
Per Protocol (PP) Population: The PP population will consist of all subjects who enter 
the Maintenance Phase of the study and have no major protocol deviations that may 
affect efficacy. This population will be as supportive analysis for the analysis of the 
primary endpoint.   
12.2 Hypothesis 
The primary endpoint for this study will be the proportion of responders to COR-003 
following 6 months of dosing in the Maintenance Phase without a dose increase during 
that phase. Additionally, subjects who previously received radiation therapy and who 
exhibit no rebound increase in mean UFC following withdrawal of COR-003 
immediately after the end of the Maintenance Phase will be considered non-responders.  
The proportion of responders in the ITT population will be estimated along with 
corresponding two-sided 95% confidence interval (CI).  The null hypothesis to be tested 
is if the proportion of responders at the end of the Maintenance Phase visit is at most 20% 
versus the alternative hypothesis that the proportion of responders at the end of the 
Maintenance Phase visit is greater than 20%; COR-003 will be considered effective if the 
null hypothesis is rejected.  The hypothesis test is to have 90% power and two-sided 5% 
Type I error. 
12.3 Sample Size Determination 
A sufficient number of subjects (estimated at approximately 90) will be enrolled into the 
Dose Titration Phase of the study to ensure that at least 70 subjects complete the 6-month 
Maintenance Phase.  The 90 subjects to be enrolled in the Dose Titration Phase will 
constitute the primary analysis population (i.e. the ITT population).  Table 3 illustrates 
the power to exclude the null hypothesis of at most a 20% responder rate, given an 
alternative response of 35% for a two-sided 5% Type I error for the ITT population. 
Results will be evaluated using a two-sided 95% lower confidence bound for the response 
rate at the end of the Maintenance Phase visit. 
Table 3 
One Sample χ2 Test: Null Hypotheses vs. Alternative Hypothesis, One 
Scenario 
Test significance level, α 
0.050 
1 or 2 sided test? 
2 
Null Hypothesis Responses %, p0 
20% 
Alternative Hypothesis Response %, pA 
35% 
Power (%) 
90 
N (ITT) 
90 
As an example, if the observed response rate at the end of the Maintenance Phase visit is 
40% with 90 subjects, then the two-sided 95% CI is (30.0%, 50.9%) which would support 
efficacy. 
In addition, the sample size of 90 subjects will be adequate to test hypotheses associated 
with the change from Baseline in CS comorbidity biomarkers expressed as continuous 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 73 of 119 
CONFIDENTIAL 
 
endpoints (secondary efficacy endpoints).  Table 4 displays the differences that can be 
detected for the secondary efficacy endpoints of CS comorbidities with 90% power for a 
two-sided 1% Type I error for 90 subjects (the 1% Type I error accounts for testing 
significance for these multiple secondary efficacy endpoints).  Results will be evaluated 
using two-sided 99% lower confidence bounds for the changes from Baseline at the End 
of the Maintenance Phase visit. 
Table 4 
Paired t-test: No (0) Mean Differences Null Hypotheses vs. Anticipated 
Mean Differences Alternative Hypothesis 
 
Glucose 
[mmol/l]1 HbA1c 
[%] 
SBP 
[mm 
Hg] 
DBP 
[mm 
Hg] 
Total 
Cholesterol 
[mmol/L] 
LDL 
[mg/dL] 
Weight 
[kg]2 
Test significance level, α 
0.010 
0.010 
0.010 
0.010 
0.010 
0.010 
0.010 
1 or 2 sided test? 
2 
2 
2 
2 
2 
2 
2 
Mean difference, md 
0.670 
0.311 
8.743 
6.174 
0.497 
0.535 
2.445 
SD difference, sd 
1.6001 
0.7501 
21.12 
14.92 
1.23 
1.292 
5.92 
Effect size, d = |md| / sd 
0.419 
0.414 
0.414 
0.414 
0.414 
0.414 
0.414 
Power (%) 
90 
90 
90 
90 
90 
90 
90 
N 
90 
90 
90 
90 
90 
90 
90 
1. Fleseriu 2012 
2. Colao 2012 
3. FDA Medical Review document for pasireotide  
12.4 General Considerations for Data Analysis 
The SAS System, Version 9.1.3 (or higher), will be used for all analyses, unless 
otherwise specified. Continuous variables (e.g., age) will be summarized using the 
number of observations (n), mean, standard deviation (SD), median, minimum, and 
maximum. Categorical variables (e.g., sex, race) will be summarized using the number of 
observations (n) and percentage in each category.  
All data used in analyses and/or collected during the study will be provided in listings. 
12.4.1 Premature Withdrawal and Missing Data 
Subjects withdrawn prior to the end of the Maintenance Phase will be considered as 
prematurely withdrawn. All available data for subjects who prematurely withdraw from 
the study will be included in all analyses. At any visits for which four 24-hour urine 
samples are planned to be collected, at least two UFC collections must be adequate by 
volume and creatinine criteria to be able to derive the mean UFC and thus be considered 
as non-missing.  Study withdrawals, reasons for withdrawal, and missing UFC collections 
will be summarized. 
Analyses of data for specific visits will be performed using two different approaches to 
account for missing data during the Maintenance Phase: 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 74 of 119 
CONFIDENTIAL 
 
1. At-Visit analysis: Missing values at post-Baseline assessments will not be 
replaced and will be regarded as missing in longitudinal analyses.  The 
longitudinal models account for missing data. 
2. Imputation analysis: Subjects withdrawing will be counted as failures for the 
primary efficacy analyses. 
At-visit analyses will be performed using the longitudinal models as the primary 
approach with the imputation approach as supportive.  Details will be provided in the 
SAP. 
12.5 Final Analyses 
12.5.1 Safety Analyses 
The final analysis of safety is considered to be coincident with the last subject visit 
following completion of the Extended Evaluation Phase (i.e. following at least 
12 months’ treatment at the Therapeutic Dose). Interim analyses of safety are planned to 
coincide with timing for the primary analysis of efficacy (i.e. after the final subject has 
completed Maintenance Phase) and for any unplanned interim efficacy analyses, in order 
to assess benefits and risks of treatment simultaneously. In addition, planned and 
unplanned safety analyses will be performed and reported on a limited basis in order to 
satisfy requirements of study oversight, for example to Institutional Review Boards and 
Competent Authorities. These limited analyses (e.g. common adverse reactions summary) 
will not be accompanied by assessments of potential benefits.  
The DSMB will review all SAEs and AESIs on a rolling basis and assess benefits and 
risk of therapy systematically at approximately 6-month intervals. 
12.5.1.1 
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.   
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 
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.  
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. 
12.5.1.2 
Adverse Events (AEs) 
AEs will be coded using MedDRA and graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events, version 4.0 [NCI CTCAE, 2009].  


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 75 of 119 
CONFIDENTIAL 
 
TEAEs will be of primary interest.  The proportion of subjects reporting at least one 
TEAE, at least one drug-related TEAE, at least one serious TEAE, at least one TEAE 
leading to discontinuation of study drug, and at least one TEAE leading to withdrawal 
from the study will be computed.  The number and the percentage of subjects reporting 
each TEAE will be summarized for all TEAEs, and separately for drug-related TEAEs, 
all serious TEAEs, all TEAEs leading to discontinuation of study drug, and all TEAEs 
leading to withdrawal from the study. 
The most common TEAEs are defined as those occurring in at least 5% of the ITT 
population. The number and the percentage of subjects reporting the most common 
TEAEs will be summarized.  Two-sided 95% CIs will be reported for such TEAEs. 
12.5.1.3 
Clinical Laboratory Evaluations 
A laboratory value that is within the normal range will be considered normal. A 
laboratory value that is outside the testing laboratory’s normal range will be considered 
an abnormal laboratory value.  The number and percentage of subjects with abnormal 
laboratory values will be summarized for each scheduled visit.  Shift tables will be 
constructed.  
Differences in laboratory values between Baseline and each scheduled laboratory 
assessment will be calculated for each laboratory test and summarized descriptively. The 
laboratory test values obtained at Baseline closest to the start of treatment will be used as 
the Baseline value.   
Further details of the categorical analysis of the laboratory evaluation and on the LFT 
evaluations will be defined in detail in the SAP. 
12.5.1.4 
Vital Signs 
Heart rate and three measurements of SBP and DBP will be taken at each visit. The mean 
of these measurements will be used as the value for each visit. Baseline will be defined as 
the mean of the values from the measurement at Baseline just prior to the start of 
treatment.  Change from Baseline for each measurement will be summarized.  In 
addition, values of clinical importance (Table 5) will be identified in the data listings.   


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 76 of 119 
CONFIDENTIAL 
 
Table 5 
Vital Sign Values of Clinical Importance 
Vital Sign 
Criteria 
Flag 
Heart Rate (HR) 
< 44 bpm 
Low (L) 
 
44-100 bpm 
Normal  
 
101-120 bpm 
High (H) 
 
>120 bpm 
Very High (VH) 
 
 
 
Systolic Blood Pressure (SBP) 
< 90 mm Hg 
Low (L) 
 
90-139 mm Hg 
Normal 
 
140-169 mm Hg 
High (H) 
 
≥170 mm Hg 
Very High (VH) 
 
 
 
Diastolic Blood Pressure (DBP) 
< 50 mm Hg  
Low (L) 
 
50-89 mm Hg 
Normal 
 
90-109 mm Hg 
High (H) 
 
≥ 110 mm Hg 
Very High (VH) 
The number and percentage of subjects with blood pressure and HR outside the pre-
defined range of clinical concern at any post-Baseline assessment will be summarized.  
Shift tables for normal vs abnormal vital signs from Baseline to each scheduled 
assessment will be constructed.  
12.5.1.5 
Electrocardiograms (ECGs) 
Summary ECGs, based on the measurement of an ECG over 5 minutes as described in 
Section 6.2.4 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.  ECGs results will be available to the 
Investigator shortly after being obtained and all ECGs will be reviewed by a central 
consulting cardiologist. The data from the central consulting cardiologist will be used in 
the evaluation of the drug effect.  While on study treatment, a QTc > 500 msec or > 60 
msec above Baseline will be of special interest (See Section 13.2.2). 
Categorical changes from Baseline and QTc values from each visit will be summarized 
by worst change and by visit. The clinically important categories (Table 6) of actual and 
change values will be tabulated and provided as listings.  
Table 6. 
QTc Interval Values of Clinical Importance 
QTc Interval 
Criteria (msec) 
Flag 
Change from Baseline 
<30 
Low (L) 
 
30-60 
Mid (M) 
 
>60 
High (H) 
 
 
 
Actual Value 
>450-480 
Low (L) 
 
>480-500 
Mid (M) 
 
>500 
High (H) 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 77 of 119 
CONFIDENTIAL 
 
 
Continuous ECG outcomes will be assessed using a paired t-tests while normal-abnormal 
shift tables will be assessed using a McNemar’s paired comparison tests. 
12.5.1.6 
Other Safety Measures 
Results from the DST during the Screening Phase will be listed by subject. ACTH, IGF-1 
and testosterone levels will be listed and summarized descriptively by time point. Results 
from pituitary MRI (tumor size) will be listed by subject and time point and descriptively 
summarized.  
12.5.2 Efficacy Analyses 
All efficacy analyses will be performed on the ITT and M populations using longitudinal 
models.  For the primary endpoint, imputation will be applied for subjects that were 
prematurely withdrawn from the study as supportive analysis. In addition, the primary 
endpoint will also be analyzed using the PP population as supportive analysis. 
Withdrawn subjects prior to the End of the Maintenance Phase Visit assessment, as well 
as those requiring a dose increase during the Maintenance Phase, will be considered non-
responders as long as the dose increase was sustained.  Additionally, subjects who 
previously received radiation therapy and who exhibit no rebound increase in mean UFC 
following withdrawal of COR-003 immediately after the end of the Maintenance Phase 
will be considered non-responders. 
12.5.2.1 Primary Efficacy Analysis 
Clinical Response Rate 
UFC data will be averaged for the End of Maintenance Phase Visit and then analyzed for 
response. The treatment estimate of the clinical response rate at the end of the 
Maintenance Phase and its associated two-sided 95% CI will be obtained from a repeated 
measures GEE model with a logit link using SAS PROC GLIMMMIX with LSMEANS 
statement.  The primary analysis will be the ITT population and analysis will be repeated 
in the M population and PP population. The longitudinal model will include visit, the 
concurrent CS medical conditions (diabetes, hypertension) as Baseline covariates as well 
as age (rounded median split), sex, disease duration, prior CS therapy, and prior radiation 
therapy, and subject will be included as a random effect.   
Dose level information for the M population and PP population will be summarized. 
If the lower bound of the 95% CI for the LSMEAN proportion of responders in the ITT 
population is ≥20% in the ITT population, then COR-003 will be considered effective.   
Although the End of Maintenance Phase marks the final analysis of primary efficacy, the 
clinical response rate will also be analyzed after each month of treatment in the 
Maintenance Phase and (secondary endpoint) and after 9 and 12 months in the extension 
phase (exploratory endpoint).  


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 78 of 119 
CONFIDENTIAL 
 
12.5.2.2 Secondary Efficacy 
UFC Analysis 
Clinical Response Rates  
UFC data will be averaged at each nominal visit and then analyzed for response in the 
same manner as for primary endpoint using the longitudinal models described in 
Section 12.5.2.1.  The proportion of UFC responders to COR-003 (defined similarly to 
the primary endpoint) along with associated 95% CIs will also be individually estimated 
at Months 1, 2, 3, 4, and 5 of the Maintenance Phase.  The longitudinal model estimates 
and the Nominal Visit estimates will both be presented.   
Complete and Partial Response Rates  
The proportion of subjects with complete and partial responses (≥ 50% reduction in mean 
UFC from Baseline at Months 1, 2, 3, 4, 5, and 6 of the Maintenance Phase) will be 
calculated and reported alongside with its associated 95% CIs and will be estimated from 
a repeated measurement model with the same covariate as for the primary endpoint 
analysis.  
Change in UFC 
Mean UFC will be calculated from adequate 24-hour urine collections. At Baseline and 
End of Maintenance Phase where four samples are to be collected, the mean UFC will 
only be calculated if there are at least two adequate samples.  The mean UFC from the 
collections at each visit will be used in the analysis of UFC.  UFC will be summarized by 
time point using descriptive statistics. In addition, change from Baseline and percent 
change from Baseline will be calculated for each post-Baseline assessment. Mean and 
individual plots of each endpoint over time will be presented for the Maintenance Phase.  
Paired t-tests will also be presented for the change from Baseline to each nominal visit. 
In addition, a shift table will be created to summarize the shift from Baseline to each 
post-Baseline time point using the following UFC normality categories: less than LLN, 
normal range, greater than ULN and less than 2X ULN, 2X to 5X ULN, 5X ULN to 10X 
ULN, greater than 10X ULN.  Shift analyses will be conducted using a generalized 
McNemar paired comparison test to account for the multiple categories. 
Salivary and Serum Cortisol Levels 
Mean salivary and serum cortisol levels will be calculated after 1, 2, 3, 4, 5, and 6 months 
of dosing in the Maintenance Phase.  Change from Baseline and percent change from 
Baseline and at-visit values will also be listed and summarized descriptively by visit.  
Values at each post-Baseline Visit will be compared with Baseline using a paired t-test. 
CS Comorbidity Biomarkers 
The changes from Baseline and percentage change from Baseline in individual 
biochemical markers of CS comorbidities (fasting glucose, HbA1c, SBP, DBP, total 
cholesterol, LDL and HDL cholesterol, and body weight) will be summarized at Months 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 79 of 119 
CONFIDENTIAL 
 
1, 2, 3, 4, 5, and 6 of the Maintenance Phase.  In addition, shifts from Baseline (with 
regards to laboratory normal range) in individual biochemical markers of CS 
comorbidities will be analyzed using a t-test paired comparison test at each scheduled 
visit. 
Calculations for the CS comorbidity biomarkers will be performed using SAS PROC 
MIXED to account for all post-Dose Titration Phase outcomes per subject with changes 
from Baseline and two-sided 99% lower confidence bounds calculated using LSMEANS. 
To account for endpoint multiplicity, conservative 99% CIs will be computed instead of 
95% CIs.  The longitudinal model will include visit, the concurrent CS medical 
conditions (diabetes, hypertension) as Baseline covariates as well as age (rounded median 
split), sex, disease duration, prior CS therapy, and prior radiation therapy, and subject as 
a random effect.   
Clinical Signs and Symptoms 
Each individual clinical sign and symptom, defined in Appendix M, will be summarized 
at each time point for assessment by number and percent of subjects.  
Each sign and symptom present at Baseline will be graded on a 0 to 3 severity scale 
(0=absent, 1=mild, 2=moderate, 3=severe).  For each subject, the severities will be 
added.  A paired t-test will be used to test if there is a significant reduction in severity at 
each visit. 
In addition, shift tables in individual clinical signs and symptoms at each post-Dose 
Titration Phase visit will be created to demonstrate any improvement gained during the 
course of treatment and analyzed using a McNemar paired comparison test. 
Cushing’s Syndrome Quality of Life Questionnaire  
QoL (Appendix L) measures and changes from Baseline will be summarized by time 
point using descriptive statistics and analyzed using a paired t-test.   
Beck’s Depression Questionnaire 
Changes from Baseline for the Beck’s Depression questionnaire (Appendix N) will be 
summarized by time point using descriptive statistics and analyzed using a paired t-test. 
Only subjects recruited under the protocol amendment or subsequent amendment will be 
included in the summary table. All data will be listed. 
Glucose Tolerance Test 
For pre-diabetic subjects as determined by the Investigator as Baseline, the number and 
percent of subjects after 3 and 6 months of dosing in the Maintenance Phase will be 
summarized for each of the following categories. 
• Normal: 2-hour glucose level is <140 mg/dL 
• Impaired glucose tolerance (pre-diabetic): glucose level ≥140 mg/dL and 
≤200 mg/dL 
• Provisional diagnosis of diabetes (diabetic): glucose level ≥200 mg/mL 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 80 of 119 
CONFIDENTIAL 
 
Glucose values during the OGTT will also be summarized by maximum value, time to 
maximum value, and AUC, and statistically analyzed with a paired t-test for each 
assessment. 
Spot Albumin/Creatinine Ratio  
For subjects who have abnormal albumin/creatinine ratio at Baseline, albumin/creatinine 
ratio and its change from Baseline after 3 and 6 months of dosing in the Maintenance Phase 
will be summarized.  At-visit values will be compared with Baseline using a paired t-test. 
CRP 
CRP value and its change from Baseline after 1, 2, 3, 4, 5 and 6 months of dosing in the 
Maintenance Phase will be summarized. 
12.5.2.3 Exploratory Efficacy 
The analyses described above in Section 12.5.2.2 for clinical response rate, complete and 
partial response rate, changes in UFC, serum and late night salivary cortisol, QoL 
(Cushing’s QoL questionnaire and Beck’s Depression Index), and change in CS 
comorbidities, OGTT, albumin/creatinine and CRP will be repeated for the Extended 
Evaluation period using the same approach as for the Maintenance Period. 
Clinical Benefit 
The proportion of subjects achieving clinical benefit at Months 1, 2, 3, 4, 5, and 6 during 
the Maintenance Phase and Months 9 and 12 in the Extended Evaluation Phase will be 
displayed graphically over time with clinical benefit defined as: 
1. Clinical response as indicated by UFC ≤ ULN, and 
2. No increase in COR-003 dose during Maintenance Phase, and 
3. A clinically meaningful improvement in any one Baseline CS comorbidity 
(diabetes, hypertension, hypercholesterolemia, weight) as will be defined in 
the SAP and  
4. No study drug related TEAE classified as severe or worse. 
Medication Changes 
Changes to concomitant medications (in particular for blood pressure, diabetes and 
cholesterol management) will be listed by subject.  In addition, the number and percent of 
subjects with medication changes during the course of the study will be summarized. The 
proportions with dose increases and decreases including new and discontinued 
medications will be displayed.   
Clinical Signs of Hypercortisolism (Photographs) 
At Baseline, End of Maintenance Phase Visit, and End of Extended Evaluation Phase 
Visit, the adjudication committee, composed of three clinician-investigator experts in CS 
will assess the subjects for changes in visible signs of hypercortisolism (e.g. moon face, 
plethora, supraclavicular and dorsal fat pads, striae, hirsutism, bruising and overall body 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 81 of 119 
CONFIDENTIAL 
 
habitus, if available) by scoring longitudinal photographs.  The scoring will be based on 
overall subjective impression of changes from Baseline as follows: obvious visible 
worsening, subtle visible worsening, no visible changes, subtle visible improvements, 
obvious visible improvements. Other methods of scoring photos may be included in the 
SAP. 
Relationship Between QTc Interval and COR-003 
The number and percentage of subjects with abnormal QTc, QTcB and QTcF results 
(abnormal categories are defined as > 450 msec, > 480 msec, > 500 msec, > 30 msec 
increase from Baseline and > 60 msec increase from Baseline) will be summarized for 
each dose level after 1, 2, 3, 4, 5 and 6 month of treatment in the Maintenance Phase and 
after 9 and 12 months in the Extended Evaluation Phase. Subjects will be summarized 
under their therapeutic dose or the maximum dose reached during the Dose Titration 
Phase if the subject discontinued prior to entering the Maintenance Phase. 
12.5.3 Pharmacokinetics Analysis 
PK model parameters will include: CL/F, V/F, Ka with associated between subject 
variability where feasible.  Model parameters will be tabulated with associated precision.  
Derived parameters including t½, AUC and Cmax will be reported, if appropriate. 
Because the PK of ketoconazole are reported to change over time, time dependent 
changes in CL/F, AUC, and t½ will be investigated and, if identified, changes will be 
described in the model. Derived parameters will be tabulated with associated summary 
statistics. 
PK data will be evaluated using a population modeling-based approach as implemented 
in NONMEM® (Version 7 level 2 or higher).  Subjects with at least one adequately 
documented dose and concentration record will be considered for inclusion in the 
population PK evaluation.  All evaluations will be conducted based on a pre-specified 
analysis plan. Standard model building and model evaluation procedures will be 
followed.  Derived parameters will be calculated from the final model. 
12.5.4 Pharmacodynamics Analysis 
The PD model parameters including UFC Imax, COR-003 dose producing UFC IC50, 
and associated estimates of between subject variability will be reported.  Individual 
maximal UFC reductions achieved will be tabulated and summary statistics (mean, 
median, SD and percent coefficient of variation) will be presented.  Stochastic 
simulations of the expected response for the preferred dose regimen will be generated to 
explore the range of UFC reduction. 
PD data (UFC) will be evaluated using a population modeling-based approach as 
implemented in NONMEM® (Version 7 level 2 or higher).  Subjects included in the 
population analysis with at least one adequately documented dose, PK record and UFC 
record will be considered for inclusion in the population PD evaluation.  All evaluations 
will be conducted based on a pre-specified analysis plan. Standard model building and 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 82 of 119 
CONFIDENTIAL 
 
model evaluation procedures will be followed.  Derived parameters such as maximal 
response will be calculated from the final model as appropriate. 
12.5.5 Subgroup Analyses 
Subgroup analyses for the primary endpoint and CS comorbidities endpoints will be 
performed for a minimum subgroup size of at least 30% of the ITT population. Details 
will be covered in the SAP. 
12.5.5.1 Prior Therapy for Cushing’s Syndrome 
Subgroup displays for the primary endpoint and the CS comorbidities endpoints will be 
generated for subjects that enter the study as medical treatment-naïve vs. medical 
treatment-experienced and surgery-naïve versus surgery-experienced. Subgroup analyses 
by number of prior surgeries, time since last surgery, and category of prior medical 
treatment will also be explored. 
12.5.5.2 Prior Radiation Therapy 
Subset displays for the primary endpoint and the CS comorbidities endpoint will be 
generated, excluding subjects who previously received radiation therapy.  The total 
number of previously irradiated subjects will not exceed 10.  
Note: A drug holiday after the last Maintenance Phase visit will be used to determine if 
UFC normalization during the Maintenance Phase can be attributed to COR-003 or to 
prior radiation therapy (i.e. a loss of normalization during temporary drug interruption 
will implicate COR-003 as primarily responsible for UFC normalization). 
12.5.5.3 Hypertensive Subjects 
Subgroup displays for the primary endpoint and the CS comorbidities endpoint will be 
generated for subjects who enter the study while being prescribed antihypertensive 
medications versus not and subjects who enter the study with a Baseline SBP 
>130 mmHg or DBP >90 mmHg regardless of antihypertensive medication status versus 
those with lower BP recordings. 
12.5.5.4 Pre-diabetic/Diabetic Subjects 
Subgroup displays for the primary endpoint and the CS comorbidities secondary efficacy 
endpoint will be performed for subjects who enter the study as pre-diabetic (Baseline 
fasting serum glucose >100 mg/dL but <126 mg/dL without concomitant use of 
antihyperglycemic medication) versus those with normal fasting glucose or diabetic 
(Baseline fasting serum glucose >126 mg/dL or lower fasting glucose while being 
prescribed antihyperglycemic medications) versus those without diabetes. Subgroups 
based on findings from stimulated glucose during the Baseline OGTT will also be 
generated. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 83 of 119 
CONFIDENTIAL 
 
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 or not related to the study drug or study conduct.   
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 Screening) that results in subject withdrawal from the study or medical 
treatment or further follow-up. 
NOTE: Abnormal values that reflect hypercortisolism (UFCs, salivary 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; 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 84 of 119 
CONFIDENTIAL 
 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death if it were more severe. 
(c) requires hospitalization or prolongation of existing hospitalization; 
NOTE:  In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or out -
patient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
(d) results in disability/incapacity; 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption. 
(e) is a congenital anomaly/birth defect, or 
(f) Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
13.2.1 Disease-Related Events 
Although symptoms of CS are quite non-specific, all AEs and their attributions will be 
collected and reviewed.  The reduction in cortisol levels, regardless of therapeutic 
intervention, is known to cause symptoms (e.g., nausea, lethargy, muscle aches), and 
these too will be captured as AEs for evaluation. 
13.2.2 Adverse Events of Special Interest (AESI) 
A serious or non-serious event of scientific and medical concern specific to a Sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 85 of 119 
CONFIDENTIAL 
 
AESIs should be reported to the designated safety group as per Section 13.7 
regardless of seriousness or causality.  Upon receipt, these AEs will be captured in the 
safety database, targeted follow-up queries will be sent to sites, and source 
documentation will be sent to the DSMB.  As deemed appropriate, analysis of any 
unscheduled PK samples collected in association with AESIs may be expedited. Once 
uploaded and reconciled in the clinical database, these results will be forwarded to the 
DSMB. 
The AESIs for this study are defined as follows: 
 Persistent QTc prolongation:  Persistent elevation of the QTc interval is defined 
as absolute QTc interval >500 msec (or >60 msec above Baseline), with an ECG 
evaluation on repeat determination continuing to demonstrate QTc prolongation in the 
absence of plausible alternative explanations. 
 
 Potential hepatic events:  Signs of hepatic dysfunction, such as: 
• ALT or AST >8X ULN 
• ALT or AST rises to >5X ULN in <4 weeks or persists for >2 weeks 
• ALT or AST >3X ULN and TBN >2X ULN or INR >1.5 not explained by any 
other cause such as viral hepatitis, and without evidence of cholestasis 
• ALT or AST >3X ULN with new onset of or worsening of fatigue, nausea, 
vomiting, fever, rash or eosinophilia, in the absence of other evident cause 
• Signs and /or symptoms suggestive of hepatic dysfunction (any of the following: 
nausea, anorexia, fever, fatigue, right upper quadrant discomfort, pruritus, dark 
urine or acholic stool) coupled with ALT and/or AST >3X ULN and/or AP >2X 
ULN, and/or TBN >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. 
 
 Adrenal insufficiency:  A suspicion or diagnosis of adrenal insufficiency, based on 
the considerations laid out in Section 6.3.3. 
13.3 Time Period, 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?"  
All AEs occurring after obtaining the informed consent until the end of the final visit 
must be reported.  All AEs must be recorded irrespective of whether they are considered 
drug-related. 
At each visit/assessment in the period defined above, AEs will be evaluated by the 
Investigator and recorded. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 86 of 119 
CONFIDENTIAL 
 
Any AEs already documented at a previous assessment and designated as ongoing, 
should be reviewed at subsequent visits as necessary.  If these have resolved, this should 
be documented.  Changes in intensity or frequency of AEs should be recorded as separate 
events (i.e., a new record started). 
The recording of AEs and SAEs are described in Section 13.4 (“Recording of AEs and 
SAEs”). 
13.4 Recording of AEs and SAEs 
All clinical events, including either observed or volunteered problems, complaints or 
symptoms are to be recorded on the Adverse Events page(s) of the CRF.  The need to 
capture this information is not dependent upon whether the clinical event is associated 
with study treatment. Adverse clinical events resulting from concurrent illnesses or 
reactions to concurrent medications are also to be recorded.  In order to avoid vague, 
ambiguous, or colloquial expressions, the AE should be recorded in standard medical 
terminology rather than the subject’s own words. 
Each adverse clinical event is to be evaluated for duration, intensity, and whether the 
event may be associated with the study drug or other causes.  Start and stop dates, 
relationship to study drug, medical management, and alternative causality of event must 
be recorded in the Adverse Events section of the CRF.  AEs believed to be possibly 
related to study drug must be followed until resolution. 
13.5 Evaluating AEs and SAEs 
13.5.1 Severity Rating 
The severity of AEs and SAEs will be graded according to NCI CTCAE, Version 4.0.  
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 pre-defined outcomes as described in 
Section 13.2 “Definition of a SAE”. 
13.5.2 Relationship to Study Drug 
SAEs will be classified as “not related” or “related” (including unknown).  
For AEs, the relationship to study treatment is to be assessed according to the following 
definitions: 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 87 of 119 
CONFIDENTIAL 
 
Definitely 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). 
Unlikely: There is no reasonable association between the study treatment and the 
suspected event and the event could have been produced by the subject's clinical 
state or other modes of therapy administered to the subject. 
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. 
Probable: The suspected event follows a reasonable temporal sequence from 
study treatment administration, abates upon discontinuation of the treatment, and 
cannot be reasonably explained by the known characteristics of the subject's 
clinical state. 
Definitely related: This designation should be reserved for those events which 
have no uncertainty in their relationship to treatment administration. 
13.6 Follow-Up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject.  Further information on SAEs will be provided to the Sponsor’s designated safety 
group on the subject’s condition within 24 hours as described in Section 13.7. 
New or updated information will also be recorded on the “SAE” CRF within 24 hours. 
13.7 Prompt Reporting of SAEs to Sponsor 
Any SAE, occurring in a subject who has signed the informed consent or if the 
Investigator becomes aware of any SAE post-treatment during the follow-up period, must 
be reported by the Investigator to the Sponsor’s designated safety group within 24 hours 
even if the SAE does not appear to be drug-related. This should be done by emailing or 
faxing a copy of the SAE Report form plus other related information to Sponsor’s 
designated safety group.  The SAE may be reported by telephone; however, this should 
be followed up within 24 hours with a copy of the SAE Report form.  Additionally, it 
may be necessary for the designated safety group to communicate with the Investigator if 
additional information is required.   
Regardless of seriousness or causality, AEs designated as AESI (instances of persistent 
QTc prolongation, potential hepatic events, and potential adrenal insufficiency) should be 
reported to the Sponsor’s designated safety group within 24 hours, in the same manner as 
SAEs (see also Section 13.2.2). 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 88 of 119 
CONFIDENTIAL 
 
During both business and non-business hours, the email address, telephone and fax 
numbers listed below should be used to notify the Sponsor. 
Cortendo Reportable Events Hotline 
Email: sae@cmedresearch.com 
24 Hour Phone: 0044 (0)1403 758462 
US Toll-Free Phone: 1 866 966 8429 
Fax: 0044 (0)1403 330459 
US Toll-Free Fax: 1 866 966 2970 
An SAE Report form must be completed and forwarded via email or facsimile to 
Cortendo’s designated safety group using the email address or fax number listed above 
within 24 hours of becoming aware of the event.  
All additional follow-up evaluations must be reported to Cortendo’s designated safety 
group.  Such data should be sent to the Sponsor within 24 hours.  All SAEs will be 
followed until the Investigator and Sponsor agree the event is satisfactorily resolved. 
The Sponsor will be responsible for completing the safety report and for notifying the 
relevant authorities of any SAE as outlined in the International Conference on 
Harmonization (ICH) Guidelines and per local regulatory requirements.  The Investigator 
and Cortendo’s designated safety group will also ensure that the appropriate Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs) are notified of the SAE. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 89 of 119 
CONFIDENTIAL 
 
14 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. 
Bochicchio D, Losa M, Buchfelder M. Factors influencing the immediate and late 
outcome of Cushing's disease treated by transsphenoidal surgery: a retrospective study by 
the European Cushing's Disease Survey Group. J Clin Endocrinol Metab. 1995 
Nov;80(11):3114-20. 
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. 
Colao A, Petersenn S, Newell-Price J, Findling J, Gu F, Maldonado M, Schoenherr U, 
Mills D, Salgado R, and Biller B for the Pasireotide B2305 Study Group. A 12-Month 
Phase 3 Study of Pasireotide in Cushing’s Disease. N Engl J Med 2012; 366, 914-924. 
Cortendo Report Number 2002-02-21, Cortendo Exp IIId and Report Number 2002-02-
21, Cortendo Exp IVa. 2002. 
Cortendo Report Number DIO-501, A phase 1/2a, randomized, placebo-controlled, 
double-blind, parallel-group, study of safety, tolerability, pharmacokinetics and activity 
of 14 days of oral dosing with the 2s,4r enantiomer of ketoconazole (dio-902) in subjects 
with type 2 diabetes mellitus. 10 April 2007 
Dalton G. Transsphenoidal hypophysectomy for pituitary tumours. Proc R Soc Med. 
1974 Sep;67(9):885-9. 
Daneshmend TK, Warnock DW. Clinical Pharmacokinetics of Ketoconazole. Clinical 
Pharmacokinetics. 1988;14:13-34. 
Daniel E, Newell-Price JD. Therapy of endocrine disease: steroidogenesis enzyme 
inhibitors in Cushing’s syndrome. European Journal of Endocrinology, European 
Federation of Endocrine Societies.  2015;172(6):R263-280. 
De Martin M, Pecori Giraldi F, Cavagnini F. Cushing's disease. Pituitary. 2006;9(4):279-
87. 
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 
Engelhardt D, Weber MM, Miksch T, Abedinpour F, Jaspers C. The influence of 
ketoconazole on human adrenal steroidogenesis: incubation studies with tissue slices. 
Clinical Endocrinology. 1991; Aug;35(2):163-8. 
Fleseriu M, Biller BMK, Findling J, Molitch M, Schteingart D, Gross C on behalf of the 
SEISMIC Study Investigators. Mifepristone, a Glucocorticoid Receptor Antagonist, 
Produces Clinical and Metabolic Benefits in Patients with Cushing’s Syndrome.  J Clin 
Endocrinol Metab 2012; 97: 2039-2049. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 90 of 119 
CONFIDENTIAL 
 
Gerber JD, Dilmaghania S, Gal J. Stereoselective pharmacokinetics (PK) of oral 
ketoconazole (K) in healthy subjects. Interscience Conference on Antimicrobial Agents 
and Chemotherapy (ICAAC) September 2003; poster #A-1569. 
Giraldi FP, Toja PM, Michailidis G, Metinidou A, De Martin M, Scacchi M, Stramba-
Badiale M, Cavagnini F. High Prevalence of Prolonged QT Interval Duration in Male 
Patients with Cushing’s Disease. Exp Clin Endocrinol Diabetes 2011; 119:221-224. 
Hatch R, Rosenfield RL, Kim MH, Tredway D.  Hirsutism:  implications, etiology, and 
management.  Am J Obstet Gynecol.  1981;140:815-830. 
Ketoconazole HRA Assessment Report.  September 25, 2014.  Committee for Medicinal 
Products for Human Use.  EMA/CHMP/534845/2014. 
Kreutzer J, Jeske I, Hofmann B, Blumcke I, Fahlbusch R, Buchfelder M, et al. No effect 
of the PPAR-gamma agonist rosiglitazone on ACTH or cortisol secretion in Nelson's 
syndrome and Cushing's disease in vitro and in vivo. Clin Neuropathol. 2009 Nov-
Dec;28(6):430-9. 
Kucers A, Hoy JF, Lindsay Grayson M, Crowe SM. The Use of Antibiotics: A Clinical 
Review of Antibacterial, antifungal and antiviral drugs. In: Butterworth, Hindman, 
editors. 5 ed: Oxford University Press; 1997. p. 1358-84. 
Lake-Bakaar G, Scheuer PJ, Sherlock S. Hepatic reactions associated with ketoconazole 
in the United Kingdom. Br Med J. 1987;294:419-422. 
Lewis JH, Zimmerman HJ, Benson GD, Ishak KG. Hepatic injury associated with 
ketoconazole therapy. Analysis of 33 cases. Gastroenterology. 1984;86:503-513. 
Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, et al. 
Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin 
Endocrinol Metab.  2001 Jan;86(1):117-23. 
Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G. High cardiovascular risk in 
patients with Cushing's syndrome according to 1999 WHO/ISH guidelines. Clinical 
endocrinology. 2004 Dec;61(6):768-77. 
National Cancer Institute. Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 4.0. June 14, 2014 http://ctep.cancer.gov/protocolDevelopment/  
Nieman LK, Biller BMK, Findling JW, et al.  The diagnosis of Cushing’s syndrome:  an 
Endocrine Society Clinical Practice Guideline.  J. Clin Endocrinol & Met. 
2008;93(5):1526-1540. 
Nieman LK. Medical therapy of Cushing's disease. Pituitary. 2002;5(2):77-82. 
Nizoral® Product Insert.  Janssen Pharmaceuticals.  July 2013. 
Petersenn S, Newell-Price J, Finding JW, Gus F, Maldonado M, Sen K, Salgado LR, 
Colao A, and Biller BMK on behalf of the Pasireotide B2305 Study Group. High 
variability in Baseline urinary free cortisol values in patients with Cushing’s disease. Clin 
Endocrinol. 2013; 0: 1-9. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 91 of 119 
CONFIDENTIAL 
 
Pivonello R, Faggiano A, Lombardi G, Colao A. The metabolic syndrome and 
cardiovascular risk in Cushing's syndrome. Endocrinol Metab Clin North Am. 2005 
Jun;34(2):327-39, viii. 
Pozza C, Graziadio C, Giannetta E, Lenzi A, Isiori A. Management strategies for 
aggressive Cushing’s syndrome:  from macroadenomas to ectopics.  J Oncol.  
2012;(2012),Article ID 685213, 9 pages. 
Rotstein DM, Kertesz DJ, Walker KA, Swinney DC. Stereoisomers of ketoconazole: 
preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. 
Schindler AE, Campagnoli C, Druckmann R, Humber J, Pasqualini JR, Schweppe KW, 
Thijssen JHH. Classification and pharmacology of progestins. Maturitas. 2003; 46S1: S7-
S16. 
Schwartz SL, Rendell M, Ahmann AJ, Thomas A, Arauz-Pacheco CJ, Welles BR. Safety 
profile and metabolic effects of 14 days of treatment with DIO-902: results of a phase IIa 
multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in patients 
with type 2 diabetes mellitus. Clin Ther. 2008 Jun;30(6):1081-8. 
Sharma ST, Nieman LK. Cushing's syndrome: all variants, detection, and treatment. 
Endocrinol Metab Clin North Am. 2011 Jun;40(2):379-91, viii-ix. 
Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med. 
1987;317:812-8. 
Steen RE, Kapelrud H, Haug E, Frey H. In vivo and in vitro inhibition by ketoconazole of 
ACTH secretion from a human thymic carcinoid tumour. Acta endocrinologica. 1991 
Sep;125(3):331-4. 
Steffensen C, Bak AM, Rubeck KZ, Jorgensen JO. Epidemiology of Cushing’s 
syndrome. Neuroendocrinology, 2010;92: Suppl 1: 1-5 
The Seventh Report of the Joint National Committee on Prevention, Detection, 
Evaluation, and Treatment of High Blood Pressure (JNC 7)—Complete Report.  August 
2004. 
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. 
Whitehouse LW, Menzies A, Mueller R, Pontefract R. Ketoconazole-induced hepatic 
phosphplipidosis in the mouse and its association with de-N-acetyl ketoconazole. 
Toxicology. 1994;94:81-95. 
 


Cortendo AB 
 
 
 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 92 of 119 
CONFIDENTIAL 
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. 
Time and Events Schedule 
Assessments 
Screening Phase 
Dose Titration Phase1 
Maintenance Phase2 
Extended Evaluation 
Phase3 
 
FU 
Visit4 
Scrn5  
Baseline6 
DL1 
(DL0) 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End of 
MP 
M 9 
M 12 
Informed Consent 
X 
 
Eligibility (Check Inclusion/Exclusion 
Criteria) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 7 and demography 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medication 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer drug/drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam & assessment of appearance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Signs & Symptoms form9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                                 
1 The approximate interval between dose adjustments will be 18 days (±4 days) including reporting time for UFC levels and safety laboratory assessments. If 
additional UFC collections are required, the approximate interval between either dose adjustments or to transition to maintenance should be 30 days (±7 days) to 
allow for additional testing and reporting time.  DL0 is a lower dose of 150 mg once daily that may be used if the subject develops signs and/or symptoms of 
adrenal insufficiency at DL1 and is to be restarted on a reduced the dose after their resolution (see Section 6.3.3 and 6.2.4.2). 
2 Maintenance visits should occur every 30 days (±7 days). 
3 Extended Evaluation visits should occur every 90 days (±14 days). 
4 Subjects who complete the Extended Evaluation Phase (M12 Visit) and are not progressing into an expanded access program should return approximately 
2 weeks after completion of treatment with COR-003 for the Follow-up Visit (and no later than 30 days). NOTE: The Follow-Up Visit is not required for subjects 
continuing into expanded access treatment.  
5 Screening procedure to be performed following ICF and PRIOR to washout (if necessary) 
6 Baseline procedures should be performed within 14 days (± 7 days) of DL1 visit. 
7 Medical history to include previous documentation of diagnosis of Cushing’s syndrome, and data on all previous LFTs, as medical records permit.  Medical 
histories should be updated at Baseline. 
8 Blood pressure, diabetes, cholesterol medications will be specifically reviewed. 
9 Assessment of Clinical Signs & Symptoms form (Appendix M) to be completed along with the physical exam once at each dose level during the Dose Titration 
Phase and at each visit during the Maintenance and Extended Evaluation Phases 
 


Cortendo AB 
 
 
 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 93 of 119 
CONFIDENTIAL 
Time and Events Schedule 
Assessments 
Screening Phase 
Dose Titration Phase1 
Maintenance Phase2 
Extended Evaluation 
Phase3 
 
FU 
Visit4 
Scrn5  
Baseline6 
DL1 
(DL0) 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End of 
MP 
M 9 
M 12 
Vital signs (BP and HR in triplicate and 
temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/height/body habitus 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abdominal Girth (in triplicate) 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
HIV / Hepatitis B and C blood test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Photographs (consenting subjects only) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
ECG – Local ECG machine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG – Spaulding10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contact subject 1 week after a new dose 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Additional safety evaluation 11  
(e.g., day 7 [±3 days]) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Late night salivary cortisol (1 night) 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Late night salivary cortisol (2 nights) 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
TSH / free T4 12 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pituitary MRI (CD only)  
 
X 13 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
FSH (women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine βHCG, females 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety clinical laboratory 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR/PT/PTT 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c  
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
                                                 
 
10 Spaulding ECGs will be obtained over a maximum of 5 minutes at Baseline and within approximately 1 – 2 h after drug administration at each dose level 
during Dose Titration Phase and at each visit during the Maintenance and Extended Evaluation Phases 
11 Additional safety assessments at higher dose levels to include:  AEs, vital signs, routine safety laboratory assessments (including LFTs), ECGs,  and serum 
cortisol levels. 
12 TSH/free T4 to be measured at DL4 Visit during the Dose Titration Phase.  If subjects reach their maximum dose before the DL4 visit during the Dose 
Titration Phase, they will have TSH/free T4 measured at the M1 visit of Maintenance Phase. 
13 Pituitary MRI at Baseline only for CD subjects and if not done in prior 6 months 
 


Cortendo AB 
 
 
 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 94 of 119 
CONFIDENTIAL 
Time and Events Schedule 
Assessments 
Screening Phase 
Dose Titration Phase1 
Maintenance Phase2 
Extended Evaluation 
Phase3 
 
FU 
Visit4 
Scrn5  
Baseline6 
DL1 
(DL0) 
DL2 
DL3 
DL4 
DL5 
DL6 
DL7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End of 
MP 
M 9 
M 12 
OGTT (pre-diabetics only) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Dexamethasone Suppression Test (DST) 
 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum cortisol 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACTH 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum lipid measurements, triglycerides 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IGF-1  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spot urine for albumin/creatinine ratio  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine for albumin/creatinine ratio (If 
abnormal at Baseline) 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Serum testosterone, free/total  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Baseline signs & AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CushingQoL questionnaire 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
BDI-II instrument 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
24-h UFC/free cortisol/creatinine/ urinary 
volume (4 collections) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
24-h urinary free cortisol/creatinine/ volume 
(2 collections) 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
24-h urinary free cortisol/creatinine/ volume 
(2 to 4 collections) 15 
 
 
X 11 
X 11 
X 11 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic sampling 
 
 
(X) 16 
(X)12 
(X)12 
(X)12 
(X)12 
(X)12 
(X)12 
(X)12 
(X)12 
 
 
 
 
                                                 
14 DST will need to be available at Baseline if not previously performed and results available within the 2 months prior to start of Screening Phase 
15 First 24-hour urine collection will be Day 10 (±1 days) followed by the second 24-hour collection (ideally on two consecutive days) after start of each dose 
level.  If UFC ≤ULN, there will be 2 additional 24-hour urine collection to confirm UFC results. 
16 Each subject will provide PK samples from at least 2 dose levels during their participation in the study.  The sample collection time and the dose level will 
vary from subject-to-subject and will be determined by the Investigator.  See Section 6.2.8.1 for details. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 95 of 119 
CONFIDENTIAL 
APPENDIX B 
LABORATORY ANALYTES 
Laboratory studies to be collected as per Time and Events Schedule (Appendix A). 
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 
 
Urinalysis 
Specific gravity 
pH, glucose, protein, blood and ketones by dipstick 
Microscopic examination (if blood or protein is > trace positive by dipstick) 
 
Other analytes 
HIV 
Hepatitis B and C antibodies  
HbA1c  
Serum lipid measurements to include: total 
cholesterol, LDL, HDL, LDL:HDL ratios, 
Triglycerides 
Serum testosterone (both men and women) 
FSH (women only) 
Pregnancy test (urine, women only) 
Serum CRP 
 
Urinary free cortisol and total creatinine and 
total volume on 24-hour urine collections 
Spot urine for albumin/creatinine ratio—if 
normal at Baseline, no further testing required 
throughout the study 
Serum cortisol 
Serum ACTH  
Serum TSH/free T4 
INR/PT/PTT 
IGF-1 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 96 of 119 
CONFIDENTIAL 
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 will be completed for each subject who is enrolled in the study. Subject 
numbers will be assigned by the eCRF system immediately following the performance of 
informed consent.  A subject screening/enrollment log, noting reasons for screen failure 
where applicable, will be maintained for all subjects who are consented. 
All information recorded on the CRFs for this study must be consistent with the subject’s 
source documentation (i.e., source documents and/or Medical Record Supplement).  The 
source documents may include the hospital and/or the physician’s chart, X-rays, or 
laboratory test documentation.   
The CRFs for each subject will be periodically checked against the subject’s source 
documents at the study site by the site monitor.  Instances of missing or unclear data will 
be discussed with appropriate site personnel for resolution.  A quality assurance audit will 
be performed on the database. 
Archiving of Study Documentation 
The Investigator shall retain records for two (2) years following the date a marketing 
application is approved for the indication pertaining to this clinical study; or, if the drug 
is planned to be terminated or if a regulatory application is not planned to be progressed, 
until two (2) years after the investigation is discontinued and the 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 course of the study, a monitor will make routine site visits to review protocol 
compliance, compare CRFs with individual subject’s original source documents, assess 
drug accountability and ensure that the study is being conducted according to pertinent 
regulatory requirements.  The review of the subjects’ original medical records will be 
performed in a manner to ensure that subject confidentiality is maintained. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 97 of 119 
CONFIDENTIAL 
APPENDIX D 
ADMINSTRATION AND REGULATORY POLICIES 
Ethical Conduct of Study 
The Investigator(s) should conduct the study in accordance with this protocol, the 
Declaration of Helsinki and ICH GCP guidelines and FDA regulations.  The 
Investigator(s) and the Sponsor will sign the protocol and study contract, to confirm 
agreement.  The Investigator(s) will not implement any amendment (deviation or changes 
of the protocol) without agreement by the Sponsor and IRB/IEC approval, except where 
necessary to eliminate immediate hazard(s) to study subjects, or when change(s) involve 
only logistical or administrative aspects of the study. 
Records that may reveal the identities of subjects must be well protected, with 
consideration given to confidentiality and the right to privacy of subjects. 
Informed Consent 
Each subject or his/her parent/legal representative must be provided with a statement that 
the investigation involves research and that the IRB/IEC has approved solicitation of 
subjects to participate; a fair explanation of the procedures to be followed and their 
purposes, including identification of any procedures which 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 the course of 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 the review of the contents will be in compliance with 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA and applicable 
data protection regulations in the countries concerned. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 98 of 119 
CONFIDENTIAL 
Institutional Review/Ethical Review 
The protocol and informed consent form for this study must be approved by an IRB/IEC.  
A copy of the Letter of Approval from the Board/Committee, which contains specific 
identification of the documents approved, must be received by the Sponsor prior to 
shipment of drug supplies to the Principal Investigator. 
All changes to the protocol, as well as a change of Principal Investigator, must also be 
approved by the Board/Committee and documentation of this approval provided to the 
study monitor.  Records of the IRB/IEC’s review and approval of all documents 
pertaining to the study must be kept on file by the Principal Investigator and are subject 
to FDA/Competent Authority inspection at any time.  IRB/IEC re-approval is required 
each year or according to 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 the 
aforementioned situation, the site should notify the Sponsor and IRB/IEC of the deviation 
as soon as possible, and should seek the written consent and approval of the Sponsor and 
the approval of the IRB/IEC. 
All results of this trial must be recorded on eCRFs.  Each subject who has been enrolled 
must have a completed eCRF.  Reasons for termination must be stated in the early 
termination section.  Study subjects are not to be identified by name on eCRFs, but rather 
by coded identifiers and subject initials.   
The study monitor will verify the accuracy of the data by reviewing pertinent source 
documents such as office records or hospital charts of the subjects. 
Study records include eCRFs, signed FDA Form 1572, original reports of test results, and 
signed informed consent forms.  IRB/IEC approval letters and other documents 
pertaining to the conduct of the study are to be kept on file by the Investigator.   If the 
study files are assigned to someone else or removed to another location, the Investigator 
is to notify the study monitor or Sponsor in writing of the change.  All study records are 
subject to FDA or Competent Authority inspection at any time. 
The Investigator shall retain records for a period as defined elsewhere (see Appendix C, 
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. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 99 of 119 
CONFIDENTIAL 
APPENDIX E 
PUBLICATION POLICY 
All data generated from this study are the property of Cortendo Inc. and shall be held in 
strict confidence along with all information furnished by Cortendo.  Independent analyses 
and/or publication of these data by the 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.  Authorship will 
be determined by mutual agreement.  For multicenter studies it is mandatory that the first 
publication is based on data from all centers, analyzed as stipulated in the protocol and 
not by individual Investigators.  Investigators participating in multicenter studies agree 
not to present data gathered from one center or a small group of centers before the full 
publication, unless formally agreed to in writing.  Written permission to Investigators to 
publish results will be contingent on review by Cortendo of the methodology and 
statistical analyses and any publication or presentation will provide for nondisclosure of 
Cortendo confidential or proprietary information.  In all cases, the parties agree to submit 
all manuscripts or abstracts to all other parties at least 60 days prior to submission.  This 
will enable all parties to protect proprietary information and to provide comments based 
on information that may not yet be available to other parties.   
Further details on the publication process are provided in individual contractual 
agreements signed by the Investigators and Cortendo. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 100 of 119 
CONFIDENTIAL 
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 as a separate document.  Each time a protocol is amended, a new 
amended version date will be added to the cover page. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 101 of 119 
CONFIDENTIAL 
APPENDIX G 
CONDITIONS ASSOCIATED WITH PSEUDO-
CUSHING’S SYNDROME 
Conditions Associated with Hypercortisolism in the Absence of Cushing’s Syndrome 
Reference:  Nieman 2008. 48-hour, 2 mg dexamethasone suppression test may be 
necessary to exclude pseudo-Cushing’s disease.  
Some clinical features of CS may be present: 
• Pregnancy 
• Depression and other psychiatric conditions 
• Alcohol dependence 
• Glucocorticoid resistance 
• Morbid obesity 
• Poorly controlled diabetes mellitus 
 
Unlikely to have any clinical features of CS 
• Physical stress (hospitalization, surgery, pain) 
• Malnutrition, anorexia nervosa 
• Intense chronic exercise 
• Hypothalamic amenorrhea 
• Cortisol-binding globulin (CBG) excess (increased serum but not urine cortisol) 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 102 of 119 
CONFIDENTIAL 
APPENDIX H 
CRITERIA FOR DIAGNOSES OF PREDIABETES AND 
DIABETES  
Reference: American Diabetes Association. Classification and diagnosis of diabetes. 
Sec. 2. In Standards of Medical Care in Diabetes—2016. Diabetes Care 
2016;39(Suppl. 1):S13–S22. 
The American Diabetes Association (ADA) standards for the diagnosis of prediabetes 
consider three different categories of prediabetes, based on measures fasting glucose, 
HbA1c, or 2-hour postprandial glucose during a 75-gram oral glucose tolerance test 
(GTT). 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 
<126 mg/dL (7.0 mmol/L) (after no caloric intake for at least 8 hours and in the absence 
of antihyperglycemic medications).   
ADA criteria for the diagnosis of diabetes will be used as follows. 
Diabetes Is Diagnosed by One of the Following Criteria: 
1. A fasting glucose of ≥126 mg/dL (7.0 mmol/L) after no caloric intake for at least 
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 (NGSP) certified 
and standardized to the Diabetes Control and Complications Trial (DCCT) assay. 
Note: In the absence of unequivocal hyperglycemia, results indicating diabetes should be 
confirmed by repeat testing using any of the above measures. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 103 of 119 
CONFIDENTIAL 
APPENDIX I 
GUIDELINES FOR HYPERTENSION 
Reference:  The Seventh Report of the Joint National Committee on Prevention, 
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), 2004 
Table 7 
Classification of Blood Pressure Levels for Adults >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 8 
Recommendations for Follow-up Based on Initial Blood Pressure 
Measurements for Adults without Acute End Organ Damage 
Initial Blood Pressure (mmHg)a 
Follow-up Recommendedb 
Normal 
Recheck in 2 years 
Pre-hypertension 
Recheck in 1 yearc 
Stage 1 hypertension 
Confirm within 2 months c 
Stage 2 hypertension 
Evaluate or refer to source of care within 1 month.  
For those with higher pressures (e.g. 
>180/110 mmHg), evaluate and treat immediately 
or within 1 week depending on clinical situation 
and complications. 
a. If systolic and diastolic categories are different, follow recommendations for shorter time follow-up (e.g. 
160/86 mmHg should be evaluated or referred to source of care within 1 month) 
b. Modify the scheduling of follow-up according to reliable information about past BP measurements, other 
cardiovascular risk factors, or target organ disease 
c. Provide advice about lifestyle modifications. 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 104 of 119 
CONFIDENTIAL 
APPENDIX J 
CONCOMITANT MEDICATIONS PROHIBITED OR 
TO BE USED ONLY WITH PRIOR PERMISSION 
 
Table 9 through Table 17 provide examples of drugs that are PROHIBITED for 
concomitant use in COR-2012-01. Table 18 through Table 20 provide examples of drugs 
that REQUIRE PERMISSION from the study Medical Monitor prior to concomitant 
use.  
Drugs listed below are categorized into one drug-interaction category per drug; however, 
some drugs could have been categorized into multiple drug-interaction categories (e.g. 
dexamethasone is both a systemic corticosteroid and a strong CYP3A4 inducer). In such 
cases, the drug is categorized into the most restricted concomitant use category as 
applicable. 
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 
COR-003, the lists intentionally omit some medications that should not be used 
concomitantly with COR-003, 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 COR-003 and other medications. Therefore, they should be 
regarded as a minimum set of excluded and precautioned concomitant medications. 
A. Prohibited concomitant medications 
Table 9 
Steroidogenesis Inhibitors and Systemic Corticosteroids (Interferes 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 
 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 105 of 119 
CONFIDENTIAL 
Table 10 
Dopamine Agonists (Interferes with study drug assessment; must be 
avoided or washed out prior to Baseline Visit) 
Apomorphine 
Pergolide 
Bromocriptine  
Piribedil 
Cabergoline (8 weeks’ washout) 
Pramipexole 
Ciladopa 
Propylnorapomorphine 
Dihydroergotamine/ergotamine 
Quinagolide 
Dihydrexidine 
Ropinirole 
Dinapsoline 
Rotigotine 
Doxanthrine 
Roxindole 
Epicriptine 
Sumanirole 
Etilevodopa (alone or with inhibitors of dopamine metabolism) 
Levodopa (alone or with inhibitors of dopamine metabolism) 
Lisuride 
Melevodopa (alone or with inhibitors of dopamine metabolism) 
Table 11 
Synthetic progestins that bind with moderate to high affinity17 to 
glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) 
(Interferes 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 12 
Somatostatin analogs (Interferes with study drug assessment and/or 
influence underlying signs/symptoms of disease; must be avoided) 
Octreotide (all forms) 
Lanreotide (all forms) 
Pasireotide (all forms) 
 
                                                 
17 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. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 106 of 119 
CONFIDENTIAL 
Table 13 
Weight Loss Medications (Interferes with endpoints assessment; must be 
avoided or washed out) 
Amfepramone 
Diethylpropion 
Orlistat 
Benzphetamine 
Ephedrine 
Phendimetrazine 
Bupropion/naltrexone 
Etilamfetamine 
Phentermine 
Buproprion 
Fenfluramine 
Phentermine 
Cathine 
Lorcaserin 
Rimonabant 
Clobenzorex 
Mazindol 
Sibutramine 
Dexfenfluramine 
Mefenorex 
Topiramate 
 
Table 14 
Drugs Predicted to Interfere with the Absorption of COR-003 (must be 
avoided; use an allowed substitute or wash out) 
Histamine H2 receptor antagonists: 
cimetidine, famotidine, nizatidine, ranitidine, 
Sucralfate 
Proton-pump inhibitors: dexlansoprazole, esomeprazole, 
lansoprazole, omeprazole, pantoprazole, rabeprazole 
 
 
 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 107 of 119 
CONFIDENTIAL 
Note on Drug-drug Interactions via CYP3A4 
COR-003 is a substrate and potent inhibitor of CYP3A4. Therefore, the following drug 
interactions may occur when COR-003 is co-administered with other drugs that interact 
with CYP3A4.  
• COR-003 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 COR-003 is prohibited for drugs 
known to present a risk of serious side effects with increased exposure 
(Table 15). 
• 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 
COR-003 by induction or inhibition of CYP3A4 or by altering absorption are 
prohibited (Table 16). 
The following drug interaction checker may be useful. However, this checker will not 
supersede the protocol excluded medications lists nor the judgment of the Medical 
Monitor or delegate: http://reference.medscape.com/drug-interactionchecker 
Table 15 
Drugs Whose Systemic Exposure is Predicted to be Significantly 
Increased by COR-003 (via CYP3A4 inhibition; must be avoided or 
washed out) 
Systemic exposure to these drugs is potentially increased significantly by the 
addition of COR-003; must be avoided 
Alprazolam, midazolam, triazolam 
HMG-CoA reductase inhibitors: 
atorvastatin, lovastatin, simvastatin, (NOT 
pravastatin, fluvastatin and rosuvastatin)  
Cisapride 
Dofetilide  
Eplerenone  
Ergot alkaloids  
(ergotamine, dihydroergotamine)  
Pimozide 
Quinidine 
Nisoldipine 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 108 of 119 
CONFIDENTIAL 
Table 16 
Drugs That Are Predicted to Reduce (Top) or Increase Significantly 
(Bottom) the Plasma Concentration of COR-003 via CYP3A4 Induction 
or Inhibition, Respectively and Are Prohibited; must be avoided 
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 
 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 109 of 119 
CONFIDENTIAL 
Table 17 
Drugs that can Cause QTc Prolongation (Must be avoided, unless no 
acceptable alternative is available; permission prior to use required) 
Alfuzosin 
Eliglustat  
Perphenazine 
Amiodarone 
Erithromycin 
Pimozide 
Anagrelide 
Fingolimod 
Pipamperone 
Arsenic 
Flecainide 
Procainamide 
Artemether 
Fluconazole 
Propafenone  
Asenapine 
Granisetron 
Propofol 
Astemizole 
Haloperidol 
Quetiapine 
Atomoxetine 
Hydrocodone ER 
Quinine 
Azithromycin 
Ibutilide 
Ranolazine 
Bedaquiline 
Iloperidone 
Risperdone 
Buprenorphine 
Imipramine 
Solifenacin 
Chloroquine 
Isradipine 
Sotalol 
Cilostazol 
Levofloxacin 
Sulpiride 
Ciprofloxacin 
Lopinavir 
Tetrabenazine 
Citalopram 
Lumefantrine 
Thioridazine 
Clomipramine 
Methadone 
Tiapride 
Desipramine 
Mirabegron 
Tizanidine 
Dolasetron 
Mirtazapine 
Tolterodine 
Disopyramide 
Moexipril/HCTZ 
Toremifene  
Domperidone 
Moxifloxacin 
Trimipramine 
Donepezil 
Norfloxacin 
Tropisetron 
Dosulepin 
Nortriptyline 
Vardenafil 
Doxepin 
Ofloxacin 
Venlafaxine 
Dronedarone 
Ondansetron  
Ziprasidone 
Droperidol 
Paliperidone 
Zuclopenthixol 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 110 of 119 
CONFIDENTIAL 
B. Concomitant medications that require prior permission to be used 
Table 18. Drugs Whose Systemic Exposure is Predicted to be Increased Moderately 
by COR-003 
Systemic exposure to these drugs is predicted to be increased by COR-003: 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 19 
Topical or Inhaled Steroids (Interferes with study drug assessment; 
Should be avoided; to be used only with prior permission) 
Inhaled corticosteroids: 
Flunisolide 
Beclomethasone 
Fluticasone furoate 
Betamethasone dipropionate 
Mometasone 
Budesonide 
Prednisolone 
Ciclesonide 
Tixocortol 
Dexamethasone 
Triamcinolone 
Topical/inhaled corticosteroids:    Fluticasone propionate 
Topical corticosteroids: 
 
Amcinonide 
Halcinonide 
Clobetasol propionate 
Halobetasol propionate 
Esocimetasone 
Halometasone 
Diflorasone diacetate 
Hydrocortisone butyrate 
Fluocinolone acetonide 
Hydrocortisone valerate 
Fluocinonide 
Mometasone furoate 
Flurandrenolide 
Traimcinolone acetonide 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 111 of 119 
CONFIDENTIAL 
Table 20 
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. 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 112 of 119 
CONFIDENTIAL 
APPENDIX K 
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 carving 
Arthralgias/Myalgias 
Dizziness (esp. on 
standing) 
Less common: 
Irritability 
Depression 
Sweating 
Fever 
Weight loss 
Hypotension 
Hyperpigmentation 
Less common: 
Hypoglycemia 
 
Serum cortisol level 
<3 μg/dL, 
Inadequate cortisol 
response to ACTH 
stimulation 
Hypoglycemia 
Moderate to high 
ACTH (assuming 
primary adrenal 
insufficiency) 
Hypocortisolemia 
 
Fatigue 
Muscle weakness 
Loss of appetite 
Weight loss 
Nausea, vomiting 
Dizziness, esp. on 
standing 
Irritability 
Depression 
Sweating  
Joint aches and pains 
 
Low blood pressure 
Symptomatic 
Orthostatic 
hypotension 
Reduction in weight 
 
Reduced serum and 
salivary cortisol 
levels 
Hypoglycemia 
 
Hypomineralocorticoidism 
 
Muscle weakness 
Fatigue 
Fainting 
Salt craving 
Irritability 
 
Low blood pressure 
Severe orthostatic 
hypotension 
 
Hyperkalemia 
Hyponatremia 
 
 
Hypogonadism 
Erectile dysfunction 
Reduction in beard and 
body hair 
Enlarged breasts (in men) 
Fatigue 
Reduced libido 
Hot flashes 
Difficulty concentrating 
 
Gynecomastia 
Reduced body hair 
Osteoporosis 
 
reduced testosterone 
levels (AE in males, 
beneficial in 
women) 
 
 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 113 of 119 
CONFIDENTIAL 
APPENDIX L 
QUALITY OF LIFE QUESTIONNAIRE 
CUSHING’S SYNDROME QUALITY OF LIFE 
QUESTIONNAIRE 
(CushingQoL) 
 
The following sentences refer to what you may think or feel about your Cushing’s 
syndrome. Your answers will help us to know how you feel and how much your 
illness has interfered in your usual activities in the past 4 weeks. 
 
Below each sentence you will find several response choices. Please read each 
sentence carefully. After reading each sentence, check the box next to the 
answer that best describes what you think is happening to you. 
 
There are NO right or wrong answers. We are simply interested in what is 
happening to you because of your Cushing’s syndrome. 
 
1.  I have trouble sleeping (I wake up during the night; it takes me a long 
time to get to sleep, etc.). 
□ Always 
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
2.  I have pain that keeps me from leading a normal life. 
□ Always 
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
3.  My wounds take a long time to heal. 
□ Always 
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 114 of 119 
CONFIDENTIAL 
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 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 115 of 119 
CONFIDENTIAL 
9.  I have had to give up my social or leisure activities due to my illness. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
10. My illness affects my everyday activities such as working or studying. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
11. It’s difficult for me to remember things. 
□ Always  
□ Often  
□ Sometimes  
□ Rarely  
□ Never 
 
12. I’m worried about my health in the future. 
□ Very much  
□ Quite a bit  
□ Somewhat  
□ Very little  
□ Not at all 
 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 116 of 119 
CONFIDENTIAL 
APPENDIX M 
ASSESSMENT OF CLINICAL SIGNS AND 
SYMPTOMS OF CUSHING’S SYNDROME 
Visit 
                            Date 
 
 
 
       DD          MMM           YYYY  
SUBJECT NUMBER: 
-
         SUBJECT INITIALS:  
 
To be completed by The Investigator 
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 included in the SPM:   
 
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______________________ 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 117 of 119 
CONFIDENTIAL 
APPENDIX N 
BECK DEPRESSION INVENTORY (BDI-II)  
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 118 of 119 
CONFIDENTIAL 
 


Cortendo AB 
 
Protocol COR-2012-01 
AMENDMENT 6 
Page 119 of 119 
CONFIDENTIAL 
 

SAP_001.pdf: 
Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 1 of 124 
BMSOP111/F2 
 
 
 
 
 
SPONSOR: 
 
CORTENDO AB 
 
 
PROTOCOL NUMBER: 
 
COR-2012-01 
 
 
STATISTICAL ANALYSIS PLAN  
(Text) 
 
 
 
 
Author: 
Jean-Luc Beffy 
Version: 
Version 1.0 
Date: 
19JUN2018 
 
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 2 of 124 
BMSOP111/F2 
 
 
 
 
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 3 of 124 
BMSOP111/F2 
 
 
 
 
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 4 of 124 
BMSOP111/F2 
 
 
 
 
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 5 of 124 
BMSOP111/F2 
 
 
 
 
 
 
Table of Contents 
 
1 
Cover and Signature Pages ........................................................ Error! Bookmark not defined. 
2 
List of Abbreviations ................................................................................................................ 8 
3 
Introduction ........................................................................................................................... 11 
4 
Study Objectives .................................................................................................................... 11 
 
OBJECTIVES .................................................................................................................... 11 
 
ENDPOINTS .................................................................................................................... 13 
5 
Study Design .......................................................................................................................... 16 
 
STUDY DESIGN AND POPULATION ................................................................................ 16 
 
STUDY TREATMENTS AND ASSESSMENTS ..................................................................... 17 
 
RANDOMIZATION, BLINDING, AND DATA INTEGRITY ................................................... 23 
 
SAMPLE SIZE JUSTIFICATION ......................................................................................... 25 
6 
Statistical Considerations ...................................................................................................... 25 
 
HYPOTHESIS TESTS ........................................................................................................ 26 
 
DEFINITIONS OF DOSE GROUPS .................................................................................... 26 
 
DATA PRESENTATION .................................................................................................... 27 
 
DEFINITIONS .................................................................................................................. 31 
 
STATISTICAL ASSUMPTIONS .......................................................................................... 33 
 
Imputation Rules ........................................................................................................... 34 
6.6.1 
Urinary Free Cortisol Response and Urinary Free Cortisol Improvement 
Categorization ....................................................................................................................... 34 
6.6.2 
Mean Urinary Free Cortisol and Cushing’s Syndrome Comorbidity Biomarkers .. 36 
6.6.3 
Partial and Missing Dates ...................................................................................... 36 
 
DERIVATION RULES ........................................................................................................ 38 
6.7.1 
Urinary Free Cortisol.............................................................................................. 38 
6.7.2 
Efficacy Endpoints ................................................................................................. 39 
6.7.3 
Vital Signs and Abdominal Girth ............................................................................ 42 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 6 of 124 
BMSOP111/F2 
 
 
 
 
6.7.4 
Study Day ............................................................................................................... 43 
7 
Analysis Sets .......................................................................................................................... 43 
8 
Methods of Analyses and Presentations ............................................................................... 48 
 
PROTOCOL DEVIATIONS ................................................................................................ 48 
 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................... 48 
 
MEDICAL HISTORY AND DISEASE CHARACTERISTICS .................................................... 48 
 
SUBJECT DISPOSITION ................................................................................................... 49 
 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................. 50 
 
PRIOR CUSHING’S SYNDROME THERAPY....................................................................... 51 
8.6.1 
Prior Cushing’s Syndrome Drug Therapy ............................................................... 51 
8.6.2 
Prior Radiotherapy for Cushing’s Syndrome ......................................................... 51 
8.6.3 
Prior Surgery for Cushing’s Syndrome ................................................................... 52 
 
STUDY DRUG EXPOSURE AND/OR COMPLIANCE .......................................................... 52 
8.7.1 
Study Drug Exposure ............................................................................................. 52 
8.7.2 
Compliance ............................................................................................................ 53 
8.7.3 
Average Daily Dose ................................................................................................ 54 
 
EFFICACY DATA ENDPOINTS AND ANALYSES ................................................................ 54 
8.8.1 
Primary Efficacy Endpoint and Analyses ............................................................... 54 
8.8.2 
Secondary Efficacy Endpoints and Analyses .......................................................... 56 
8.8.3 
Exploratory Efficacy Endpoints and Analyses ........................................................ 71 
8.8.4 
Other Exploratory Analysis .................................................................................... 74 
 
PHARMACOKINETIC/ PHARMACODYNAMIC ENDPOINTS AND ANALYSES .................... 76 
8.9.1 
Pharmacokinetic Endpoints and Analyses ............................................................. 76 
8.9.2 
Pharmacodynamic Endpoints and Analyses .......................................................... 76 
 
QUALITY OF LIFE OR PHARMACOECONOMIC ENDPOINTS AND ANALYSES .................. 76 
 
SAFETY DATA ENDPOINTS AND ANALYSES .................................................................... 76 
8.11.1 
Adverse Events ...................................................................................................... 77 
8.11.2 
Clinical Laboratory Evaluations ............................................................................. 79 
8.11.3 
Hormones and Biomarkers Laboratory Evaluations .............................................. 81 
8.11.4 
Vital Signs .............................................................................................................. 82 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 7 of 124 
BMSOP111/F2 
 
 
 
 
8.11.5 
Electrocardiograms ................................................................................................ 83 
8.11.6 
Physical Examination Findings ............................................................................... 84 
8.11.7 
Other Safety Measures .......................................................................................... 85 
 
Subgroup Analysis ......................................................................................................... 85 
9 
Timing of Analysis and Reporting .......................................................................................... 89 
 
DATA SAFETY MONITORING BOARD ............................................................................. 90 
10 List of Laboratory Analytes, Units and Precision ................................................................... 90 
11 Clarifications and Changes from Planned Analyses in the Protocol ...................................... 93 
12 Tables, Figures And Listing Shells .......................................................................................... 95 
13 Document History.................................................................................................................. 95 
14 References ............................................................................................................................. 96 
15 Appendices ............................................................................................................................ 96 
 
PROCEDURE SCHEDULE FOR SCREENING, DOSE TITRATION, MAINTENANCE AND 
EXTENDED EVALUATION PHASES .............................................................................................. 97 
15.1.1 
Table 14: Study Flow Chart for Screening, Dose Titration, Maintenance and 
Extended Evaluation Phases .................................................................................................. 98 
 
WORST-CASE RESULTS FOR LABORATORY PARAMETERS, VITAL SIGNS AND ECG 
PARAMETERS ........................................................................................................................... 106 
 
VISIT WINDOWS .......................................................................................................... 111 
 
BDI-II SCORING INFORMATION ................................................................................... 115 
 
STUDY ENDPOINTS BY POPULATION, PHASE AND TIMING OF ANALYSIS ................... 120 
 
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 8 of 124 
BMSOP111/F2 
 
 
 
 
1 List of Abbreviations 
 
 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse Event 
ALT  
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
BID 
Twice daily 
BMI 
Body mass index 
CD 
Cushing’s Disease 
CI 
Confidence Interval 
CL/F 
Apparent clearance following oral administration 
Cmax 
Peak concentration 
CRF 
Case Report Form 
CRH 
Corticotropin-releasing hormone 
CRP 
C-reactive protein 
CS 
Cushing´s Syndrome 
DBP 
Diastolic blood pressure 
DLn 
Dose level number 
DSMB 
Data Safety Monitoring Board 
DST 
Dexamethasone Suppression Test 
ECG 
Electrocardiogram/electrocardiograph 
eCRF 
Electronic Case Report Form 
FSH 
Follicle stimulating hormone 
GGT 
Gamma-glutamyl transferase 
HbA1c 
Hemoglobin A1C 
HDL-C 
High density lipoprotein-associated cholesterol 
HR 
Heart rate 
HRQoL 
Health-related quality of life 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 9 of 124 
BMSOP111/F2 
 
 
 
 
IC50 
Half maximal suppression of urinary free cortisol 
ICH 
International Conference on Harmonisation 
IGF-1 
Insulin-like Growth Factor-1 
Imax 
Maximal suppression of urinary free cortisol 
INR 
International Normalized Ratio 
ITT 
Intent-to-Treat 
Ka 
Absorption rate constant 
LDL-C 
Low density lipoprotein-associated cholesterol 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LNSC 
Late-night salivary cortisol 
LSMEAN 
Least Squares Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
M 
Maintenance 
MAR 
Missing at Random 
MRI 
Magnetic Resonance Imaging 
NCI-
CTCAEv4  
National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 4.0 
OGTT  
Oral glucose tolerance test 
PD 
Pharmacodynamic(s) 
PK  
Pharmacokinetic(s) 
PP 
Per Protocol 
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 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 10 of 124 
BMSOP111/F2 
 
 
 
 
SD 
Standard deviation 
t½  
Half-life 
TEAE 
Treatment-emergent Adverse Event 
TFL(s) 
Tables, Figures and Listings 
TSH  
Thyroid stimulating hormone 
UFC 
Urinary free cortisol 
ULN 
Upper limit of normal 
V/F  
Apparent volume of distribution following oral administration 
VAS 
Visual analog scale 
WBC 
White blood cell 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 11 of 124 
BMSOP111/F2 
 
 
 
 
2 Introduction 
The purpose of this document is to describe the statistical methods, data derivations and data 
summaries to be employed in the analysis of Study COR-2012-01, An Open Label Study to Assess 
the Safety and Efficacy of COR-003 (2S,4R-Ketoconazole) in the Treatment of Endogenous 
Cushing’s Syndrome (CS). 
The preparation of this statistical analysis plan (SAP) has been based on International Conference 
on Harmonisation (ICH) E3 and E9 Guidelines and in reference to Protocol COR-2012-01 (version 
03, 10 April 2013) and its Amendment 1 (09 September 2013), Amendment 2 (20 October 2013), 
Amendment 3 (26 February 2014), Amendment 4 (28 August 2014), Amendment 5 (16 April 2015) 
and Amendment 6 (25 October 2016). In addition, there are also some country-specific versions  
of the protocol. 
The original protocol is dated the 10 April 2013. This current SAP is based on Protocol Amendment 
6 (25 October 2016).  The handling of the specific endpoints impacted by changes due to Protocol 
Amendment 5 are also described in relevant sections throughout this document. 
Data collected under protocol amendments prior to Protocol Amendment 5 and 6 but no longer 
required as per Protocol Amendment 5 and 6 will be listed but not summarized. 
Subjects were consented to start the study under Protocol Amendment 2 onwards. Subjects 
originally consented prior to Protocol Amendment 6 were re-consented for Protocol Amendment 
6, or earlier if applicable. 
Discontinuations from the study are discussed in Section 6.2 (definitions of Dose Titration Phase 
and Maintenance Phase), Section 6.6.3 (Partial and missing dates for Adverse Events / Clinical 
Signs and Symptoms of CS) and Section 8.4 (Subject Disposition). 
3 Study Objectives 
 OBJECTIVES 
Primary objectives: 
• 
To evaluate the clinical responder rate, defined as the proportion of subjects with normal  
Urinary free cortisol (UFC) after 6 months of treatment with COR-003 in the Maintenance 
Phase without dose increase; and to evaluate the range of effective doses in subjects with 
various levels of hypercortisolism. 
Secondary objectives: 
• 
To identify the proportion of subjects with clinical response, defined as reduction in mean 
24-hour UFC levels to below or equal to the upper limit of normal (≤ ULN) after each 
month of treatment with COR-003 without a dose increase during the Maintenance 
Phase; 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 12 of 124 
BMSOP111/F2 
 
 
 
 
• 
To identify the proportion of subjects with complete or partial response, defined as ≥50% 
reduction in mean 24-hour UFC levels from Baseline after each of the 6 months of 
treatment with COR-003 without a dose increase during the Maintenance Phase; 
• 
To characterize changes in mean 24-hour UFC levels from Baseline during the 6 months 
of treatment with COR-003 in the Maintenance Phase regardless of dose increases; 
• 
To characterize shifts in normality for mean 24-hour UFC levels from Baseline during the 
6 months of treatment with COR-003 in the Maintenance Phase regardless of dose 
increases;  
• 
To characterize changes in serum and late-night salivary cortisol (LNSC) concentrations 
during the  6 months of treatment with COR-003 in the Maintenance Phase; 
• 
To assess the effects on Clinical Signs and Symptoms of CS, the quality of life (QoL) 
measures obtained from the Cushing QoL questionnaire and the severity of depression 
obtained from the Beck’s Depression Inventory II (BDI-II) in the Maintenance Phase; 
• 
To evaluate changes in the biomarkers of CS-comorbidities (diabetes, hypertension, 
hypercholesterolemia and obesity) in the Maintenance Phase; 
• 
To assess the safety and tolerability of COR-003. 
Exploratory objectives: 
• 
To assess the clinical responder rate (defined for the initial inference of efficacy as the 
proportion of subjects with normal 24-hour UFC levels after 6 months of treatment with 
COR-003 in the Maintenance Phase without dose increase) beyond 6 months of 
treatment (Extended Evaluation Phase); 
• 
To assess the proportion of subjects with complete or partial response (defined for the 
initial inference of efficacy as ≥50% reduction of 24-hour UFC levels from Baseline after 6  
months of treatment with COR-003 in the Maintenance Phase without dose increase) 
beyond 6 months of treatment (Extended Evaluation Phase); 
• 
To characterize changes in 24-hour UFC levels from Baseline beyond 6 months of 
treatment with COR-003 (Extended Evaluation Phase);  
• 
To characterize shifts in normality for 24-hour UFC levels from Baseline beyond 6 months 
of treatment with COR-003 (Extended Evaluation Phase);  
• 
To characterize changes in serum and LNSC concentrations beyond 6 months of treatment 
with COR-003 (Extended Evaluation Phase); 
• 
To assess the effects on Clinical Signs and Symptoms of CS, the QoL measures obtained 
from the Cushing QoL questionnaire and the severity of depression obtained from the 
BDI-II beyond 6 months of treatment with COR-003 (Extended Evaluation Phase); 
• 
To evaluate changes in the biomarkers of CS comorbidities (diabetes, hypertension, 
hypercholesterolemia and obesity) beyond 6 months of treatment with COR-003 
(Extended Evaluation Phase); 
• 
To describe the Clinical Benefit after 6 months of treatment with COR-003 in the 
Maintenance Phase, and after 9 and 12 months of treatment (Extended Evaluation 
Phase), defined as follows: 
• 
Clinical response as indicated by UFC ≤ ULN, and 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 13 of 124 
BMSOP111/F2 
 
 
 
 
• 
No increase in COR-003 dose during Maintenance Phase, and 
• 
A clinically meaningful improvement in any one Baseline CS comorbidity 
(diabetes, hypertension, hypercholesterolemia, weight) as defined in the SAP, 
and  
• 
No study drug related treatment-emergent adverse event (TEAE) classified as 
severe or worse; 
• 
To assess changes in anti-diabetic, anti-cholesterol and antihypertensive therapies after 
6 months of treatment with COR-003 in the Maintenance Phase, and after 9 and 12 
months of treatment (Extended Evaluation Phase); 
• 
To assess the change in clinical signs of hypercortisolism obtained from standardized 
photographs and rated by an adjudication committee after 3 and 6 months of treatment 
with COR-003 in the Maintenance Phase, and after 12 months of treatment (Extended 
Evaluation Phase). 
Pharmacokinetic/Pharmacodynamic Objectives:  
• 
To evaluate the pharmacokinetics (PK) of COR-003 in subjects with CS;  
• 
To explore the dose-response relationship for safety, including dose-response for adverse 
events of special interest (AESIs) such as QT corrected for heart rate (QTc), if data allow; 
• 
To explore the dose-response relationship for reduction of UFC levels if data allow. 
 ENDPOINTS 
Primary Endpoint:  
• 
Proportion of subjects with response to COR-003, defined as reduction in mean 24-hour 
UFC levels to ≤ULN following 6 months of Maintenance Phase therapy without a dose 
increase during that phase, summarized by Maintenance Phase dose level and overall.  
Secondary Endpoints: 
• 
Proportion of subjects with clinical response to COR-003, defined as mean UFC level 
≤ ULN, to be determined after 1, 2, 3, 4 and 5 months of dosing without a dose increase 
in the Maintenance Phase; 
• 
Proportion of subjects with complete or partial response to COR-003, defined as mean 
UFC level ≥ 50% reduction from Baseline after 1, 2, 3, 4, 5 and 6 months of dosing without 
a dose increase in the Maintenance Phase; 
• 
Change and percentage change from Baseline in mean 24-hour UFC levels after 1, 2, 3, 4, 
5 and 6 months of dosing in the Maintenance Phase regardless of dose increases; 
• 
Shift in UFC normality categories from Baseline to 1, 2, 3, 4, 5 and 6 months of dosing in 
the Maintenance Phase regardless of dose increases; 
• 
Change and percentage change from Baseline in serum and LNSC levels after 1, 2, 3, 4, 5 
and 6 months of dosing in the Maintenance Phase. 
• 
Changes from Baseline in Clinical Signs and Symptoms of CS after 1, 2, 3, 4, 5 and 6 months 
of dosing in the Maintenance Phase;  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 14 of 124 
BMSOP111/F2 
 
 
 
 
• 
Changes from Baseline in the QoL measures obtained from the Cushing QoL questionnaire 
and the severity of depression obtained from the BDI-II after 3 and 6 months of dosing in 
the Maintenance Phase; 
• 
Change from Baseline in CS comorbidities biomarkers (fasting glucose, hemoglobin A1C 
(Hb1Ac), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, 
low and high density lipoprotein-associated cholesterol [LDL-C, HDL-C, respectively], and 
body weight) after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase; 
• 
Changes from Baseline for oral glucose tolerance test (OGTT) (pre-diabetics only) and spot 
albumin/creatinine ratio as a measure of microalbuminuria (only if abnormal at baseline) 
after 3 and 6 months of dosing in the Maintenance Phase;  
• 
Changes from Baseline for C-reactive protein (CRP) after 1, 2, 3, 4, 5 and 6 months of 
dosing in the Maintenance Phase;  
• 
Safety evaluations as described further below. 
Exploratory Endpoints: 
• 
Proportion of subjects with long-term clinical response to COR-003, defined as mean UFC 
level ≤ ULN, after 9 and 12 months (Extended Evaluation Phase); 
• 
Proportion of subjects with long-term complete or partial response to COR-003, defined 
as mean UFC level ≥ 50% reduction from Baseline after 9 and 12 months (Extended 
Evaluation Phase); 
• 
Change and percentage change from Baseline in mean 24-hour UFC levels after 9 and 12 
months (Extended Evaluation Phase); 
• 
Shift in UFC normality categories from Baseline at 9 and 12 months (Extended Evaluation 
Phase); 
• 
Change and percentage change from Baseline in serum and LNSC levels after 9 and 12 
months (Extended Evaluation Phase); 
• 
Changes from Baseline in Clinical Signs and Symptoms of CS, on the QoL measures 
obtained from the Cushing QoL questionnaire, and on the severity of depression obtained 
from the BDI-II after 9 and 12 months of dosing (Extended Evaluation Phase); 
• 
Change from Baseline in CS comorbidities biomarkers (fasting glucose, HbA1c, SBP, DBP, 
total cholesterol, LDL-C, HDL-C and body weight) after 9 and 12 months of dosing 
(Extended Evaluation Phase); 
• 
Changes from Baseline for OGTT (pre-diabetics only) and spot albumin/creatinine ratio as 
a measure of microalbuminuria (only if abnormal at Baseline) after 9 and 12 months of 
dosing (Extended Evaluation Phase);  
• 
Changes from Baseline for CRP after 9 and 12 months of dosing (Extended Evaluation 
Phase); 
• 
Clinical Benefit rate determined after 1, 2, 3, 4, 5 and 6 months of dosing in the 
Maintenance Phase and at 9 and 12 months in the Extended Evaluation Phase. Clinical 
Benefit is defined as follows: 
1. UFC response as indicated by UFC ≤ ULN, and 
2. No increase of COR-003 dose during Maintenance Phase, and 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 15 of 124 
BMSOP111/F2 
 
 
 
 
3. A clinically meaningful improvement in any one Baseline CS comorbidity (diabetes, 
hypertension, hypercholesterolemia, weight) as defined in (Section 6.7.2) and  
4. No study drug related TEAE classified as severe or worse; 
• 
Changes in the doses of concomitant medications and in particular anti-diabetic, anti-
cholesterol and antihypertensive medications after 6 months of dosing with COR-003 
during the Maintenance Phase and during the Extended Evaluation Phase relative to 
Baseline doses of such medications; 
• 
Changes in the severity score for clinical signs of hypercortisolism obtained from 
standardized photographs and rated by an adjudication committee after 3 and 6 months 
of dosing with COR-003 during the Maintenance Phase and at 12 months in the Extended 
Evaluation Phase. 
Safety Endpoints: 
• 
Incidence and severity of TEAEs, including serious TEAEs, and TEAEs of special interest. 
• 
Changes from Baseline in safety laboratory parameters (hematology, chemistry, 
urinalysis, coagulation) and incidence of abnormal laboratory parameters results at each 
post-baseline visit in the Maintenance Phase; 
• 
Changes from Baseline in biomarkers and hormone laboratory parameters (Thyroid 
stimulating hormone [TSH], Free T4, Adrenocorticotropic hormone [ACTH], Insulin-like Growth 
Factor-1 (IGF-1) and testosterone concentrations) and incidence of abnormal laboratory 
parameters results at each post-baseline visit in the Maintenance Phase;  
• 
Changes from Baseline in vital signs (SBP, DBP, heart rate [HR], and body temperature) 
and incidence of abnormal vital signs (SBP, DBP, and HR) at each post-baseline visit in the 
Maintenance Phase; 
• 
Changes from Baseline for quantitative electrocardiogram (ECG) parameters, including 
QTc interval, from centrally read ECGs and incidence of abnormal QTc intervals at each 
post-baseline visit in the Maintenance Phase;  
• 
Changes from Baseline in pituitary tumor size, among subjects with Cushing’s disease (CD) 
at Baseline, assessed by central reading of magnetic resonance image (MRI) at 6 months 
in the Maintenance Phase. 
 
Pharmacokinetic Endpoints and Pharmacokinetic/Pharmacodynamic Modeling 
• 
The following will make use of PK samples collected during the Dose Titration and 
Maintenance Phases:   
o Estimate the following parameters using population PK modeling: apparent 
clearance following oral administration (CL/F), apparent volume of distribution 
following oral administration (V/F), absorption rate constant (Ka) with associated 
between subject variability where feasible. These parameters will be used to 
calculate half-life (t½), area under the concentration time curve (AUC) and peak 
concentration (Cmax) if feasible.  Because the PK of ketoconazole are reported to 
change over time, time dependent changes in CL/F, AUC and t½ will be 
investigated, and if identified, will be incorporated into the model.   


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 16 of 124 
BMSOP111/F2 
 
 
 
 
o Estimate 
the 
following 
pharmacodynamic 
(PD) 
parameters: 
COR-003 
concentration producing half maximal UFC suppression (IC50), the maximal 
suppression of UFC (Imax) and associated estimates of between subject 
variability, if feasible. The range of UFC reduction by dose will be explored.  
o Other safety and efficacy endpoints will also be explored graphically by dose or 
summary metrics of exposure.  
o The relationship of AESI including QTc interval to dose of COR-003 will be 
evaluated if data allow. 
o The relationship of UFC reduction to dose of COR-003 will be evaluated if data 
allow. 
4 Study Design 
  STUDY DESIGN AND POPULATION 
This study is the first clinical study investigating the safety and efficacy of COR-003 in subjects 
with endogenous Cushing´s Syndrome (CS). Endogenous Cushing´s syndrome (CS) is a rare but 
serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure to 
human organs. 
This study is a single arm, non-randomized, open-label, dose titration study to assess efficacy, 
safety, tolerability, and PK of COR-003 in subjects with endogenous CS as illustrated in Figure 1.  
 
 
 
 
 
 
 
 
Figure 1. Study Design 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 17 of 124 
BMSOP111/F2 
 
 
 
 
Following an initial screening and washout period, this study will be conducted in 3 study phases 
as follows: 
• 
Dose Titration Phase: approximately 2 to 21 weeks to achieve an effective and tolerable 
maximum dose (the Therapeutic Dose); 
• 
Maintenance Phase: 6 months of treatment at the Therapeutic Dose following Dose 
Titration Phase; 
• 
Extended Evaluation Phase: 6 months of continued treatment after the Maintenance 
Phase. 
Approximately 90 subjects that meet eligibility criteria and sign informed consent will be enrolled 
into the Dose Titration Phase of the study to ensure that at least 70 subjects complete the 6-
month assessment period in the Maintenance Phase of the study. 
 STUDY TREATMENTS AND ASSESSMENTS  
The time and events schedule for the screening, Dose Titration, Maintenance and Extended 
Evaluation Phases is given in Table 1 in Section 15.1.1. 
After signing the informed consent, subjects will enter the Screening Period.  After performing 
initial Screening assessments, subjects on prior CS therapies or other prohibited medications must 
enter a washout period, as applicable (see Protocol Section 5) before completing all Screening 
assessments detailed in Table 1.  Baseline measurements will be obtained as part of the Screening 
assessments, after washout and completion of all initial Screening procedures.   
All subjects having signed off the informed consent and who meet inclusion criteria (and none of 
the exclusion criteria) will begin treatment on 150 mg twice daily (BID) (DL1), approximately every 
12 hours, and will be dose-titrated approximately every 18 (± 4) days until the Therapeutic Dose 
is reached.   
COR-003 will be administered BID according to the titration scheme in Table 2 (starting at DL1) 
until one of the following criteria has been met: 
• 
Mean 24-hour UFC levels are ≤ ULN established for the assay being used at a central 
laboratory, 
• 
Reached the highest protocol-specified dose, 
• 
Reached the highest tolerated dose at the discretion of the Investigator. 
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 18 of 124 
BMSOP111/F2 
 
 
 
 
Table 2: Dosing Titration Scheme 
Dose Level 
(DL) 
Morning 
Dosing 
Evening Dosing 
 Total Daily Dose 
Dose group label 
DL0 
0 mg 
150 mg 
150 mg 
COR-003 150 mg 
DL1 
150 mg 
150 mg 
300 mg 
COR-003 300 mg 
DL2 
150 mg 
300 mg 
450 mg 
COR-003 450 mg 
DL3 
300 mg 
300 mg 
600 mg 
COR-003 600 mg 
DL4 
300 mg 
450 mg 
750 mg 
COR-003 750 mg 
DL5 
450 mg 
450 mg 
900 mg 
COR-003 900 mg 
DL6 
450 mg 
600 mg 
1050 mg 
COR-003 1050 mg 
DL7 
600 mg 
600 mg 
1200 mg 
COR-003 1200 mg 
*DL0, permitted for dose reductions, is a dose of 150 mg once daily administered in the 
evening, except on the day of the in-clinic procedures, when the dose should be administered 
in the clinic 
Titration rules and adjustment criteria: 
After confirmation of eligibility at the Baseline Visit, including confirmation of increased UFC levels 
as per eligibility requirements, each subject will return to the investigational site to receive study 
medication and will begin dosing at dose level 1 (DL1), with an initial dose of 150 mg BID, taken 
as one tablet in the morning and one tablet in the evening.  Decisions for subsequent dose 
increases will be based on each subject’s drug tolerability, assessment of UFC levels and safety 
data and will be made by the Investigator. The approximate interval between dose adjustments 
will be 18 (±4) days. 
All subjects will be asked to collect two adequate 24-hour urine specimens starting at 
approximately Day 10 (±1 day) after the start of each dose level, ideally on two consecutive days. 
Urine volume and creatinine will be measured as a marker of the adequacy of each collection 
(Section 6.7.1). The subjects are asked to bring (or ship per courier service) their two urine 
collections to the clinic as soon as possible (approximately Day 12) for measurement of 24-hour 
UFC levels from each sample.  Subjects will continue on their current dose of COR-003 until the 
UFC results have been obtained from the central laboratory (within approximately 2-4 days).  
Based on their UFC results and tolerability, subjects will be asked to return to do one of the 
following:  
• 
Return to the clinic for scheduled assessments and receive the first dose of drug for the 
next Dose Titration interval; 
• 
Have a confirmatory UFC evaluation (e.g. two additional UFC measurements to determine 
if the Therapeutic Dose of COR-003 has been reached; Protocol Section 4.2.1.1); or 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 19 of 124 
BMSOP111/F2 
 
 
 
 
• 
Enter the Maintenance Phase (if an alternative determination of Therapeutic Dose of 
COR-003 has been made; Protocol Section 4.2.1.1) as applicable.   
Determination of the effective and tolerable dose of COR-003 (Therapeutic Dose): 
A Therapeutic Dose for a subject will be considered established when mean UFC levels 
(determined from a total of four adequate 24-hour urine collections) are ≤ULN of the assay, or 
the maximum dose allowed has been reached, or a clinically meaningful partial response was 
achieved and the maximal tolerated dose has been reached.  Once the Therapeutic Dose has been 
reached the subject can begin the Maintenance Phase of the study. 
Steps for Determination of Therapeutic Dose: 
• 
If the mean value for the first two UFC test levels is ≤ULN of the assay of two adequate 24-
hour urine collections, the subject should be notified immediately and asked to begin the next 
two 24-hour urine collections, for the purpose of confirming a biochemical response.  The two 
additional urine collections should be completed and returned to the clinic, as soon as 
practical (for example, if samples were provided to site on Day 12 following the dose 
escalation visit and results were received on Day 15, the subject should ideally begin collection 
the following day (Day 16) and return the two additional samples to the site immediately upon 
completion of collection (Day 18).  The next visit for the subject should be scheduled to 
coincide with receipt of the results (Day 30 [±7 days]) and the mean of the four UFC test values 
is available to make the determination of whether or not the Therapeutic Dose has been 
achieved. 
• 
When confirmatory urine sample collection is required, in order to allow for adequate time 
for urine sample collection and analysis between visits, the subject should return no later than 
37 days after the prior dose escalation visit for either the next dose escalation visit or start of 
the Maintenance Phase (based on the mean of the four UFC values). 
• 
If the mean value of four adequate 24-hour urine collections is ≤ULN of the assay, the subject 
may enter the Maintenance Phase at the current dose level (i.e. Therapeutic Dose level) 
[Protocol Section 4.3].  The total duration of the Titration Phase should not be any longer than 
approximately 21 Weeks; assuming approximately 3 weeks of treatment for each dose level. 
• 
If the mean value of four adequate 24-hour urine collections is >ULN of the assay of four 
adequate 24-hour urine collections, the subject should proceed to the next Dose Level. 
Alternative determination of Therapeutic Dose: 
• 
If the subject has reached the highest allowed dose level and UFC levels remain > ULN of the 
assay for the mean of two adequate 24-hour urine collections, yet there is a clinically 
meaningful UFC partial response from Baseline, the subject may enter the Maintenance Phase 
at that dose level. 
• 
If the subject has reached the highest tolerated dose and UFC levels remain > ULN of the assay 
for the mean of two adequate 24-hour urine collections, yet there is a clinically meaningful 
UFC partial response from Baseline, the subject may enter the Maintenance Phase at that 
dose level at the discretion of the Investigator.  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 20 of 124 
BMSOP111/F2 
 
 
 
 
• 
If UFC is > ULN and liver function tests (LFTs) are elevated, the Investigator may maintain the 
dose in the Dose Titration Phase in consultation with the Medical Monitor before a decision 
is made to progress to the next dose level or into Maintenance Phase. 
NOTE:  If UFC levels remain > ULN of the assay for the mean of two adequate 24-hour urine 
collections, and there is no clinically meaningful UFC partial response from Baseline upon reaching 
the highest allowed dose or the highest tolerated dose, discontinuation should be considered. 
Consultation with the Medical Monitor is encouraged.  
Dose Titration to the Therapeutic Dose: 
Subjects will continue the process of dose titration until the Therapeutic Dose has been reached 
(Protocol Section 4.2.1.1): 
• 
If UFC levels are >ULN of the assay for the mean of two adequate 24-hour urine 
collections, the dose should be increased to the next dose level, unless the highest 
tolerable dose or the highest protocol-specified dose has already been reached. 
• 
If UFC levels are >ULN of the assay for the mean of two adequate 24-hour urine 
collections, the subject should return no later than 22 days (18 days ± 4 days) after the 
prior dose escalation visit for the next dose escalation visit. 
Other factors that are to be considered during the Dose Titration Phase: 
• 
Subjects will have ECG evaluations at Baseline, during Dose Titration Phase at each dose 
level within approximately 1 to 2 hours after drug administration (i.e., at ~ Cmax), 
monthly (at the Therapeutic Dose) during the Maintenance Phase and at each visit during 
the Extended Evaluation Phase using the Spaulding ECG device for collection up to 
5 minutes of continuous ECG (see Protocol Section 6.2.4).  The dose of study medication 
will be reduced if the confirmed COR-003 related QTc interval persistently increases to > 
500 msec or > 60 msec from Baseline.  
• 
If the subject develops signs and/or symptoms of adrenal insufficiency (e.g., orthostatic 
hypotension, nausea, vomiting, and/or abdominal pain), based on further investigation 
(see Protocol Section 6.3.3) and clinical judgment, the Investigator may temporarily stop 
dosing of the study medication to allow resolution of these symptoms. In such cases, at 
the discretion of the Investigator, the dose will be reduced and restarted at a preceding 
dose level (see Protocol Section 6.2.4.2).  In the event that this observation is made at 
DL1, the subjects may receive a lower dose of 150 mg once daily (DL0) based on the 
medical discretion of the Investigator and agreement with the Sponsor.  Subjects may 
resume the Dose Titration scheme after a dose reduction at the discretion of the 
Investigator and agreement with the Sponsor.   
COR-003 has only been dosed up to 600 mg/day in diabetic subjects. The safety in subjects at 
doses beyond 600 mg/day is unknown. For this reason, subjects that reach total daily doses of 
>600 mg/day (i.e., doses of 750, 900, 1050, and 1200 mg/day) must be monitored more closely in 
order to ensure proper evaluation of the safety of doses at these levels.  In addition to the 
assessments that will be carried out during dose escalation for doses ≤600 mg/day, for each dose 
escalation beyond 600 mg/day, subjects will be asked to return for one additional safety 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 21 of 124 
BMSOP111/F2 
 
 
 
 
evaluation 7 days (±3 days) after each dose escalation to include the following assessments:  AEs, 
vital signs, routine safety laboratory assessments (including LFTs), ECGs, and morning serum 
cortisol levels as outlined in Table 1.  Subjects will be advised to contact the Investigator 
immediately in the event of developing adrenal insufficiency (see Protocol Section 6.3) or other 
AEs at any time. 
• 
Return 7 days (±3 days) after each dose level escalation visit for DL4 through DL7 for additional 
safety assessment (see Protocol Section 6.2.7.1);  
• 
Start the collection of two adequate 24-hour urine samples 10 days (±1 day) after the dose 
level escalation visit for DL4 through DL7 - provide containers to sites as soon as possible after 
completion (approximately 12 days after dose level escalation); 
• 
If the mean value for the first two adequate 24-hour urine collections is >ULN of the assay, 
the subject should return no later than 22 days (18 days ± 4 days) after the prior dose 
escalation visit for next dose escalation visit;  
• 
If the mean value for the first two adequate 24-hour urine collections is ≤ULN of the assay 
and additional UFC tests are needed to confirm the mean value of ≤ULN, the subject should 
be notified to collect an additional two 24-hour urine samples and return them to the site, as 
soon as possible after completion (see timing details in Protocol Section 4.2.1.1). 
Maintenance Phase: 
During the Maintenance Phase, doses may not be increased to maintain UFC levels at or below 
ULN of the assay unless it is confirmed that a dose increase is deemed medically necessary, based 
on a totality of evidence including other disease markers or symptoms, at the discretion of the 
Investigator, after discussion with the Medical Monitor. The reason for this restriction is that some 
variability in mean UFC levels from two urine collections is expected, and such variability in and 
of itself is not considered a sufficient reason for further dosage adjustment. If it is deemed 
medically necessary, prior to increasing the dose during the Maintenance Phase, two additional 
adequate 24-hour urine collections should be obtained within two weeks of the first UFC samples 
for analysis to provide a total of four UFC samples for analysis.  If confirmed hypercortisolemia is 
present, the COR-003 dose may be increased by 150-mg increments as medically indicated up to 
the maximally allowed dose of 1200 mg/day, and the subject may stay in the study through 
completion.  
During the Maintenance Phase the COR-003 dose may also be reduced temporarily or 
permanently for safety reasons, including but not limited to LFT elevation (see Protocol Section 
5.3.2., instructions for re-challenge), QTc prolongation (Protocol Section 5.3.1) and adrenal 
insufficiency (Protocol Section 6.3.3). If medically indicated, the dose should be resumed at the 
individual’s Therapeutic Dose.  All dose adjustments during the Maintenance Phase must be 
documented. 
Transition from Maintenance Phase to Extended Evaluation Phase: 
Prior to the End of Maintenance Phase Visit, four complete 24-hour urine collections will be 
obtained and subjects may enter the Extended Evaluation Phase (Protocol Section 4.5). 
Exclusion of Treatment Effect Due to Delayed Onset of Radiation Therapy (Protocol Section 4.4.1): 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 22 of 124 
BMSOP111/F2 
 
 
 
 
Previously irradiated subjects must stop treatment with COR-003 for at least 2 weeks after the 
end of the 6-month Maintenance Phase (End of Maintenance Phase Visit) and provide four 
complete 24-hour urine collections for UFC measurements collected at least 14 days following the 
End of Maintenance Phase Visit.  If the 24-hour UFC results indicate that UFC levels are elevated, 
the subject may subsequently restart therapy and continue into the Extended Evaluation Phase, 
at the discretion of the Investigator (Protocol Section 4.5).  [NOTE: Subjects restarting therapy 
should initiate therapy as soon as the need is identified and should return for their next in-clinic 
visit (M9) for study assessments and resupply of study medication 90 days (±14 days) from the 
End of Maintenance Visit.] 
Extended Evaluation Phase: 
The end of the Maintenance Phase visit will be the start of the Extended Evaluation Phase. In the 
6-month Extended Evaluation Phase, subjects will return to the clinical site every three months 
(every 90 days ± 14 days) for assessments, (i.e., at the end of Months 9 and 12) and will have 
safety and efficacy evaluations as indicated in Table 1. 
After completion of treatment in this study, if subjects do not extend treatment through the 
expanded access program (Protocol Section 4.7), they will return for a Follow-Up Visit as indicated 
in Table 1.  The Follow-Up Visit should be a minimum of 2 weeks (14 days) and no longer than 30 
days following the completion of treatment. [NOTE: The Follow-Up Visit is not required for 
subjects continuing into expanded access treatment or into another Phase 3 study with COR-003 
(see Protocol Section 4.7 and Protocol COR-2017-01, also known as LOGICS)]. 
Stopping Criteria: 
Dosing with the study medication will cease due to any of the following observations: 
• 
Intolerability to the study medication based on the subjects’ signs or symptoms in 
accordance with the Investigator’s medical judgment 
• 
Lack of any clinically relevant response at the maximally tolerated dose, in the opinion of 
the Investigator 
• 
QTc prolongation as specified in Protocol Section 5.3.1 at 150 mg/day 
• 
LFT abnormalities as specified in Protocol Section 5.3.2 
• 
Adrenal insufficiency at the lowest dose of COR-003 (150 mg daily)—See also Protocol 
Section 6.3.3 for more details 
• 
Any withdrawal criteria specified in Protocol Section 5.3. 
Subjects who are withdrawn early will complete the Follow-Up Visit (see Table 1) and provide two 
adequate 24-hour urine collections within approximately 2 weeks of termination of treatment 
with COR-003. 
The cause for withdrawal will be documented and appropriately captured in the database.  
Optional Expanded Access Program and Open Label Extension Studies: 
An expanded access program (COR-2015-EAP) will be made available, as local regulations allow, 
to sites participating in this study.  Subject interest and eligibility for participating in the expanded 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 23 of 124 
BMSOP111/F2 
 
 
 
 
access program will be evaluated at the M9 visit, including the informed consent process.  If 
eligible, they will begin participation in the COR-2015-EAP program upon completion of the M12 
visit.  Subjects continuing directly into expanded access program will NOT be required to complete 
the Follow-Up Visit for COR-2012-01.  
The Sponsor is planning an open label extension study that will be open to subjects who complete 
visit M12 in COR-2012-01 (Study COR-2017-OLE, also known as OPTICS).  The study protocol for 
the open label extension study is in development as of the writing of this SAP. If subjects continue 
directly into OPTICS, they will NOT be required to complete the Follow-Up Visit for COR-2012-01. 
The Sponsor is implementing a double-blind, randomized withdrawal following open label therapy 
study to assess the safety and efficacy of COR-003 (Study COR-2017-01, also known as LOGICS).  
This study is open to subjects who complete visit M12 in COR-2012-01. If subjects continue 
directly into LOGICS, they will NOT be required to complete the Follow-Up Visit for COR-2012-01. 
In the event that continued access to COR-003 is anticipated but delayed for any reason, and 
dosing with COR-003 will be interrupted for more than 2 weeks, the Follow-Up Visit should occur 
according to Table 1. 
 RANDOMIZATION, BLINDING, AND DATA INTEGRITY 
This is a non-randomized study. All subjects that meet eligibility criteria and sign informed consent 
will begin treatment on 150 mg BID in the Dose Titration Phase. 
Although the study is open-label, access to much of the data is restricted to certain team members 
to minimize bias introduction prior to the Maintenance Phase (i.e. primary efficacy endpoint) 
database lock. Details are provided in the “Data Restriction Plan (currently Version 1.0, September 
2016)”. The following description includes elements of this plan; however, the Plan stands alone 
as the complete and definitive description of data restrictions on the study prior to database lock.  
If the Data Restriction Plan is amended subsequent to the finalization of this SAP, then the 
amended Plan will supersede the current version of the Plan. 
Dummy data will be used for programming Tables, Figures and Listings (TFLs) containing restricted 
data prior to the Maintenance Phase database lock. Restricted data are summarized in Table 3.   
One or more dry runs (i.e. creation of data outputs prior to the Maintenance Phase database lock 
to review the outputs, layout and derivations) using dummy data will be performed. 
Refer to Section 9 for details regarding the timing of the two planned database locks and analyses, 
one at the end of the Maintenance Phase and one at the end of the Extended Evaluation Phase, 
including the Follow-up visits. 
Table 3: Restricted Data  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 24 of 124 
BMSOP111/F2 
 
 
 
 
Variable 
Data Captured 
Reason for Restriction 
UFC 
Includes 24-hour UFC and UFC 
adjusted for urine creatinine 
Primary efficacy endpoint 
(and 
some 
secondary 
endpoints) 
LNSC results 
Cortisol concentration 
Secondary efficacy endpoint 
PK* 
All measures of blood concentration 
of study drug(s) for PK analyses 
PK believed directly related 
to clinical efficacy of study 
drug 
Serum Cortisol 
Cortisol concentration 
Secondary efficacy endpoint  
Standardized Photo 
Assessments 
Subject photographs, all views 
Signs 
of 
hypercortisolism 
(i.e., visual assessment of the 
disease) 
Disease 
Comorbidity 
biomarkers 
Includes concentrations of fasting 
glucose, HbA1c, lipids (total C, LDL-C, 
HDL-C, triglycerides and LDL-HDL-C 
ratio), CRP, body weight and urine 
microalbumin to creatinine ratio 
Secondary efficacy endpoints 
Cushing 
QoL 
questionnaire+ 
All data collected using the Cushing 
QoL instrument 
Secondary efficacy endpoint 
BDI-II instrument+ 
All data collected using BDI-II 
Secondary efficacy endpoint 
Cushing’s 
Clinical 
Signs 
and 
Symptoms+ 
All data collected using the Signs and 
Symptoms assessment questionnaire 
Secondary efficacy endpoint 
Dose 
level 
and 
compliance+  
Data pertaining to dispensed dosage 
of study drug, including disclosure of 
dose-level, 
dose 
changes, 
and 
compliance with study medication 
Dose level will only be 
restricted when combined 
with other Restricted Data in 
this table. Data summaries 
produced prior to database 
lock for the general study 
team will not display dose 
levels. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 25 of 124 
BMSOP111/F2 
 
 
 
 
+ These data will not be restricted in the clinical database. However, programming conducted 
prior to clinical database lock will use dummy data generated by the restricted programming 
team.  
* Except by the medical monitor or designee for purposes of evaluating an adverse event (AE) 
report. 
 SAMPLE SIZE JUSTIFICATION 
A sufficient number of subjects (estimated at approximately 90) will be enrolled into the Dose 
Titration Phase of the study assuming that at least 70 subjects complete the 6 months 
Maintenance Phase.  The approximately 90 subjects to be enrolled in the Dose Titration Phase 
will be the primary analysis population (i.e. the intent-to-treat [ITT] population; see Section 7). 
Table 4 illustrates the power to exclude the null hypothesis of at most a 20% responder rate, given 
an alternative response of 35% for a two-sided 5% Type I error for the ITT population under these 
sample size assumptions. Results will be evaluated using a two-sided 95% lower confidence bound 
for the response rate at the End of the Maintenance Phase visit.  
Table 4: One Sample χ2 Test: Null Hypothesis vs. Alternative Hypothesis, One Scenario 
 
 
Test significance level, α 
0.050 
1 or 2 sided test? 
2 
Null Hypothesis Responses %, p0 
20% 
Alternative Hypothesis Response %, pA 
35% 
Power ( % ) 
90 
N (ITT) 
90 
In addition, the sample size of 90 subjects will be adequate to test hypotheses associated with the 
change from Baseline in CS comorbidity biomarkers expressed as continuous endpoints. Table 4 
in Protocol Section 12.3 displays the differences that can be detected for the secondary efficacy 
endpoints of CS comorbidities with 90% power for a two-sided 1% Type I error for 90 subjects (the 
1% Type I error accounts for testing significance for these multiple secondary efficacy endpoints). 
Results will be evaluated using two-sided 99% lower confidence bounds for the changes from 
Baseline at the End of the Maintenance Phase visit.  
For more detail on the sample size justification see Protocol Section 12.3. 
5 Statistical Considerations 
The SAS system, version 9.3 (or higher), will be used for all analyses, unless otherwise specified. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 26 of 124 
BMSOP111/F2 
 
 
 
 
 HYPOTHESIS TESTS 
Details on hypothesis tests are provided in Section 5.4.  
 DEFINITIONS OF DOSE GROUPS 
Throughout the document,  
• 
The expression “dose group” refers to a group of subjects who were receiving a given 
dose level (DL0 through DL7) as of the dates of their entries in the Maintenance Phase.  
The subject’s dose at the start of the Maintenance Phase is also referred to as the 
subject’s Therapeutic Dose. Subsequent dose adjustments that may have been made 
after a subject’s entry date into the Maintenance Phase do not change membership in a 
subject’s primary dose group.  
• 
There are three exceptions to use of this general definition: The first exception is made 
for subjects  who never enter the Maintenance Phase of the study (for any reason); the 
second exception is for summaries that are limited to the Dose Titration Phase (i.e. the 
summary does not include Maintenance Phase assessments and thus does not include 
doses at entry into the Maintenance Phase); the third exception is for summaries made 
for the final database lock at the end of the study (i.e. after the last subject has completed 
the Extended Evaluation Phase) that include subjects who enter the Extended Evaluation 
Phase. Summaries by dose group in these three exceptions are defined immediately 
below.  
• 
Exceptions 1 and 2 as above:  Summaries by dose for subjects who do NOT enter the 
Maintenance Phase and summaries limited only to the Dose Titration Phase will use the 
following conventions: 
• 
For summaries of AEs and concomitant medications, the AEs and concomitant 
medications will be summarized by the last dose received on or before the AE or 
concomitant medication started.  
• 
For the summary of disposition in the Dose Titration Phase, subjects will be 
summarized by the last dose received in the Dose Titration Phase.  
• 
For summaries of demographics and Baseline characteristics, medical history and 
disease characteristics, prior medications, and prior CS therapy for the ITT 
population, subjects who do NOT enter the Maintenance Phase will be 
summarized by the last dose received in the Dose Titration Phase. 
• 
For summaries of any other parameter/variable in the Dose Titration Phase, the 
results will be presented by dose level, not by-visit. Refer to Section 6.3 for 
details. 
• 
For other summaries, specific rules will be provided in the relevant sections. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 27 of 124 
BMSOP111/F2 
 
 
 
 
• 
Exception 3 as above: Because the protocol provides for dosage adjustments during the 
Extended Evaluation Phase, in the final analysis (i.e. after last subject completes the final 
study visit), summaries by dose for subjects who enter the Extended Evaluation Phase will 
use the following conventions: 
• 
For assessments collected by visits, subjects will be summarized by the dose they 
received at the previous visit; 
• 
For the summary of disposition in the Extended Evaluation Phase, subjects will be 
summarized by the last dose received in the Extended Evaluation Phase. 
• 
For all other summaries, subjects will be included in the dose group 
corresponding to the last dose they received on or before the relevant 
assessment or event. 
• 
The “All dose groups combined” includes all subjects regardless of their dose group, as 
defined above. 
 
 DATA PRESENTATION 
• Page Orientation: Landscape 
• Post-text outputs, will be generated in lst and converted to rtf. Figures will be generated 
directly in .rtf format. All the outputs will also be generated in .pdf format. 
• Font: Courier New font with minimum of 9-point font size 
• Margins: top: 3/8”, bottom: 3/8”, left: 3/4” and right: 3/8” on Letter paper  
• Alignment: Columns header will be left aligned. 
• Dose level designations:  
• 
Dose level designation labels will be as described in the last column in Table 2 in 
Section 5.2. The All dose groups combined will be labeled as “All Subjects” in the 
tables. 
• 
For the Dose Titration Phase, subjects will generally be summarized under the 
different doses they received during that period, with some exceptions (see 
Section 6.2 for details).  
If there is only one subject who received 150 mg dose, then there is no need for 
a ‘150 mg’ column in the Dose Titration Phase tables. The subject’s data at that 
dose will just be displayed in the listings, and this decision will be documented 
in the Clinical Study Report. 
• 
For the Maintenance Phase, subjects will be summarized under the dose they 
received at the beginning of the Maintenance Phase . If the subject did not reach 
the Maintenance Phase and is included in the summaries and analyses for the 
ITT Population (Section 7) (i.e., summaries and analyses of UFC response and 
UFC improvement rates), the subject will be summarized under the last dose the 
subject received in the Dose Titration Phase.   


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 28 of 124 
BMSOP111/F2 
 
 
 
 
• 
For the Extended Evaluation Phase, subjects will be summarized under the most 
recent dose level received (see Section 6.2 for details).  
• By-phase table layouts: Because the number of subjects who received each dose level is  
      different for each phase, assessments that occur in more than one study phase will be   
      summarized in the following way: 
• 
The Dose Titration Phase will not be summarized by visit, only by dose level.  
If a subject has more than one assessment of mean UFC at the same dose level 
during the Dose Titration Phase, then the average of the mean UFC results will 
be included in the summaries on the mean UFC, UFC response and UFC 
improvement. 
If a subject has more than one assessment of any other parameter/variable than 
mean UFC at the same dose level during the Dose Titration Phase, then the 
worst-case result will be included in the summary. The determination of the 
worst-case results for a subject at a dose level will include all results (including 
those from unscheduled visits) while at that dose level under consideration. 
Refer to Appendix 15.2 for determining which results are considered the worst 
results for other laboratory parameters, vital signs and ECG parameters. 
All results will be included in the listings, and where applicable the worst-case 
result will be flagged. The N for each dose level will be the number of subjects 
who received the given dose level at any time during the Dose Titration Phase. 
• 
The Maintenance Phase will be summarized on a separate page, by visit and dose 
level. The N for each dose level will be the number of subjects receiving the given 
dose level at the beginning on the Maintenance Phase (i.e., the Therapeutic 
Dose). 
• 
The Extended Evaluation Phase and Follow-up visit will be summarized on a 
separate page, by visit and dose level. The N for each dose level will be the 
number of subjects who received the dose level at any stage during the Extended 
Evaluation Phase. For all summaries of the Extended Evaluation Phase the 
number of subjects who received the dose level at the given visit will also be 
presented.  
• 
The Screening/Baseline visit or period will be presented for each by-phase table.     
• Visit labels for the visits for all study phases are displayed in Table 5 below. 
Table 5: Visit labels 
Study Phase 
Period (per the Protocol) 
Tables, Figures 
and Listings 
Label 
Screening / Baseline 
Historical Data 
 
Screening/ Baseline 
BAS 
Dose Titration Phase 
All 
DT 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 29 of 124 
BMSOP111/F2 
 
 
 
 
Study Phase 
Period (per the Protocol) 
Tables, Figures 
and Listings 
Label 
Maintenance 
Phase** 
Month 1* 
M1 (D1) 
Month 2 
M1 (D30) 
Month 3 
M2 (D60) 
Month 4 
M3 (D90) 
Month 5 
M4 (D120) 
Month 6 
M5 (D150) 
End of Maintenance Phase 
M6 (D180) 
Extended Evaluation 
Phase*** 
Month 9 
M9 
Month 12 
M12 
Follow-up 
Follow-up  
FU 
* In protocol versions prior to Amendment 5, this visit was labelled Month 0.  The time window 
did not change, only the label.  For analysis, Day 1 of Month 1 in the Maintenance Phase will 
be labelled ‘Month 1’ regardless of the protocol version. 
** As per protocol Amendment 6, time window is considered as (30 ± 7 days) for each visit 
during the Maintenance Phase after Month 1 visit. 
*** As per protocol Amendment 6, time window is considered as (90 ± 14 days) for each visit 
during the Extended Evaluation Phase. 
• Repeated Screening assessments: Where the subject has been re-screened, or had 
repeat assessments during the Screening period (Section 6.4), the last value prior to first 
dose will be summarized.   
• Nominal visits, post-baseline: Nominal visits will be defined as the assessment(s) closest 
to the planned visit day and within the visit window (see Appendix 15.3) Nominal visits will 
be used in the summary, analysis and graphical representation of the data.  
• 
For UFC, depending on the visit considered, 2 to 4 samples are collected. All 
adequately collected samples (see Protocol Section 6.2.6.1) within the visit 
window will be used to derive the mean.     
• 
SBP, DBP and abdominal girth are measured in triplicate and for each, the 
endpoint is defined as the mean of those 3 measures.  Therefore, for each 
assessment, only those performed on the same day will be used for the 
derivation of the endpoint. For each endpoint, if there is more than one mean 
value within a visit window that is equally distant from the nominal visit, the last 
calculated mean will be flagged for analysis. If there are more than 3 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 30 of 124 
BMSOP111/F2 
 
 
 
 
assessments on the same day, the repeat and unscheduled assessments will not 
be used to derive the mean. 
• 
LNSC, depending on the visit considered, may be collected for 2 nights at a visit 
(see Table 1). When this occurs, the mean LNSC will be derived and analyzed. A 
LNSC sample is adequate if there is no comment associated to the sample which 
specifies that it is not adequate. If there are more than 2 adequate samples 
available within 4 days, repeat and unscheduled assessment(s) will not be used 
to derive the mean. If inadequate samples are repeated within the 4 days, up to 
2 adequate samples will be used selecting those closest to the scheduled 
collection time. 
• 
For all other assessments, if there is more than one assessment in the visit 
window that is equally distant from the nominal visit, the last assessment will be 
flagged for analysis.  
• Other unscheduled visits or repeat assessments:  
• 
All abnormal values detected at unscheduled visits, or not identified as a nominal 
visit, will be included in shift tables pooled over study phase (see Section 8.11.2, 
Section 8.11.3, Section 8.11.4, Section 8.11.5). 
• 
All data, scheduled and unscheduled, will be listed. 
• 
Continuous variables (e.g., age) will be summarized using the number of observations (n), 
mean, standard deviation (SD), median, minimum, and maximum.  
• 
Categorical variables (e.g., sex, race) will be summarized using the number of 
observations (n) and percentage in each category.  
• 
The number of missing values will be presented as a separate category with no 
percentage, but only if 1 or more subjects have missing data for the summary.  
Otherwise, all categories will be presented (even if no subjects are counted in 
the category). 
• 
Counts of zero in any category will be presented without a percentage.  
• 
Unless otherwise specified, percentages will be calculated based on the number 
of subjects in the population. 
 
For shifts from Baseline and incidence of abnormalities, percentages will 
be calculated based on the number of subjects with non-missing results 
for the assessment and visit (if applicable).  
• 
Precision of summary statistics: 
Integer – Sample size (n, N) and number of missing responses (if displayed) 
• 
One additional decimal place than reported/collected (see Section 10 for 
laboratory assessments) for mean, geometric mean, median, other percentile, 
confidence interval (CI) 
• 
Two additional decimal places than reported/collected for SD 
• 
Same number of decimal places as reported/collected for minimum, maximum 
• 
Percentages: 
 <0.1, if the percentage is < 0.1%, 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 31 of 124 
BMSOP111/F2 
 
 
 
 
 Otherwise: one decimal place. 
• 
P-values presented to the ten-thousandth, except values that are less than the 
level of precision will be presented as <0.0001.  Similarly, large p-values will be 
presented as >0.9999. 
• Data will be presented on listings in order of center, subject, visit, assessment date / time 
and assessment type / assessment (in order collected on Case Report Form [CRF], unless 
otherwise specified). 
• Relative day calculations will be [date of interest – relative date + 1 (date of interest >= 
relative date)]. This calculation will result in dates prior to the relative date being presented 
as negative days, and those occurring on or after the relative date as Day 1 or later, i.e., 
there will be no Day 0. 
• Dates will be presented in format DDMMMYYYY. 
• Partial dates will be presented as - -MMMYYYY or - - - - - YYYY.  
• All laboratory data results will be received from central laboratories, so no data 
conversion will be performed, results will be summarized based on the standard 
international units reported, with one exception. For HbA1c, the values will be summarized 
in tables and figures in conventional unit, ie, as %. The HbA1c values will be presented in the 
listings in both conventional and international units. 
• For results reported as ‘<’ or ‘>’ the result just below or just above (using the precision 
for the lab test) will be analyzed (i.e. if the result is < 5.0, then it will be summarized as 4.9, 
if the result is > 5200 then it will be summarized as 5201). 
• Dictionary names and versions will be included in the footnotes of the AEs and 
medications tables and listings. 
• Source footnotes: Each table will have a footnote that lists the source data listing(s). Each 
figure will have a footnote that lists the source tables(s), if available, or the source data 
listing(s), otherwise. 
• Minor deviations between template and actual data display are acceptable.  For 
example, changes in numbering or title, modifications or additions to footnotes for clarity, 
or minor differences in appearance should not be considered deviations from the TFL shells. 
Further changes in the templates may occur after review of the dry runs prior to the 
Maintenance Phase database lock. 
 DEFINITIONS 
• Baseline is defined on an assessment level as the last value/result where assessment 
date is less than the date of first study treatment, unless otherwise specified. For UFC and 
LNSC all adequate samples within the visit window and prior to the first dose of treatment 
will be considered to derive the Baseline mean.  
• Screening / Baseline period: all assessments performed strictly prior to the first dose of 
study drug administration. Results from assessments collected at Screening and/or Baseline 
visits will not be summarized separately, but the Baseline results (defined above as the last 
non-missing result prior to the first dose of study drug administration) will be summarized 
(if applicable) on all tables unless otherwise specified in the TFLs shell document.  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 32 of 124 
BMSOP111/F2 
 
 
 
 
• Dose Titration Phase: all assessments performed between the first dose date up to (and 
including) the first visit after the Investigator has determined that the subject has reached 
their Therapeutic Dose (referred to as M1 (D1)) or the date of discontinuation if the subject 
discontinued prior to the Maintenance Phase.  
• Maintenance Phase: all assessments performed between the day after the M1 (D1) visit 
up to (and including) the last assessment date at the End of Maintenance Phase or the last 
date of data collection if the subject discontinued prior to the End of Maintenance Phase.  
For a subject who completed the Maintenance Phase, the assessment considered for the 
analysis of the last assessment in the Maintenance Phase will be defined as the 
assessment(s) closest to the planned Month 6 visit day (D180) and within the visit window 
allowed for Month 6 visit. 
For a subject who withdrew during or at the end of the Maintenance Phase, the assessment 
considered for the analysis of the last assessment in the Maintenance Phase will be defined 
as the assessment(s) closest to the planned day of the last assessed nominal visit in the 
Maintenance Phase and within the visit window allowed for that last assessed nominal visit. 
For a subject who withdrew during or at the end of the Maintenance Phase, the data from 
the Follow-up visit (if performed) may be included in the summaries for the Maintenance 
Phase based on the visit windows specified in Appendix 15.3. 
• Extended Evaluation Phase: all assessments performed between the day after the last 
assessment performed at the End of the Maintenance Phase visit up to (and including) the 
date of completion of the last visit of the Extended Evaluation Phase or the last date of data 
collection if the subject discontinued at any time during the Extended Evaluation Phase. For 
subjects who withdraw during the Extended Evaluation Phase, the data from their Follow-
up visit (if performed) may be included in the summaries for Extended Evaluation Phase 
based on the visit windows in Appendix 15.3. 
• TEAE: Any AE that started on or after the date of first dose or that worsened in intensity 
after the first dose of treatment and started prior to or on the last dose date + 30 days. If 
the start time of the AE is known, it will be used to determine whether the AE is a TEAE or 
not.  Otherwise, if the AE started on the day of the first dose or started prior to the first dose 
and worsened (increased in intensity, became related to the study drug and/or became 
serious AE [SAE]) on or after the day of first dose it will be categorized as a TEAE. For subjects 
who withdraw during or at the end of the Dose Titration Phase, any reported AE that starts 
after withdrawal but within 30 days of their last dose will be included in the summaries for 
the Dose Titration Phase. For subjects who withdraw during or at the end of the 
Maintenance Phase, any reported AE that starts after withdrawal but within 30 days of their 
last dose will be included in the summaries for the Maintenance Phase. For subjects who 
enter the Extended Evaluation Phase, any reported AE that starts within 30 days after the 
last dose will be included in the summaries for the Extended Evaluation Phase. 
• N: Number of subjects in the population and dose group, regardless of the study phase. 
• Dose increase during the Maintenance Phase: is defined as any dose increase above the 
Therapeutic Dose the subject received at the beginning of the Maintenance Phase recorded 
in the Dose Adjustment electronic CRF (eCRF) page during the Maintenance Phase. If the 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 33 of 124 
BMSOP111/F2 
 
 
 
 
dose was reduced during the Maintenance Phase due to any reason and then increased to 
the Therapeutic Dose it is not considered as a dose increase.  
  STATISTICAL ASSUMPTIONS 
The primary analysis of the primary endpoint for this study will be the proportion of clinical 
responders (ie, a reduction in mean 24-hour UFC levels to ≤ULN) to COR-003 in the ITT population, 
following 6 months of dosing in the Maintenance Phase without a dose increase during that 
phase.  
As stated above, subjects who had a dose increase above the Therapeutic Dose at any time during 
the Maintenance Phase will be considered non-responders. 
Withdrawn subjects prior to the End of the Maintenance Phase visit assessment will be considered 
non-responders.  These include subjects in the ITT population who did not enter the Maintenance 
Phase (i.e., the DT population). All other subjects who have missing mean UFC at M6 [D180] for 
any other reason, including insufficient number of adequate samples, will also be considered non-
responders at M6 [D180]. 
Additionally, subjects who previously received radiation therapy and who exhibited no rebound 
increase in the first assessment of mean 24-hour UFC levels following withdrawal of COR-003 
immediately after the end of the Maintenance Phase (i.e. mean 24-hour UFC levels ≤ ULN) will be 
considered non-responders. For the subjects who previously received radiation therapy and 
achieved clinical response at the End of the Maintenance Phase, the first assessment of mean 24-
hour UFC levels following withdrawal of COR-003 immediately after the end of the Maintenance 
Phase will be calculated if there are at least two adequate 24-hour urine samples collected at least 
14 days after the end of the Maintenance Phase visit and before the drug intake is resumed. If 
there is only one adequate sample that qualifies for such a subject, then the mean 24-hour UFC 
levels will be missing and the subject will be considered a non-responder. If the subject  stopped 
the treatment intake for less than 14 days after the End of the Maintenance Phase visit and had 
at least two adequate 24-hour urine samples collected during that period so that the mean 24-
hour UFC levels was available for that subject, then the subject will be considered a responder if 
the mean 24-hour UFC levels > ULN (i.e. the subject rebounded in that period) and a non-
responder if the mean 24-hour UFC levels ≤ ULN (conservative approach). 
The proportion of responders in the ITT population will be estimated along with its corresponding 
two-sided 95% CI. The null hypothesis to be tested is if the proportion of responders at the end 
of the Maintenance Phase visit is at most 20% versus the alternative hypothesis that the 
proportion of responders at the end of the Maintenance Phase visit is greater than 20%; COR-003 
will be considered effective if the null hypothesis is rejected. The null hypothesis will be rejected 
if the lower bound of the two-sided CI is greater than 20%. The hypothesis test was planned to 
have 90% power with two-sided 5% Type I error, if the alternative response was 35%. 
Multiplicity adjustment: 
All secondary efficacy endpoints will be analyzed; however, statistical inferences for the 
secondary endpoints will be made only if the primary objective is met.  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 34 of 124 
BMSOP111/F2 
 
 
 
 
For each of the 8 CS comorbidities biomarkers (fasting glucose, Hb1Ac, SBP, DBP, total cholesterol, 
low and high density lipoprotein-associated cholesterol [LDL-C, HDL-C, respectively], and body 
weight), the primary analysis will be the analysis of the change from Baseline to the End of 
Maintenance Phase (Month 6 [Day 180]) visit (or to the last assessed visit of the Maintenance 
Phase). The formal statistical testing will only be performed for this primary analysis. The null 
hypothesis to be tested for each of the 8 CS comorbidities biomarkers is if the mean change from 
Baseline at the End of Maintenance Phase is at most 0 versus the alternative hypothesis that the 
mean change from Baseline is greater than 0.  Given there will be a total of 8 statistical tests, the 
statistical significance level will be adjusted using the Hochberg method [4], controlling the family-
wise error rate at 5%. 
Each of the other secondary efficacy endpoints will be analyzed using two-sided tests with an 
alpha level of 5%.  The type I error will not be adjusted for multiplicity testing of these other 
secondary endpoints.  
Some exploratory efficacy endpoints for the Extended Evaluation Phase will be analyzed through 
95% CI and/or statistical tests, but the resulting CIs and p-values will be used for descriptive 
purposes only; no statistical inferences will be made. 
Some safety endpoints will be analyzed using two-sided tests with a 5% alpha level. The tests are 
for safety signal detection rather than formal hypothesis testing; no statistical inferences will be 
made. Interpretation of safety results, when possible, will be made based on the pattern of results 
overall rather than individual assessment results. 
The protocol has been amended to define the visit windows to be used to determine the nominal 
visits (see Section 6.3). Data collected from the assessment(s) that are no longer collected 
following a protocol amendment will be listed rather than summarized. Data collected from new 
assessment(s) following protocol amendments will be listed, summarized and/or analyzed only 
for subjects who have been enrolled under that protocol amendment and subsequent 
amendments. 
 Imputation Rules 
Following ICH E9, the following imputation methods will be used.  
Under the Missing at Random (MAR) assumption, the longitudinal analyses provide an unbiased 
estimate of the treatment effect that would have been observed if all subjects had continued on 
treatment for the full study duration.  
5.6.1 
Urinary Free Cortisol Response and Urinary Free Cortisol Improvement 
Categorization  
See Section 6.7.2 for the definitions of UFC response and UFC improvement. UFC response is 
referred to as clinical response in the protocol. The term “clinical response” will still be used in 
the SAP and TFLs to refer to the primary efficacy endpoint, while the term “UFC response” will be 
used in the SAP and TFLs for the at-visit analysis.  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 35 of 124 
BMSOP111/F2 
 
 
 
 
UFC improvement is referred to as complete or partial response in the protocol. The term “UFC 
improvement” will be used in the SAP and TFLs instead. 
Analysis of data for specific visits in the Maintenance Phase will be performed using three 
different approaches to account for missing data during the Maintenance Phase. 
1. At-visit analysis considering dose increase (imputation scheme #1):  
a. For ITT subjects who did not enter the Maintenance Phase:  Such subjects will be 
considered non-responders and non-UFC-improvers at each visit in the 
Maintenance Phase. 
b. Subjects with a dose increase (see Section 6.4) during the Maintenance Phase will 
be considered non-responders and non-UFC-improvers for all Maintenance Phase 
visits after the dose increase. 
c. If mean 24-hour UFC levels are missing for reasons other than a) above,  UFC 
response and improvement will also be missing (i.e. no imputation). 
2. At-visit analysis regardless of dose increase (imputation scheme #2):  
a. For ITT subjects who did not enter the Maintenance Phase:  Such subjects will be 
considered non-responders and non-UFC-improvers at each visit in the 
Maintenance Phase. 
b. For subjects who entered the Maintenance Phase:  
i. If mean UFC is missing at only one visit in the Maintenance Phase: 
- If the mean UFC is missing at a visit Month X, which is before M6 
[D180], then the subject will be considered as a responder at Month X if 
the subject is also a responder/improver at the visit immediately before 
and the visit immediately after Month X. Otherwise, the subject will be 
considered as a non-responder/non-improver. 
- If the mean UFC is missing at M6 [D180], then the subject will be 
considered as a responder at M6 [D180] if the subject is also a responder 
at M5 [D150] and at the Month 9 visit. Otherwise, the subject will be 
considered as a non-responder (including the case where the mean UFC 
at the Month 9 visit is not available). 
ii. If mean UFC data are missing at more than one intermediate visit in the 
Maintenance Phase or the End of Maintenance Phase (Month 6 [Day 
180]): Missing assessments in the Maintenance Phase will be categorized 
as non-response/non-improvement. 
3. At-visit analysis using the worst-case approach (imputation scheme #3) 
a. The worst-case approach assumes that the subject will be systematically 
considered as a non-responder/non-improver at a given visit of the Maintenance 
Phase if mean UFC data is missing at that visit regardless of any other 
consideration (including the case of an ITT subject who did not enter the 
Maintenance Phase). 
The primary analysis for UFC response will be performed as described in Section 6.5. 
A first sensitivity analysis will be conducted with the imputation scheme #1.  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 36 of 124 
BMSOP111/F2 
 
 
 
 
A second sensitivity analysis will be conducted with the imputation scheme #2, i.e. where dose 
increase does not negate the response.  
Finally, a third sensitivity analysis using the worst-case approach (imputation scheme #3) will be 
conducted to assess the robustness of the results from the analyses based on the the imputation 
schemes #1 and #2. 
5.6.2 
Mean Urinary Free Cortisol and Cushing’s Syndrome Comorbidity Biomarkers 
Missing values at post-baseline assessments will not be replaced and will be regarded as missing 
in longitudinal analyses. The longitudinal model will account for missing data for the primary 
analysis. 
5.6.3 
Partial and Missing Dates 
The following rules will be used when imputing partial or missing dates for reporting purposes, 
such as defining in which study phase an AE started, or under which visit the Clinical Sign and 
Symptoms occurred. Imputed dates, unless otherwise specified, will not be presented in data 
listings. 
5.6.3.1 
Adverse Events / Clinical Signs and Symptoms of CS 
• The start and stop date will be imputed to determine if the event is treatment- 
emergent or not and to derive an imputed AE duration. Imputed AE durations,  
but not the imputed dates, will be displayed in listings. Imputed AE durations will 
be flagged in the listings.  
 
Imputation of Event Stop Dates 
• 
If the AE or Clinical Sign/Symptom of CS is not reported as resolved, or is 
reported as ongoing, or if the status is missing or reported as unknown, a stop 
date will not be imputed and the duration will not be calculated. 
• 
If the AE or sign/symptom is reported as resolved and: 
i. The stop date is completely missing, the stop date will be imputed as 
the date of the subsequent visit (i.e. the visit following the AE start date) 
or study completion date if the subject withdrew prior to a subsequent 
visit. 
ii. A partial stop date is recorded, and: (1) The stop day is missing and the 
month is recorded, the stop day will be imputed as the last day of the 
month; or  (2) The stop day is recorded and the month is missing, the 
stop month will be imputed as the month of the last attended visit;  or 
(3) The stop year is missing; the stop year will be imputed as the year of 
the last attended visit.  
• 
If the stop date is missing and the event lead to death, the stop date will be 
imputed as the date of death. The imputed event stop date in that instance will 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 37 of 124 
BMSOP111/F2 
 
 
 
 
be displayed in the listings. Any imputed date will be flagged as such in the 
listings. 
Imputation of Event Start Dates 
• 
If the start date is completely missing it will be imputed as the earliest date 
between the date of the 1st dose and the (imputed) stop date. If the (imputed) 
stop date occurs before the imputed start date then the (imputed) stop date will 
be changed to the imputed start date + 1 day. 
• 
If a partial start date is recorded and: (1) The start day is missing and the month 
is recorded, the start day will be imputed as the first day of the month or the 
first dose day if the month is the same as the month of the first dose; or (2) The 
start day is recorded and the month is missing, the start month will be imputed 
as month of the first dose; or (3) The start year is missing; the start year will be 
imputed as the year corresponding to the year of the first dose. 
5.6.3.2 
Prior, Continuing and New Medications  
They are considered to have started at the earliest relevant date and end at the      
latest relevant date.  
Table 6 displays some examples of date imputation (date format is DD-MMM-YYYY), missing day 
are listed with “- -“ and missing month with “- - -“. 
 
 
Table 6: Example of Partial and Missing Dates Imputation  
Data Type 
Start Date 
Imputed 
Start Date 
First 
Dose 
date 
Last 
Dose 
Date 
End Date 
Imputed 
End 
Date 
Prior/Concomi
tant Meds 
--FEB2012 
01FEB2012 
01JAN2012 
01MAR2012 
--FEB2012 
29FEB2012 
Prior/Concomi
tant Meds 
--FEB2012 
01FEB2012 
15FEB2012 
01MAR2012 
--MAR2012 
31MAR2012 
Prior/Concomi
tant Meds 
-----2012 
01JAN2012 
15FEB2012 
01MAR2012 
--FEB2012 
29FEB2012 
Prior/Concomi
tant Meds 
--FEB2012 
01FEB2012 
15FEB2012 
01MAR2012 
-----2012 
01MAR2012 
Adverse Event 
--FEB2012 
01FEB2012 
01JAN2012 
01MAR2012 
--FEB2012 
29FEB2012 
Adverse Event 
--FEB2012 
15FEB2012 
15FEB2012 
01MAR2012 
--MAR2012 
31MAR2012 
Adverse Event 
-----2012 
15FEB2012 
15FEB2012 
01MAR2012 
-----2012 
16MAR2012£ 
Adverse Event 
 
15FEB2012 
15FEB2012 
01MAR2012 
--MAR2012 
31MAR2012 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 38 of 124 
BMSOP111/F2 
 
 
 
 
Data Type 
Start Date 
Imputed 
Start Date 
First 
Dose 
date 
Last 
Dose 
Date 
End Date 
Imputed 
End 
Date 
Adverse Event 
--JAN2012 
01JAN2012 
15FEB2012 
01MAR2012 
 
01MAR2012* 
£ Subject discontinued on 16MAR2012; * Subject discontinued on 01MAR2012. 
5.6.3.3 
CS Diagnosis Date 
• 
If the day is missing but both the month and year are non-missing, then the 
missing day will be imputed the day 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 01 January. 
• 
If the date is completely missing, then it will not be imputed. 
 
  DERIVATION RULES 
5.7.1 
Urinary Free Cortisol 
When at least four 24-hours urine samples are to be collected to provide a robust estimate of the 
UFC, as at the final visit of the Maintenance Phase, the mean UFC will be derived from adequate 
24-hours urine samples only, as follow: 
• At least 2 samples must be adequate to derive the mean UFC from the resulting     
      measurements ([3]). 
•  If only 1 or no adequate 24-hour sample was collected, the mean UFC will not be     
reported and will be considered missing  for both categorization purposes and parametric 
analytic purposes. 
At visits when two 24-hour urine samples were to be collected for calculation of mean UFC: 
• If only 1 adequate sample was collected it will be used to represent the mean UFC for  
      that visit. 
• If no adequate 24-hour sample was collected, the mean UFC will not be reported and will  
      be considered missing. 
An adequate urine sample is defined as an adequate volume collected in 24-hours with an 
acceptable 24-hour creatinine excretion, i.e. the below criteria should be met to have an adequate 
sample collection. 
• Total volume of urine is at least 400 mL and less than or equal to 4000 mL per day. 
•  24-hour Creatinine Excretion (as provided by the central lab) is within the expected  
ranges or there is a superseding reason for the sample to be outside the expected range 
(see below for Medical interpretation rules). Table 7 shows the expected ranges used for 
this study. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 39 of 124 
BMSOP111/F2 
 
 
 
 
Table 7: Minimum 24-hours’ Creatinine Excretion to be Considered Adequate 
Gender 
Age (years) 
Minimum 24-hour Creatinine Excretion in Normal 
Population 
Male  
18 to 50 
18.5 mg/kg/day 
 
51 to 70 
15.7 mg/kg/day 
Female 
18 to 50 
16.5 mg/kg/day 
 
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. 
Prior to the End of Maintenance Phase database lock and again, prior to the final database lock, 
the Cmed or Cortendo Medical Monitor will review the urine collection data and determine which 
samples are not adequate using the following procedure. Using the database freeze data, Cmed 
will generate a listing of creatinine excretion and urine volume in an xlsx format. The listing (see 
Listing 16.2.10-1 of the SAP TFL shells) will include subject ID, visit, demographic and safety lab 
data, and a derived assessment of collection adequacy based strictly upon the volume and 24-
hour excretion criteria derived from a normal population (Table 7). The listing will not reveal any 
restricted data. The Cortendo Medical Monitor will then review the results and indicate (Yes/No) 
the adequacy of each sample based upon the above criteria for the subject population. The 
updated xlsx file will be imported in the analysis dataset, and the Medical Review of adequacy will 
be used to produce the final analysis. A copy of the updated xlsx file will be appended to the 
classification meeting minutes. A listing of differences between the programmatically derived 
sample adequacy and the Medical Review derived sample adequacy, by subject, will be generated 
(see Listing 16.2.10-2 of the SAP TFL shells). A sensitivity analysis of the primary endpoint will 
make use of the programmatically derived sample adequacy. 
5.7.2 
Efficacy Endpoints 
• UFC Response (also referred to as Clinical Response for the primary efficacy endpoint): 
The mean UFC will be determined at each visit from adequately collected samples (see 
Section 6.7.1 for definition of adequately collected samples) and then compared to the ULN.  
• 
UFC response will be met if the mean UFC is ≤ ULN.  The subject is considered a 
responder at a visit based solely on the UFC value (even if there is a dose increase 
prior to the UFC collection at that visit).  However, for purposes of the primary 
endpoint a subject is considered a responder only if this definition is met at the 
End of the Maintenance Phase and there is not a preceding dose increase 
(relative to the Therapeutic Dose) during the Maintenance Phase. 
• 
UFC response will not be met if the mean UFC is > ULN. The subject is considered 
a non-responder if this definition is met at the End of the Maintenance Phase. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 40 of 124 
BMSOP111/F2 
 
 
 
 
• 
UFC response will be imputed (as described in Section 6.6.1) if the mean UFC is 
missing for any reason, if the subject has withdrawn early, if there is a dose 
increase during the Maintenance Phase (always imputed as non-responder) or if 
there are not enough adequately collected samples.  
• UFC Improvement: The UFC will be determined at each visit from adequate samples. UFC 
improvement is defined as a ≥ 50% reduction from Baseline mean UFC at Months 1, 2, 3, 4, 
5, or 6 of the Maintenance Phase. If the UFC and/or Baseline UFC is missing, the UFC 
improvement will be set to missing.  UFC improvements are not categorized accounting for 
dose increases; however, UFC improvement will be imputed in the same manner as 
described above for UFC response. 
• Total hirsutism score: is the sum of all the scores obtained in each of the 9 locations. 
Total score can vary between 0 and 36. A high score means that the hirsutism is more visible.  
The total hirsutism score is applicable to females only and will therefore not be derived for 
males. If one location has a missing score, then the missing score will be imputed as the 
average of the non-missing scores for that location in the ITT population. If there are more 
than 25% of the locations (i.e. 3 or more locations out of 9) with a missing location score at 
a given time point, then the total score will be set to missing. 
• Total peripheral edema score: is the sum of all the scores obtained in each of the 3 
locations. Total score can vary 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. 
• QoL Questionnaire: The Cushing QoL questionnaire is a general questionnaire of 12 
items that assesses subject health-related quality of life. Answers to QoL are based on Likert 
scales with five response categories, rated on a scale of 1-5, where ‘1’ corresponds to 
‘Always’ or ‘Very much’ and ‘5’ to ‘Never’ or ‘Not at all’. Therefore, the lower the score, the 
lower the health-related quality of life (HRQoL). The total score for QoL is the sum of all the 
item responses and can range from 12 (worst score) to 60 points (best score). A standardized 
total score on a scale from 0 (worst HRQoL) to 100 (best HRQoL) will be calculated with the 
following formula: 
         Standardized total score = 
 
where ‘min’ is the minimum (min=12 if all 12 item responses are non-missing), and ‘max’ is   
the maximum possible score (max=60 if all 12 item responses are non-missing). 
If more than 3 items have a missing response, then the total score will be considered missing    
for that visit. The score can be interpreted (as above) if the number of unanswered items 
does not exceed 3 (25% of the questions). In this case, the standardized total score will have 
min = the number of item responses that are non-missing and max = 5 x the number of items 
responses that are non-missing. 
• Beck Depression Inventory II: This questionnaire comprises 21 questions with a score 
from 0 to 3. Scores for each question are summed to create an overall score. A score 
between 0 and 13 indicates minimal depression, 14 to 19 mild depression, 20 to 28  
100
min
max
min ×
−
−
TotalScore


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 41 of 124 
BMSOP111/F2 
 
 
 
 
moderate depression and 29 to 63 severe depression. Scoring information for the 21 
questions is in Appendix 15.4. If one question has a missing score, then the missing score will 
be imputed as the average of the non-missing scores for that question in the ITT population. 
If there are more than 25% of the locations (i.e. 6 or more questions out of 21) with a missing 
score at a given time point, then the total score will be set to missing. 
• Acne Visual Analog (VAS) Questionnaire: Each type of lesion is graded with a value 
depending on the severity: 0 - No Lesions, 1 - Greater than or equal to one comedone, 2 - 
Greater than or equal to one papule, 3 - Greater than or equal to one pustule, 4 - Greater 
than or equal to one nodule. Factor is dependent on the location of the lesion: 2 – Forehead, 
2- Right Cheek, 2- Left Cheek, 1 – Nose, 1 – Chin and 3- Chest and Upper Back.   
The score for each area (Local score) is calculated using the formula: 
Local score = Factor × Grade (0-4) 
The global score is the sum of local scores as follows: 
Global score = Sum (all local scores) 
If one area has a missing local score, then the missing local score will be imputed as the 
average of the non-missing local scores for that area in the ITT population. If there are more 
than 25% of the areas (i.e. 2 or more areas out of 6) with a missing local score at a given time 
point, then the global score will be set to missing. 
• Clinical Benefit: a subject with Clinical Benefit meeting all 4 criteria at any visit after 
completing Dose Titration (M1 and higher) as listed below: 
1. Mean UFC ≤ ULN, and 
2. No COR-003 dose increase relative to the Therapeutic Dose (prior to the nominal 
visit in the Maintenance Phase only), and 
3. A clinically meaningful improvement in any one Baseline CS comorbidity 
(diabetes, hypertension, hypercholesterolemia, weight) without confounding 
medication change, as described in the “Clinically meaningful improvement” 
bullet point later in this section, and 
4. No study drug-related (i.e. probable or definitely related as per the Investigator) 
TEAE classified as severe or worse. 
• Clinical Benefit regardless of dose increase: a subject with Clinical Benefit meeting all 3  
criteria listed below (see above description of Clinical Benefit for further details): 
1. UFC response as indicated by UFC ≤ ULN, and 
2. A clinically meaningful improvement in any one Baseline CS comorbidity 
(diabetes, hypertension, hypercholesterolemia, weight) without confounding 
medication change as described below, and  
3. No study drug-related TEAE classified as severe or worse. 
• Clinical Benefit with Partial UFC Normalization (i.e., UFC Improvement): a subject with 
partial Clinical Benefit  
meeting all 3 criteria listed below (see above description of Clinical Benefit for further 
details): 
1. UFC improvement as indicated by a ≥ 50% reduction from Baseline, and 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 42 of 124 
BMSOP111/F2 
 
 
 
 
2. A clinically meaningful improvement in any one Baseline CS comorbidity 
(diabetes, hypertension, hypercholesterolemia, weight) as described below but 
regardless of medication change, and 
3. No study drug related TEAE classified as severe or worse. 
• Clinically meaningful improvement: a subject with clinical meaningful improvement in a  
 comorbidity is one who meets at least one of the criteria listed below: 
1. Fasting glucose: relative decrease of at least 17.9% from Baseline and Baseline 
result above normal range AND also maintained stable doses of background 
anti-diabetic medications OR reduced the dose of background anti-diabetic 
medications OR permanently discontinued anti-diabetic medications OR if not 
treated with anti-diabetic medications at Baseline, not started on anti-diabetic 
medication at or prior to the nominal visit. 
2. Hb1Ac: an absolute decrease of 0.3 percentage units from Baseline and Baseline 
result outside of normal range AND also; maintained stable doses of background 
anti-diabetic medications OR reduced the dose of background anti-diabetic 
medications OR permanently discontinued anti-diabetic medications OR if not 
treated with anti-diabetic medications at Baseline, not started on anti-diabetic 
medication at or prior to the nominal visit. 
3. SBP, DBP:  an absolute decrease of 2 mmHg in either SBP or DBP among subjects 
with hypertension AND also; maintained stable doses of background 
antihypertensive medications OR reduced the dose of background 
antihypertensive medications OR permanently discontinued antihypertensive 
medications OR if not treated with antihypertensive medication at Baseline, not 
started on antihypertensive medication at or prior to the nominal visit. 
4. LDL-C:  a relative 24% decrease in LDL-C from Baseline and without a 
corresponding relative decrease in HDL-C of greater than 12%, where Baseline 
LDL-cholesterol result is outside of the normal range AND also; maintained 
stable doses of background cholesterol-lowering medications OR reduced dose 
of background cholesterol-lowering  medications OR permanently discontinued 
use of cholesterol-lowering medications OR if not treated with cholesterol-
lowering medication at Baseline, not started on cholesterol-lowering 
medication at or prior to the nominal visit. 
5. Body weight:  a relative decrease of at least 5% from Baseline, without addition 
of weight loss medication at or prior to the nominal visit. 
5.7.3 
Vital Signs and Abdominal Girth  
• Blood Pressure and Abdominal Girth: are collected in triplicate at each visit. The mean 
of the assessments will be calculated if there are at least two assessments and used in the 
summary tables.  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 43 of 124 
BMSOP111/F2 
 
 
 
 
5.7.4 
Study Day 
• Study Day: is calculated using the start date of assessment, blood draw or specimen 
collection. Study day is derived from the date of first dose of study drug intake for the Dose 
Titration Phase: 
1. If date of assessment is before the date of first dose: Study Day = [Start Date of 
Assessment – Date of First Dose of Study Drug],  
2. If date of assessment is after the date of first dose: Study Day = [Start Date of 
Assessment – Date of First Dose of Study Drug + 1],  
3. If date of assessment is the same as the date of first dose: Study Day = 1,  
4. If the first dose was never given the study day will be missing. 
6 Analysis Sets 
The following populations will be considered in the data analysis: 
All Subjects 
This population is used for all data listings and selected data summaries. This includes all subjects 
enrolled into the study, defined as having signed an informed-consent form, regardless of 
whether or not they received the study drug. Subjects who did not receive study drug were 
considered screen failures; screen failures are summarized only in the summaries of subject 
disposition and analysis population.  
Intent-to-Treat (ITT) Population 
The ITT population will include all subjects who receive at least one dose of COR-003. The ITT is 
the primary population and will be used for the evaluation of efficacy and all safety analyses. 
Subjects will be summarized as follows for by-visit tabulations: 
• For the Dose Titration Phase, subjects will be summarized under the different doses they  
      received during that period (see Section 6.2).  
• For the Maintenance Phase, subjects will be summarized  
      based on their Therapeutic Dose (i.e. the dose they received on the date they entered      
      the Maintenance Phase), regardless of any dose changes. 
• 
For the Extended Evaluation Phase, subjects will be summarized under the most recent 
dose level received. 
For the Baseline characteristics and demographics, AEs (including Clinical Signs and Symptoms of 
CS) and Medications, summaries by dose group will be based on the Therapeutic Dose.   
Dose Titration (DT) Population 
The DT population will consist of all ITT subjects who entered the Dose Titration Phase but did not 
start the Maintenance Phase. This population, which is not pre-specified in the protocol, will be 
used for supportive evaluations of Baseline characteristics, selected efficacy, adverse events and 
safety laboratory outputs. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 44 of 124 
BMSOP111/F2 
 
 
 
 
Maintenance (M) Population 
The M population will consist of all ITT subjects who entered the Maintenance Phase and 
completed visit M1 (D1). This population will be used for supportive evaluations of Baseline 
characteristics and the primary and selected other efficacy endpoints during the Maintenance 
Phase. 
Maintenance-Completer (MC) Population 
The MC population will consist of all ITT subjects who entered the Maintenance Phase and 
completed the End of Maintenance Phase (Month 6 [Day 180]) visit. This population, which is not 
pre-specified in the protocol, will be used for supportive evaluations of Baseline characteristics, 
study drug exposure and compliance, the primary efficacy endoint, all secondary efficacy 
endpoints and ACTH during the Maintenance Phase. 
Per Protocol (PP) Population 
The PP population will consist of all ITT subjects who entered and completed the Maintenance 
Phase of the study and had no major protocol deviations that may affect the primary efficacy 
assessment (see Section 8.1). This population will be used for supportive evaluations of study drug 
exposure and compliance, the primary efficacy endpoint and the secondary endpoints of UFC 
response and/or improvement rates by visit during the Maintenance Phase.  
Pharmacokinetic (PK) population 
The PK population may include all ITT subjects with at least one available valid (i.e. not flagged for 
exclusion) PK concentration measurement. The definitive description of the PK population will be 
provided in a separate population PK/PD analysis plan. 
Pharmacodynamic (PD) population 
The PD population may include all ITT subjects with at least one adequately collected 24-hour 
urine sample for UFC. The definitive description of the PD population will be provided in a 
separate population PK/PD analysis plan. 
Table 8 below describes which analysis population will be used for the different analyses 
considered in this SAP. Detailed information regarding each analysis and the analysis populations 
used is given in Section 8.      
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 45 of 124 
BMSOP111/F2 
 
 
 
 
Table 8: Analysis populations broken down by analysis type 
Analysis Type   
Population 
All 
ITT 
DT 
M 
MC 
PP 
PK 
PD 
Summary of Subject Disposition 
X 
X 
 
 
 
 
 
 
Summary of Analysis Populations 
X 
 
 
 
 
 
 
 
Summary of Demographics and Baseline Characteristics 
 
X 
X 
X 
X 
X 
 
 
Summary of Protocol Deviations Leading to Exclusion from the PP Population 
 
X 
 
 
 
 
 
 
Summary of Medical History  
 
X 
X 
 
X 
 
 
 
Summary of Disease Characteristics 
 
X 
X 
 
X 
 
 
 
Summaries of Prior, New and Continuing Medications  
 
X 
 
 
 
 
 
 
Summaries of Prior CS Drug Therapy, Radiotherapy and Surgery  
 
X 
 
 
 
 
 
 
Study Drug Exposure and Compliance 
 
X 
 
 
X 
X 
 
 
Primary Analysis of UFC Response (ie, Clinical Response after 6 Months of 
Maintenance Treatment) 
 
X 
 
X 
X 
X 
 
 
Other Analyses of UFC Response and/or Improvement 
 
X 
 
X 
X 
X 
 
 
Summaries and plots of UFC Response and/or Improvement by Visit (and/or 
Dose, if applicable) 
 
X 
X* 
X* 
X 
X* 
 
 
Summaries of UFC values by Visit (and/or Dose, if applicable) 
 
X 
 
 
X 
 
 
 
Individual Plots of Change from Baseline to End of Maintenance Phase in UFC  
 
 
 
 
X 
 
 
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 46 of 124 
BMSOP111/F2 
 
 
 
 
Analysis Type   
Population 
All 
ITT 
DT 
M 
MC 
PP 
PK 
PD 
Plots of Effect of Dose Increases During the Maintenance Phase of UFC  
 
 
 
 
X 
 
 
 
Summaries of Serum and LNSC 
 
X 
 
 
X 
 
 
 
Summaries and Plots of LNSC Normalisation  
 
X 
 
 
X 
 
 
 
Summaries and plots of CS Comorbidities Biomarkers  
 
X 
 
 
X 
 
 
 
Analyses of Change from Baseline in CS Comorbidities Biomarkers  
 
X 
 
 
X 
 
 
 
Summaries and plots of Clinical Signs and Symptoms of CS 
 
X 
 
 
X 
 
 
 
Summaries of Cushing QoL Total Score  
 
X 
 
 
X 
 
 
 
Summaries of Total BDI-II Score  
 
X 
 
 
X 
 
 
 
Summaries of OGTT  and Spot Albumin/Creatinine Ratio 
 
X 
 
 
X 
 
 
 
Summaries of Clinical Benefit Rate  
 
X 
 
 
 
 
 
 
Summaries of changes to Antihypertensive, Anti-diabetic, Cholesterol-lowering 
Medications  
 
X 
 
 
 
 
 
 
Shift Tables of Visible Signs of Hypercortisolism from Photograph Scores  
 
X 
 
 
 
 
 
 
Summaries of within Visit Variability for Applicable Efficacy Parameters 
 
X 
 
 
 
 
 
 
Summaries of Diabetes Mellitus, Hypertensiion,  Hypercholesterolaemia and 
Obesity Responders  
 
X 
 
 
 
 
 
 
Summaries of AEs  
 
X 
X^ 
 
 
 
 
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 47 of 124 
BMSOP111/F2 
 
 
 
 
Analysis Type   
Population 
All 
ITT 
DT 
M 
MC 
PP 
PK 
PD 
Summary Statistics and Box-and-whisker plots of Absolute Clinical Laboratory 
Results 
 
X 
X^ 
 
 
 
 
 
Summaries of Change from Baseline in Clinical Laboratory Assessments 
 
X 
 
 
 
 
 
 
Shift Tables and all other Plots of Clinical Laboratory Assessments  
 
X 
X^ 
 
 
 
 
 
Summaries of Abnormal Spot Albumin to Creatinine Ratio  
 
X 
 
 
 
 
 
 
Summaries of Hormones and Biomarkers Laboratory Evaluations  
 
X 
 
 
 
 
 
 
Summaries of ACTH  
 
X 
X 
 
X 
 
 
 
Summaries and Plots of Vital Signs 
 
X 
 
 
 
 
 
 
Summaries and Plots of ECG Parameters 
 
X 
X^ 
 
 
 
 
 
Summaries of Tumor Size and Tumor Volume 
 
X 
 
 
 
 
 
 
Data listings 
X 
 
 
 
 
 
 
 
* Selected summaries only, see Section 8.8 for further details 
^ Selected Summaries only, see Section 8.11 for further details.  
Note: There are no entries under the PK and PD columns, since the population PK and PD endpoints and planned analyses will be described in a 
separate population PK/PD analysis plan. 
 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 48 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
7 Methods of Analyses and Presentations 
 PROTOCOL DEVIATIONS  
Protocol deviations are departures from the protocol. Protocol deviations may be identified from 
different sources and methods such as algorithmic queries or medical reviews of the clinical 
database, Clinical Research Associate (CRA) monitoring notes, audits, etc.  
Protocol deviation criteria are defined and documented separately from this SAP in the protocol 
deviation criteria form (PDCF). Protocol deviations that should lead to exclusion from one or more 
of the analysis populations, including the PP population, are also indicated in the PDCF. 
Protocol deviations thus identified will be manually reviewed during a classification meeting that 
will be held prior to the Maintenance Phase database lock. The PP population will be finalized 
following this meeting.  Protocol deviations leading to exclusion from the PP population will be 
termed as major protocol violations and summarized by dose group and for All dose groups 
combined. A second classification meeting will be held prior to the Extended Evaluation Phase 
database lock, but none of the protocol deviations during this Phase will lead to exclusion from 
the PP population.  
All subjects with protocol deviations impacting the Clinical Study Report and/or data integrity will 
be listed, including protocol deviations leading to exclusion from the PP population. 
 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and Baseline characteristics (age, sex, race, ethnicity, height, weight, BMI, child 
bearing potential if female (Yes [Y]/No [N]), work night shift or alternate work/sleep schedule 
(Y/N), diagnosis of CD (Y/N), diagnosis of diabetes (Y/N), diagnosis of impaired fasting glucose 
without diabetes (Y/N), diagnosis of hypertension (Y/N)) will be summarized for all subjects in the 
ITT, DT, M, MC and PP populations, and the summary will be performed by dose group and for All 
dose groups combined.  
Diagnosis of CD, diagnosis of diabetes, and diagnosis of hypertension will be based on the 
presence (Y/N) of the condition as recorded in the Diagnosis and History of CS eCRF. Diagnosis of 
impaired fasting glucose without diabetes (i.e., prediabetes) will be based on the response (Y/N) 
to the question “Is subject pre-diabetic?” in the OGTT eCRF at Baseline. 
 MEDICAL HISTORY AND DISEASE CHARACTERISTICS 
Medical history and disease characteristics will be summarized for all subjects in the ITT, DT and 
MC populations by dose group and for All dose groups combined.   
Medical history, CS history, CS diagnosis and associated laboratory values as well as CS prior 
medical treatments, prior radiotherapies and prior surgeries will be listed for all subjects. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 49 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
the version provided in the corresponding table and listing footnotes, and tabulated by System 
Organ Class and Preferred Term.  
The following disease characteristics will be summarized:  
• Disease etiology: CD, Adrenal-dependent CS (includes adenomas and  
hyperplasia), Ectopic ACTH secretion, Ectopic corticotropin-releasing hormone [CRH] 
secretion, Etiology unknown, 
• Time since CS diagnosis (months) (calculated relative to the date of first dose of COR- 
  003).  
• Associated Metabolic Complications: Diabetes mellitus, hypertension,  
      hypercholesterolemia, osteoporosis, and reproductive dysfunction), Others, 
• Duration of associated medical complications, 
• Receiving medication (Yes, No) for associated medical complications,  
• Prior medication (Yes, No) for management of CS, 
• Prior radiotherapy (Yes , No) for management of CS (pituitary, adrenal other), 
• Prior surgery (Yes, No) for management of CS,  
• Locations of prior radiotherapies (pituitary, adrenal, other) for management of CS, 
• Number of prior surgeries (1, 2, 3 and > 3) for management of CS, 
• Treatment naive (Yes, No) for management of CS (treatment naive means the subject has  
      not received either prior medication or prior radiotherapy and has not had 
      surgery),  
• Baseline Mean UFC from adequate 24-hour urine samples.  
 SUBJECT DISPOSITION  
A summary of subject disposition will be presented, showing the number and percentage of 
subjects treated, as well as the number and percentage of subjects who completed each study 
phase or withdrew from the study for the ITT population, alongside the primary reason for 
discontinuation. For the Dose Titration Phase, the subjects treated will be counted in two ways - 
under any dose they received and under the last dose they received (i.e. two rows of treated 
subjects will be displayed in the summary). The summary will be presented for all subjects, by the 
last dose level at the time of discontinuation or completion for the Dose Titration Phase and 
Extension Evaluation Phase (see Section 6.2), and by dose group for the Maintenance Phase. 
Information on analysis populations, study phase completion and discontinuation will also be 
displayed in subject listings.  
For the primary reason for discontinuation, the reasons “Adverse event”, “QTcF interval 
prolongation” and “Liver function test” will be combined in the disposition table into a single 
category of “Adverse event”. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 50 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Completion/ongoing/discontinuation status from each phase will be derived from the Treatment 
Completion Phase eCRF. A subject listing will be provided and will include the protocol 
amendment under which the subject was enrolled. 
  PRIOR AND CONCOMITANT MEDICATIONS 
Medications will be coded using the WHO-DRUG dictionary; the version will be provided in the 
corresponding table  and  listing footnotes. The medications, depending on when they started and 
stopped relative to the date of first dose of COR-003, will be classified in the following categories: 
• 
Prior Medication: Any medication that stopped before the date of the first dose of study 
drug. 
• 
Continuing Medication: Any medication that started before the date of the first dose of 
study drug and stopped on or is ongoing after the date of the first dose of study drug.  
• 
New Medication: Any medication that started on or after the date of the first dose of 
study drug. 
• 
New medications and continuing medications will be classified further by when they were 
used relative to each study phase.   
• 
Continuing Medication by phase: Any medication that started before the date of the first 
visit of each study phase, and stopped on or is ongoing after the date of the first visit of 
the study phase. 
• 
New Medication by phase: Any medication that started on or after the date of the first 
visit of the study phase and before the first visit of the next phase.    
Note: In case of partial or missing start and stop dates, imputation examples and rules detailed in 
Table 6 and Section 6.6.3 will be used. 
All summaries below will be presented for the ITT population. 
All medications (including, separately for each, medications for management of CS, anti-diabetic 
medications, antihypertensive medications and cholesterol-lowering medications) will be 
summarized, at a minimum, by therapeutic class and by study phase. Listings will be generated 
that also include preferred terms.  
New medications summaries will be presented by study phase. New medications started during 
the Dose Titration or the Extended Evaluation Phase will be summarized under the most recent 
dose level received. New medications started during the Maintenance Phase will be summarized 
at the Therapeutic Dose. New medications will only be counted in the phase when the medication 
was started, e.g. if a new medication is started in the Dose Titration Phase and continued into the 
Maintenance Phase it is only counted under the Dose Titration Phase.   
For summaries of prior and continuing medications for the ITT population across all 3 phases 
combined, summaries by COR-003 dose level will use the dose level received during the 
Maintenance Phase (ie, the Therapeutic Dose). Subjects in the ITT population who did not reach 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 51 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
the Maintenance Phase will be summarized under the last COR-003 dose level received in the 
Dose Titration Phase.  
A medication will be counted only once under a therapeutic class, and where applicable, only once 
under a preferred term within a therapeutic class.  
Separate subject data listings will be provided for the following categories. In addition, prior, 
continuing and new medications will be flagged within each listing. 
• 
Medications used for the management of CS, 
• 
Anti-diabetic medications, 
• 
Antihypertensive medications, 
• 
Cholesterol-lowering medications,  
• 
Other medications  
 PRIOR CUSHING’S SYNDROME THERAPY 
Prior CS therapies will be summarized for the ITT population. All summaries will be prepared for 
each dose group and for All dose groups combined. 
7.6.1 
Prior Cushing’s Syndrome Drug Therapy 
A summary of the prior medications used for management of CS will be provided by therapeutic 
class, preferred term and for each dose group and for All dose groups combined (See Section 8.5). 
The total estimated duration of each preferred term will be calculated as the number of unique 
days the drug was taken. (e.g. each unique period of drug use will be counted, any overlapping 
periods will be counted only once). The total estimated duration will be summarized by dose 
group and for All dose groups combined. 
Under each CS drug therapy preferred term, the number and percent of subjects taking each dose 
of CS drug therapy at the time of enrollment will be presented. For dose categories within a 
preferred term, the total estimated duration as defined above will be listed. 
7.6.2 
Prior Radiotherapy for Cushing’s Syndrome  
The number and percent of subjects who received prior radiotherapy for CS will be summarized. 
Summaries will be presented for the following: 
• 
Location (pituary, adrenal gland, other). 
• 
Time since end of radiotherapy (date of first dose of COR-003  - end of radiotherapy date). 
• 
Duration of radiotherapy (end of radiotherapy date – start of radiotherapy date +1). 
• 
Cumulative dose. 
All radiotherapy data (including type and outcome) will be listed. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 52 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
7.6.3 
Prior Surgery for Cushing’s Syndrome 
The number and percent of subjects who received prior surgery for CS and the procedure they 
received will be presented. The estimated time since surgery data will be summarized by location 
of surgery, surgical procedure and overall. 
  STUDY DRUG EXPOSURE AND/OR COMPLIANCE 
Days on study drug, study drug compliance and average daily dose will be summarized by study 
phase (Dose Titration Phase, Maintenance Phase and Extended Evaluation Phase), by visit (for the 
Maintenance and Extended Evaluation Phases), by dose group and for All dose groups combined 
for the ITT, MC, and PP Populations. The cumulative dose will also be summarized for the 
Maintenance and Extended Evaluation Phases only. 
For the Dose Titration Phase and the Extended Evaluation Phase, subjects will be summarized 
under each dose level they received, and for a given dose level only data related to that dose will 
be taken into account to derive the days on study drug, study drug compliance and average daily 
dose for both phases and cumulative dose for the Extended Evaluation Phase.   
The occurrence and timing of dose interruptions, dose reductions and dose increases will be 
listed, and the incidence of subjects with dose unchanged, decreased and increased between 
visits will be summarized by study phase (for the Maintenance and Extended Evaluation Phases 
only), by dose group and for All dose groups combined. 
7.7.1 
Study Drug Exposure 
The overall days on study drug by study phase is defined as the number of days between the first 
dose given at the start of the phase and the last dose taken at the end of the phase + 1 day. The 
following convention will be used: 
• 
Start of Dose Titration Phase: date of first dose 
• 
End of Dose Titration Phase: last dose date (for subjects who discontinued before the 
Maintenance Phase) or date of drug returned at M1 (D1) visit. 
• 
Start of the Maintenance Phase: date of drug dispensed for M1 (D1) visit  
• 
End of the Maintenance Phase: last dose date on study completion page for Maintenance 
Phase 
• 
Start of Extended Evaluation Phase: last dose date on study completion page for 
Maintenance Phase 
• 
End of Extended Evaluation Phase: last dose date on study completion page for Extended 
Evaluation Phase.  
The days on study drug in each visit i in the Maintenance and Extended Evaluation Phases is 
defined as the number of days between the date the study drug was returned at visit i+1 and the 
date the study drug was dispensed at visit i, + 1 day. If a subject discontinued at visit i+1, then the 
last dose date of study drug will be used rather than the date the study drug was returned.  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 53 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Subjects who do not return the study drug at visit i+1 will not included in the summaries for visit 
i. 
In addition overall study drug exposure acoss the entire study will be calculated and summarized 
for all subjects combined (i.e. regardless of dose) as the time between first dose and last dose + 1 
day, regardless of the study phase.  The overall study drug exposure for the combined 
Maintenance and Extended Evaluation Phases will be calculated and summarized by Therapeutic 
Dose. 
7.7.2 
Compliance  
Compliance by subject is calculated in a visit (or study phase) as follows: 
( )
100
(mg)
 
expected
 
dose
 
Cumulative
(mg)
 
received
 
dose
 
Cumulative
%
 
Compliance
×






=
 
For any dose level the cumulative expected dose for visit i is calculated as the following: 
(
)
(
) (
)1
dispensed
 
 tablets
Date
returned
 
 tablets
Date
150
1
DL
 
(mg)
 
expected
 
dose
 
Cumulative
1
+
−
×
×
+
=
+
i
i
i
 
Where DL is the numeric dose level for the treatment period.  
For visits during the Maintenance Phase, DL is the planned dose level at the beginning of the 
Maintenance Phase.  
The cumulative dose received for visit i is the calculated as the following: 
(
) 150
lost
 
 tablets
of
Number 
returned
 
 tablets
of
Number 
dispensed
 
 tables
of
Number 
 
(mg)
 
received
 
dose
 
Cumulative
1
1
×
+
−
=
+
+
i
i
i
i
 
For a study phase, the cumulative dose received is the sum of the cumulative dose received for 
all the visits within the given study phase. Similarly the cumulative dose expected for a study 
phase is the sum of the cumulative dose expected for all the visits within the given study phase.  
The following rules will be applied when determining the compliance: 
•    If the number of tablets returned is missing at a visit i+1, then the reconciliation will be    
  done  at the next visit when the number of tablets returned is available. In such a case,        
  the compliance at visit i cannot be calculated, however. 
•   If the number of tablets returned is never available, the compliance will not be  
      calculated.  
• If the number of tablets lost is missing it will be assumed to be 0. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 54 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Compliance will be summarized using descriptive statistics, and the number (%) of subjects with 
compliance < 80 %, between 80% and 120% and > 120% will also be reported by study phase and 
dose level.  
For the Dose Titration Phase compliance will be summarized under the relative dose, compliance 
for the entire Dose Titration Phase will be summarized under All dose groups.  
For the Maintenance Phase compliance will be summarized by visit and overall under the dose 
level received at the beginning of the Maintenance Phase.  
For the Extended Evaluation Phase compliance will be summarized by visit under the relative dose 
group. The overall compliance during the Extended Evaluation Phase will be summarized under 
All dose groups.   
7.7.3 
Average Daily Dose 
The average daily dose for each study phase, dose level and visit (for the Maintenance and 
Extended Evaluation Phases only) will be derived as the cumulative dose received divided by the 
number of days on study drug for the considered period. Also, the average daily dose level will be 
calculated across all doses for each phase and for the entire study duration.  
If the dose level changes between visits during the Dose Titration Phase or the Extended 
Evaluation Phase, the average daily dose will be assigned to more than one dose level for the 
interval as follows:  the sum of the cumulative dose received during the visit interval will be 
divided by the number of days in the visit interval on study drug at each dose level. For the 
Maintenance Phase, the average daily dose will only be summarized under the dose level assigned 
at the beginning of the phase. 
 EFFICACY DATA ENDPOINTS AND ANALYSES  
7.8.1 
Primary Efficacy Endpoint and Analyses 
For the primary efficacy analysis, UFC response to COR-003 is defined as a reduction in mean 24-
hour UFC levels to ≤ ULN following 6 months of Maintenance Phase therapy without dose 
increase.  
Analysis Method 
The proportion of responders at the End of Maintenance Phase visit, following 6 months of 
treatment in the Maintenance Phase, for All dose groups combined will be estimated using a 
generalized linear model with repeated measurements and with region (US vs. non-US), 
concurrent CS medical conditions (diabetes [Yes/No], hypertension [Yes/No]), age (rounded 
median split based on the ITT population), sex, disease duration (years), prior CS medication 
(Yes/No), prior radiation therapy (Yes/No) as Baseline covariates and visit as an independent 
factor. Prior CS medication and prior radiation therapy will be based on the response (Y/N) as 
recorded in the Diagnosis and History of CS eCRF. Region (US vs. non-US) was not a pre-specified 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 55 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
effect in the longitudinal models that were pre-specified in the protocol, but it has been added to 
the model to adjust for possible regional differences in efficacy. All repeated measurement 
models that will be utilized to analyze the primary and secondary efficacy endpoints will include 
visits from the Maintenance Phase only  (i.e. from M1 [D1] (if applicable) or M1 [D30] to M6 [D180] 
only). 
The least squares mean (LSMEAN) estimate of the UFC response after 6 months of treatment in 
the Maintenance Phase alongside its 95% Wald CI will be presented as well as the associated 
standard error. P-values for each parameter of the model from the Type III tests of fixed effects 
will also be presented. Only assessments performed during the Maintenance Phase (excluding all 
follow-up assessments) will be included in the analysis as per the rules described in Section 6.1 
(visit window). 
Estimation will be performed based on a generalized linear model with  repeated measurements 
with a logit link using SAS® PROC GLIMMIX with LSMEANS. The ILINK option will be used to obtain 
the estimated proportions. An unstructured covariance matrix will be selected for the repeated 
measure covariance.  For any repeated measurements model utilized in an analysis, if the 
unstructured covariance matrix results in non-convergence of the model, other covariance 
structures will be explored by use of Akaike’s information criteria. If the model still does not 
converge, the model will be simplified by keeping only the covariates/effects that have Type III 
tests of fixed effects p-values ≤ 0.35. 
Primary analysis 
The primary analysis will be based on the ITT population. As described in Section 6.5, subjects 
who: a) withdrew prior to the end of the Maintenance Phase, including those in the DT population, 
or b) have a dose increase (relative to their Therapeutic Dose) during the Maintenance Phase or 
c) previously received radiation therapy and exhibited no rebound increase in mean UFC following 
withdrawal of COR-003 immediately after the end of the Maintenance Phase will be imputed as 
non-responders.  Subjects in the DT population will be considered as non-responders at each visit 
(i.e. from M1 [D30] to M6 [D180]) in the Maintenance Phase. Subjects who entered the 
Maintenance Phase but withdrew prior to the End of the Maintenance Phase will be considered 
as non-responders at each visit in the Maintenance Phase after their withdrawal. Subjects with a 
dose increase (relative to their Therapeutic Dose) during the Maintenance Phase will be 
considered as non-responders at each visit in the Maintenance Phase after the dose increase. 
Subjects who previously received radiation therapy and exhibited no rebound increase in mean 
UFC following  mean UFC following withdrawal of COR-003 immediately after the end of the 
Maintenance Phase will be considered as non-responders at M6 [D180] only. All other subjects 
who have missing mean UFC at M6 [D180] for any other reason, including insufficient number of 
adequate samples, will also be considered non-responders at M6 [D180]. 
A supportive analysis that does not require statistical modeling will also be performed by 
calculating a Clopper-Pearson two-sided 95% CI for the one-sample binomial proportion. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 56 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
The analysis of the primary efficacy endpoint will also be performed on the M, MC, and PP 
populations. 
 
Sensitivity analyses for primary analysis 
Three supportive analyses will be run using the first, second and third imputation methods 
described in Section 6.6.1. Analyses results from the M and MC populations with each of the three 
imputation schemes will also be presented to support the primary analysis conclusions. 
In addition, to assess the impact of the protocol deviations on the study results, the same analysis 
will be repeated on the PP population using each of the three imputation schemes.    
P-values for each parameter of the model from the Type III tests of fixed effects will also be 
presented. Only assessments flagged for analysis, collected at a nominal visit (see Section 6.3) 
during the Maintenance Phase (excluding follow-up assessments) will be included in the analysis. 
A supportive analysis that does not require statistical modeling will also be performed by 
calculating a Clopper-Pearson two-sided 95% CI for the one-sample binomial proportion. 
7.8.2 
Secondary Efficacy Endpoints and Analyses 
All secondary efficacy endpoints are assessments of outcomes during the Maintenance Phase of 
the study. In general, however, descriptive summaries will also be presented in the Dose Titration 
Phase across All Visits by dose group and All dose groups combined for endpoints that were also 
planned to be assessed during the Dose Titration Phase. In descriptions of some of the graphical 
presentations, however, it will be stated that the graphs will be produced not just for the 
Maintenance Phase but for the Extended Evaluation Phase as well. 
7.8.2.1 
CS Comorbidities Biomarkers 
Eight CS comorbidities biomarkers (fasting glucose, HbA1c, SBP, DBP, total cholesterol, LDL-C, 
HDL-C, body weight) are identified in Section 4.2.  In addition, CRP, BMI and abdominal girth are 
also considered as CS comorbidities biomarkers. It should be noted that change from Baseline in 
CRP during the Maintenance Phase is already identified as a secondary efficacy endpoint in 
Section 4.2.    
The data for the 11 CS comorbidities biomarkers will be summarized and analyzed for the ITT 
population and, where specified in Table 8, the MC population. 
The statistical model for the End of Maintenance Phase will include only the visits during the 
Maintenance Phase. For HbA1c and  abdominal girth, the scheduled visits in the Maintenance 
Phase are M1 [D1], M3 [D90], and M6 [D180]. For all other CS comorbidities biomarkers, the 
scheduled visits are all the visits in the Maintenance Phase listed in Table 5. No imputation for 
missing data beyond that embedded within the analysis method (repeated measures model) will 
be made. To account for the multiplicity of statistical tests on the CS comorbidities biomarkers 
primary endpoints, a Hochberg method will be applied for the adjustment of the statistical 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 57 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
significance level for the 8 CS comorbidities biomarkers that were pre-specified in the protocol 
(see further details in Section 6.5). 
For each of the 11 CS comorbidities biomarkers (fasting glucose, HbA1c, SBP, DBP, total 
cholesterol, LDL-C, HDL-C, body weight, abdominal girth, CRP and BMI), the following summaries, 
analyses and graphics will be provided.  All data will be presented in subject listings. 
Statistical Summaries and Univariate Tests 
The CS comorbidities biomarkers results, including baseline, change from Baseline and percentage 
change from Baseline will be summarized by study phase, visit and/or dose group and for All dose 
groups combined. 
Wilcoxon signed rank tests comparing the Baseline results to each post-baseline visit will be 
performed by dose group and for All dose groups combined. The median difference between 
Baseline and post-baseline results and its associated distribution-free 99% CI, using the Hahn and 
Meeker method [5], and two-sided p-value from the Wilcoxon signed rank test will be displayed. 
The Wilcoxon signed rank tests will be performed and the 99% CIs will be obtained using SAS® 
PROC UNIVARIATE. The results of these tests are for descriptive purposes only and are supportive 
to the results from the first longitudinal analysis described below. In general, due to the small 
sample sizes, results by dose group from univariate tests may not show nominal significance. 
Longitudinal Analyses 
Changes and percent changes from Baseline will be presented for the  Maintenance Phase in All 
dose groups combined and will each be estimated using a generalized linear model with repeated 
measurements for nominal visit (M1 [D30] to M6 [D180]) and with region (US vs. non-US), 
concurrent CS medical conditions (diabetes [Yes/No], hypertension [Yes/No]), age (rounded 
median split), sex, disease duration (years), prior CS therapy (Yes/No), prior radiation therapy 
(Yes/No) and the corresponding Baseline CS comorbidity biomarker result as Baseline covariates, 
visit as an independent factor, and subject as a random effect. The Baseline CS comorbidity 
biomarker result was not a pre-specified covariate in the model described in the protocol, but it 
has been included in the model to adjust for the possible effect of the Baseline values on the 
magnitudes of the changes from Baseline. 
Estimation will be performed using SAS® PROC MIXED with LSMEANS and REPEATED statement. 
An unstructured covariance matrix will be selected for the repeated measure analysis. 
The LSMEAN estimate of the change from Baseline in each CS comorbidities biomarker at each 
post-baseline visit alongside its two-sided 99% CI will be presented with the associated standard 
error and two-sided p-value.  The p-values corresponding to the End of the Maintenance Phase 
visit (Month 6 [Day 180]) will be assessed for statistical significance using the Hochberg method 
at a family-wise error rate of 0.05. The 99% CIs are considered as supportive results. 
Two-sided p-values for each parameter of the model from the Type III tests of fixed effects will 
also be presented.  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 58 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
A separate longitudinal model for the changes from Baseline will be provided with the time trend 
p-value presented. The results from this separate longitudinal model will be supportive to the 
results from the first longitudinal model described above. The change from Baseline in All dose 
groups combined will be estimated using a generalized linear model with repeated measurement 
(study day [from date of first dose]) and with region (US vs. non-US), concurrent CS medical 
conditions (diabetes [Yes/No], hypertension [Yes/No]), age (rounded median split), sex, disease 
duration (years), prior CS therapy (Yes/No), prior radiation therapy (Yes/No), Baseline CS 
comorbidity biomarker result as Baseline covariates, study day as an independent factor, and 
subject as a random effect.   
Estimation will be performed using SAS® PROC MIXED with LSMEANS and REPEATED statement. 
An unstructured covariance matrix will be selected for the repeated measure analysis. 
P-values for each parameter of the model from the Type III tests of fixed effects will also be 
presented. All assessments (including unscheduled / repeat assessments) performed during the 
Maintenance Phase (excluding follow-up assessments) will be included in the analysis. 
Incidence of Abnormal Values and Shifts from Baseline  
Incidence of abnormal results (i.e. outside of the normal range) for fasting glucose, HbA1c, total 
cholesterol, LDL-C, HDL-C, and CRP will be summarized for each study phase by visit and by dose 
group and for All dose groups combined.  
Shifts from Baseline from the normal range (Low, Normal, High and abnormal [low/high]) for 
fasting glucose, HbA1c, total cholesterol, LDL-C, HDL-C, and CRP will be summarized for each study 
phase (Maintenance and Extended Evaluation Phases) by dose group and visit.  
Additional Summaries 
The absolute mean and median and the mean and median change from Baseline of the blood 
pressure assessment at Month 6 (or the last assessed visit in the Maintenance Phase) will be 
presented in the M population both overall and broken down by diagnosis of hypertension at 
baseline (Yes/No) and use of blood pressure medication at any time between the first dose of 
COR-003 in the study and the End of the Maintenance Phase (Yes/No). Distribution-free 99% CIs 
of the median change from Baseline will be generated using SAS® PROC UNIVARIATE.  
Shifts in hypertensive status between Baseline and Month 6 (or the last assessed visit in the 
Maintenance Phase) will be presented for All dose groups combined in the M population. The 
hypertensive status will be derived as Normal, pre-hypertension, hypertension stage 1 or 
hypertension stage 2 as defined in the protocol appendix I.  
Shifts in subject diabetes status between Baseline and Month 6 (or the last assessed visit in the 
Maintenance Phase) will be presented for All dose groups combined in the M population. The 
diabetes status will be derived as Normal, pre-diabetes or diabetes as defined in the protocol 
appendix H.  


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 59 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Shifts in subject HbA1c category between Baseline and Month 6 (or the last assessed visit in the 
Maintenance Phase) will be presented for All dose groups combined in the M population. The 
HbA1c categories are defined as <5.7%, 5.7 – <6.5%, 6.5 – <8.0% and ≥8.0%.  
Similar shifts in subject status or category between Baseline and Month 6 (or the last assessed 
visit in the Maintenance Phase) with respect to each of the other CS comorbidity biomarkers will 
also be presented for All dose groups combined in the M population. The fasting glucose 
categories are < 6.1, 6.1 – 6.9, and >6.9 mmol/L.  The total cholesterol categories are < 200, 200-
239, and ≥240 mg/dL.  (Note: 200 mg/dL=5.172 mmol/L; 240 mg/dL=6206 mmol/L.)  The LDL-C 
categories are <70, 70 - <100, 100 - <130, and ≥130 mg/dL.  (Note: 70 mg/dL=1.8102 mmol/L; 100 
mg/dL=2.586 mmol/L; 130 mg/dL=3.3618 mmol/L)  The HDL-C categories are <40, 40 - <60, and 
≥60 mg/dL. (Note: 40 mg/dL=1.034 mmol/L; 60 mg/dL=1.552 mmol/L) The BMI categories are 
<18.5, 18.5 - <25, 25 - <30, 30 - <40, and ≥40 kg/m2. The abdominal girth categories for males are 
≤102 and >102 cm, and for females ≤88 and >88 cm. 
Graphical Representation 
For All dose groups combined, the LSMEAN of the change from Baseline for each parameter at 
each visit in the Maintenance Phase alongside its 99% CI will be plotted. 
The percentage of subjects using antihypertensive, anti-diabetic and cholesterol-lowering drugs 
prior to the first dose (i.e., Baseline) and at the end of Maintenance Phase will be presented by 
Maintenance Phase dose as a bar chart. The counts and percentages will also be presented by 
visit and dose group in supporting summary tables. 
A stacked bar chart of hypertensive and diabetes status will be presented for All dose groups 
combined by Maintenance Phase visit. Diabetes status will be defined as per the definitions in the 
protocol appendix H and hypertensive status will be defined as per the definitions in the protocol 
appendix I.    
Line plots of Mean HbA1c ± SE over time in the Maintenance and Extended Evaluation Phases will 
be generated for All dose groups combined by diagnosis of diabetes at Baseline. In addition line 
plots of the Mean ± SE for all CS comorbidity biomarkers over time in the Maintenance and 
Extended Evaluation Phases will be presented for All dose groups by Clinical Response status.  
Line plots of Mean ± SE of HbA1c and fasting glucose over time in the Maintenance and Extended 
Evaluation Phases will be generated for All dose groups combined by anti-diabetic drug category. 
Anti-diabetic drug category will be classed as None, Oral monotherapy only, Oral agent 
combinations at any time or Insulin at any time.  
7.8.2.2 
Secondary UFC Analyses 
7.8.2.2.1 
UFC Response by Visit and Dose 
For the ITT, M, MC and PP populations, the UFC response rates will be summarized by visit in the 
Maintenance Phase, dose group and for All dose groups combined using all three imputation 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 60 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
schemes (as defined in Section 6.6). For the ITT population, subjects who do not enter the 
Maintenance Phase will be considered as non-responders at each visit.  
In addition, for All dose groups combined, the UFC response rates at each visit during the 
Maintenance Phase will be estimated using the same generalized linear model with repeated 
measurements described in Section 8.8.1.  
The LSMEAN estimate of the UFC response at each visit alongside its Wald 95% CI will be 
presented as well as the associated standard error.  Two-sided p-values for each parameter of the 
model from the Type III tests of fixed effects will also be presented. Only assessments within the 
visit window (see Section 6.3) and performed during the Maintenance Phase excluding all follow-
up assessments will be included in the analysis. 
A supportive analysis that does not require statistical modeling will also be performed at each visit 
(during the Maintenance and Extended Phases) for All dose groups combined by calculating a  
Clopper-Pearson two-sided 95% CI for the one-sample binomial proportion. 
For the Maintenance Phase the response rate using the 3rd imputation scheme will be displayed 
on a bar chart by dose group and visit. These bar charts will be repeated for the following 
subgroup, if they include at least 25% of Maintenance Population: 
• Subjects with at least one occurrence of a dose increase (in the Maintenance Phase) 
7.8.2.2.2 
UFC Improvement by Visit and Dose 
The UFC improvement rates will be summarized, analyzed and graphically represented as per the 
UFC response by visit and dose (see Section 8.8.2.2.1) on the ITT, M, MC and PP populations using 
all 3 imputation schemes (as defined in Section 6.6).  
7.8.2.2.3 
Mean, Change From Baseline And Percentage Change From Baseline in Mean UFC 
The following summaries and analyses will be performed both on the ITT and MC populations 
unless specified otherwise. 
The mean UFC, change from Baseline in mean UFC and percent change from Baseline in mean 
UFC will be summarized by study phase, visit and/or dose group and for All dose groups combined. 
Paired t-tests comparing the Baseline results to each post-baseline visit in the Maintenance Phase 
will be performed for All dose groups combined, mean of the difference between Baseline and 
post-baseline results and its associated 95% CI and two sided p-value from the test will be 
displayed. The paired t-tests will be performed using SAS® PROC TTEST with PAIRED statement. 
In addition, mean UFC, change from Baseline in mean UFC and percent change from Baseline in 
mean UFC by study phase (Maintenance and Extended Evaluation Phases) will be plotted via line 
plots by dose group and All dose groups combined.  
For the Maintenance and Extended Evaluation Phases, individual by-subject plots (spaghetti) of 
mean UFC will be plotted by dose group based on the ITT population. A horizontal line will 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 61 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
represent the ULN.  In addition, a plot per subject of mean UFC result at each visit (with dose 
information) will also be presented.   
A needle plot representing each subject’s mean UFC from Baseline to the End of the Maintenance 
Phase will also be displayed (subjects in blue will be subjects with a decrease in mean UFC while 
subjects in red will be subjects with a mean UFC increased). The y-axis will be ordered by the 
subject’s Baseline mean UFC. This display will be produced for the MC population only.  
The change from Baseline and percent change from Baseline in mean UFC will be summarized by 
dose group at Month 6 (or at the last assessed visit in the Maintenance Phase) by Baseline mean 
UFC category in the M population. Bar charts of mean percentage change + SE from Baseline to 
Month 6 (or at the last assessed visit in the Maintenance Phase) will be produced by dose group 
and Baseline UFC category. Baseline UFC will be categorized in three strata as follows: 1.5X-<2.0X 
ULN, 2.0X-<5.0X ULN and ≥5.0XULN.  
7.8.2.2.4 
Improvement in Mean UFC 
The change from Baseline in mean UFC will be categorized as below, and incidence rates for each 
category will be summarized by study phase, visit and/or dose group and for All dose groups 
combined on both the ITT and MC populations. Percentages will be based on the number of 
subjects with an assessment (i.e. have at least one Baseline and post-baseline assessment for the 
corresponding visit). 
• 
No Improvement: Percent reduction from Baseline < 25%, 
• 
Partial Improvement: Percent reduction from Baseline ≥ 25% and < 50%,  
• 
Improvement: Percent reduction from Baseline ≥ 50% and < 75%, 
• 
Marked Improvement: Percent reduction from Baseline ≥ 75%. 
 
7.8.2.2.5 
Shift in Mean UFC abnormalities 
The shifts from Baseline in mean UFC relative to the reference range will be summarized at each 
time point by study phase and dose group and for All dose groups combined on both the ITT and 
MC populations. The following categorization will be used:   
• Less than lower limit of normal (LLN) (< LLN), 
• Within the normal range ([LLN; ULN]), 
• Greater than ULN and less than or equal to 2x ULN ((ULN; 2 x ULN]), 
• Greater than 2x ULN and less than or equal to 5x ULN ((2 x ULN; 5 x ULN]), 
• Greater than 5x ULN (>5 x ULN) 
For All dose groups combined, two-sided p-values from a generalized McNemar’s test (also known 
as Bowker’s test of symmetry) will be provided at each post-baseline visit in the Maintenance 
Phase to test the paired difference for the shift from Baseline to each post-baseline visit on both 
the ITT and MC populations. The Bowker’s test of symmetry will be performed using SAS® PROC 
FREQ with TABLES statement and AGREE and TSYMM as option. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 62 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
In addition, the UFC category relative to the reference will be summarized by dose level and 
Baseline severity at Month 6 (or the last assessed visit in the Maintenance Phase) in the M 
population. Counts of the number of responders, the percentage of responders and the Clopper-
Pearson two-sided 95% CI will be presented.   
7.8.2.3 
Serum and Late-night Salivary Cortisol Levels 
Serum and mean LNSC levels following 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance 
Phase, including change from Baseline and percent change from Baseline will be listed and 
summarized descriptively by dose group and for All dose groups combined on the ITT and MC 
populations.  
In addition shift tables will be presented for changes from Baseline in LNSC category in the 
Maintenance and Extended Evauation Phases as follows: >ULN or ≤ULN.  
Paired t-tests comparing the Baseline results to each post-baseline visit in the Maintenance Phase 
will be performed for All dose groups combined on both the ITT and MC populations.  Mean of 
the difference between Baseline and post-baseline results and their associated two-sided 95% CIs 
and two-sided p-values from the tests will be displayed. The paired t-tests will be performed using 
SAS® PROC TTEST with PAIRED statement. 
Individual and mean LNSC levels will be presented in data listings. 
7.8.2.4 
Clinical Signs and Symptoms of CS 
In addition to the ITT population, the following summaries and analyses will be performed on the 
MC population.  
Summaries of Clinical Signs and Symptoms (as per the eCRF page “Clinical Signs and Symptoms of 
CS”) will be presented by signs/symptoms and grading by study phase, visit, and/or dose group 
and for All dose groups combined.  
Note:  Only the signs and symptoms (moon facies, facial plethora, striae, bruising, supraclavicular 
fat, menstrual abnormalities – irregular menstruation and menstrual abnormalities – 
dysmenorrhea, hirsutism, peripheral edema, and acne) as listed in Protocol Amendments 5 and 6 
will be included in the analyses. Therefore, only subjects consented under Protocol Amendment 
5 or 6 will be included in the summaries/analyses of these endpoints. All signs and symptoms, 
including those from earlier amendments, will be listed.   
The assessment of hirsutism was not described in the protocol as being intended for females only. 
This was an oversight.  Assessment of hirsutism in males is different than in females.  The 
instrument used to collect signs and symptoms was intended for females only.  In March 2017, a 
note was sent to Investigators describing the oversight and asking them to update the study 
procedures to omit the assessment in males.  Analyses of changes in hirsutism will be restricted 
to females. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 63 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Shifts in severity of sign or symptom from Baseline will be provided by study phase, visit, and/or 
dose group and for All dose groups combined.  
For All dose groups combined, two-sided p-values from a generalized McNemar’s test will be 
provided at each post-baseline visit in the Maintenance Phase to test the paired difference for the 
shift from Baseline to each post-baseline visit. The Bowker’s test of symmetry will be performed 
using SAS® PROC FREQ with TABLES statement and AGREE and TSYMM as options.  
As the assessment of the Clinical Signs and Symptoms is based on the date the signs/symptom 
started/stopped, improved or worsened, each sign/symptom will be slotted in a visit/period 
based on the following rules: 
• For each visit/period (Titration Visit 1, Titration Visit 2, etc. for the Dose Titration Phase, 
M1 [D30], M2 [D60], M3 [D90], and so on) until subject discontinued or completed the 
study, for each of the clinical signs/symptoms listed on the eCRF, a grade is assigned. If 
there was no occurrence of a sign/symptom during a period (for example M1 [D30]) the 
sign/symptom will be assign a grade of 0 (absence). In addition, for each subject, the 
Clinical Signs and Symptoms will be plotted. 
• If the sign/symptoms started after the stop date of the period or stopped before the start 
date of the period, the sign/symptom will be associated with a grade of 0 (none/absent). 
• If the sign/symptom started (or changed in intensity) before or on the stop date of the 
period, the sign/symptom will be counted under the last grade recorded for this period 
(see Table 9 and Figure 2).  
• If a visit was not done the subject will not be counted under that visit (for example if M2 
[D60] was not done, the subject will be included under M1 [D30] and M3 [D90]).  
In the below example (see Table 9 and Figure 2), the clinical sign /symptom of moon facies started 
on 01JAN2014 and stopped on the 18APR2014. The first dose was on 24JAN2014, so the last grade 
recorded prior to the date of first dose is 3. At the end of the Titration Visit 1 period (Dose Titration 
Level 300 mg) the moon facies event is grade 2. The severity of symptom stayed the same until 
the 31st of March, at the start of the Maintenance Phase (where it decreased to 1). Therefore, 
during the Dose Titration Phase at each visit, the symptom is summarized under grade 2. At the 
end of the Maintenance Phase Month 1 (i.e. M1 [D30]), the symptom has a grade of 1 so is 
summarized under grade 1 at Month 1.  
For each subject, the severities for each sign and symptom (graded from 0 = none to 3 = severe) 
will be summed by visit.  Total score and change from Baseline of the severity total score will be 
presented by visit. Total score will be equal to the sum of the severities for each sign or symptom 
assessed. To standardize the total scores for the number of signs and symptoms actually assessed, 
the sum of the individual severity scores will be divided by the number of signs and symptoms 
actually assessed and multiplied by the maximum number of signs and symptoms assessable at 
any time on the study.  If more than 25% of the individual signs and symptoms have missing scores 
at a given time point for a subject, then the total score will be set to missing. 


Sponsor: CORTENDO AB 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 64 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Paired t-tests comparing the Baseline results to each post-baseline visit in the Maintenance Phase 
will be performed for All dose groups combined, mean of the difference between Baseline and 
post-baseline results and its associated 95% CI and two-sided p-value from the test will be 
displayed. 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 65 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Table 9: Example of Clinical Sign and Symptom of CS aligned per visit (one subject) 
Sign/ 
Symptom 
Seq. 
nb. 
Signs/symptom 
Interval (Period) 
Visit 
for 
summary  
Grade 
summariz
ed 
 
Start date 
Stop date 
Gra
de 
Visit Start 
Start date 
Visit Stop 
Stop date 
 
 
Moon 
facies 
 
01 
01JAN2014 
15JAN2014 
3 
BAS 
10JAN2014 
BAS 
24JAN2014 
BAS 
 
Moon 
facies 
02 
16JAN2014 
19JAN2014 
2 
BAS 
10JAN2014 
BAS 
24JAN2014 
BAS 
 
Moon 
facies 
03 
20JAN2014 
25JAN2014 
3 
BAS 
10JAN2014 
Titration # 
1 
24JAN2014 
BAS 
3 
Moon 
facies 
03 
20JAN2014 
25JAN2014 
3 
BAS 
25JAN2014 
Titration # 
1 
04FEB2014 
Titration # 
1 
 
Moon 
facies 
04 
26JAN2014 
30MAR2014 
2 
Titration # 
1 
25JAN2014 
Titration # 
1 
04FEB2014 
Titration # 
1 
 
Moon 
facies 
04 
26JAN2014 
30MAR2014 
2 
Titration # 
1 
05FEB2014 
M1 (D1) 
14FEB2014 
Titration # 
2 
2 
Moon 
facies 
04 
26JAN2014 
30MAR2014 
2 
Titration # 
1 
15FEB2014 
M1 (D1) 
27FEB2014 
Titration # 
3 
2 
Moon 
facies 
04 
26JAN2014 
30MAR2014 
2 
Titration # 
1 
28FEB2014 
M1 (D1) 
14MAR2014 
Titration # 
4 
2 
Moon 
facies 
04 
26JAN2014 
30MAR2014 
2 
Titration # 
1 
15MAR2014 
M1 (D1) 
13APR2014 
M1 (D1) 
 
Moon 
facies 
05 
31MAR2014 
15APR2014 
1 
M1 (D1) 
15MAR2014 
M1 (D30) 
13APR2014 
M1 (D1) 
1 
Moon 
facies 
05 
31MAR2014 
15APR2014 
1 
M1 (D1) 
14APR2014 
M1 (D1) 
14MAY2014 
M1 (D30) 
 
Moon 
facies 
06 
16APR2014 
18APR2014 
2 
M1 (D1) 
14APR2014 
M1 (D1) 
14MAY2014 
M1 (D30) 
 
Moon 
facies 
07 I 
19APR2014 
15MAY2014 
0 
M1 (D1) 
14APR2014 
M2 (D60) 
14MAY2014 
M1 (D30) 
0 
Moon 
facies 
07 I 
19APR2014 
15MAY2014 
0 
M1 (D1) 
14APR2014 
M2 (D60) 
14MAY2014 
M2 (D60) 
 
Moon 
facies 
08 
16MAY2014 
18MAY2014 
3 
M2 (D60) 
15MAY2014 
M2 (D60) 
14JUN2014 
M2 (D60) 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 66 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Sign/ 
Symptom 
Seq. 
nb. 
Signs/symptom 
Interval (Period) 
Visit 
for 
summary  
Grade 
summariz
ed 
 
Start date 
Stop date 
Gra
de 
Visit Start 
Start date 
Visit Stop 
Stop date 
 
 
Moon 
facies 
09 
19MAY2014 
Ongoing 
2 
M2 (D60) 
15JUN2014 
Early 
Terminati
on* 
16JUL2014 
M2 (D60) 
2 
Moon 
facies 
09 
19MAY2014 
Ongoing 
2 
M2 (D60) 
15JUN2014 
Early 
Terminati
on* 
16JUL2014 
M3 (D90) 
2 
* Early Termination occurred after Month 4, no Month 5 period started. Nominal visits used. 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 67 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Figure 2: Visual representation of the example presented on Table 9. 
 
 
 
Baseline Visit: Moon facies – Severe 
Visit 1: Moon facies – Moderate 
Visit 2: Moon facies – Moderate 
Visit 3: Moon facies – Moderate 
Visit 4: Moon facies – Moderate 
 
M1 (D30): Moon facies – Mild 
M2 (D60): Moon facies – Absent (no 
symptom of moon facies) 
M3 (D90): Moon facies – Moderate 
M4 (D120): Moon facies – Moderate 
 
Dose Titration Phase 
Maintenance Phase 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 68 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
7.8.2.4.1 
Visual analog scale questionnaire – subject assessments 
As per Protocol Amendment 5, the subject’s assessment from the VAS questionnaire are no longer 
collected. All prior data will be listed by subject and visit. 
7.8.2.4.2 
Physical signs and proximal myopathy 
As of Protocol Amendment 5, the physical signs and proximal myopathy are no longer collected. 
All prior data will be listed by subject and visit. 
7.8.2.4.3 
Hirsutism  
Total hirsutism score and change from Baseline of total score will be summarized at each visit up 
to the end of the Maintenance Phase by dose group and for All dose groups combined for female 
subjects only. Data collected for male subjects will be listed by subject and visit. 
7.8.2.4.4 
Peripheral edema 
Total peripheral edema score and change from Baseline will be summarized at each visit up to the 
end of the Maintenance Phase, by dose group and for All dose groups combined. 
7.8.2.4.5 
Acne 
Acne global score and change from Baseline in acne global score will be summarized at each visit 
up to the end of the Maintenance Phase, by dose group and for All dose groups combined.  
7.8.2.5 
Cushing QoL Questionnaire 
Since the Cushing QoL questionnaire is not planned to be assessed during the Dose Titration 
Phase, all summaries and analyses will be performed on the M population (rather than the ITT 
population) and the MC population. 
Cushing QoL question responses and total standardized derived score will be listed by subject. 
Quality of life total standardized score and change from Baseline in total standardized score (see 
Section 6.7.2) will be summarized by visit up to the end of the Maintenance Phase, and by dose 
group and for All dose groups combined using descriptive statistics.  
Paired t-tests comparing the Baseline results to each post-baseline visit in the Maintenance Phase 
will be performed by dose and for All dose groups combined. Means of the differences between 
Baseline and post-baseline results and their associated two-sided 95% CI and two-sided p-values 
from the test will be displayed. The paired t-tests will be performed using SAS® PROC TTEST with 
PAIRED statement. 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 69 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
7.8.2.6 
Beck Depression Inventory II 
Since the Beck Depression Inventory II is not planned to be assessed during the Dose Titration 
Phase, all summaries and analyses will be performed on the M population (rather than the ITT 
population) and the MC population. 
The BDI-II total derived score will be listed by subject.  
The BDI-II total score and change from Baseline in total score (see Section 6.7.2) will be 
summarized by visit up to the end of the Maintenance Phase, and by dose group and for All dose 
groups combined using descriptive statistics. Only subjects who were enrolled under Protocol 
Amendment 5 or subsequent amendments will be included in the data summary.  
Paired t-tests comparing the Baseline results to each post-baseline visit in the Maintenance Phase 
will be performed for All dose groups combined, means of the differences between Baseline and 
post-baseline results and their associated two-sided 95% CI and two-sided p-values from the test 
will be displayed. The paired t-tests will be performed using SAS® PROC TTEST with PAIRED 
statement. 
Shifts from Baseline in severity of depression (see Section 6.7.2) will be displayed by dose group 
and for All dose groups combined. 
7.8.2.7 
Oral Glucose Tolerance Test and Spot Albumin/Creatinine Ratio 
Since the OGTT and spot albumin/creatinine ratio are not planned to be assessed during the Dose 
Titration Phase, all summaries and analyses will be performed on the M population (rather than 
the ITT population) and the  MC population. 
OGTT: 
Interpretation of the glucose concentration at 2 hours post administration of 75 g of glucose will 
be summarized for subjects with impaired fasting glucose without diabetes at Baseline. If 75 g of 
glucose was not administered, any test results will not be interpreted. Individual glucose levels 
from the 30-min, 60-min, 90-min and 120-min blood samples will be listed in subject data listings.  
Missing glucose values will not be imputed. 
• Normal: 2-hour post-glucose load plasma glucose level is < 140 mg/dL 
• Impaired glucose tolerance: 2-hour post-glucose load plasma glucose level >= 140 mg/dL 
and <= 200 mg/dL 
• Provisional diagnosis of diabetes: 2-hour post-glucose plasma glucose level > 200 mg/mL 
Incidence of normal, impaired glucose tolerance and diabetic categories, as defined above, from 
the OGTT results will be summarized at each visit during the Maintenance Phase (including 
Baseline results) by dose group and All dose groups combined, for  subjects with impaired fasting 
glucose without diabetes at Baseline.  
Shifts from Baseline to each category will be summarized for each study phase by dose group and 
All dose groups combined and by visit.  


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 70 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Glucose values during the OGTT, including changes and percent changes from Baseline, will also 
be summarized descriptively by maximum value, time to maximum value, and incremental and 
total areas under the glucose concentration-vs. time-curve calculated using the trapezoidal 
method.  
Paired t-tests comparing the Baseline results to each post-baseline visit in the Maintenance Phase 
will be performed for All dose groups combined, means of the differences between Baseline and 
post-baseline results and associated two-sided 95% CI and two-sided p-values from the tests will 
be displayed. The paired t-tests will be performed using SAS® PROC TTEST with PAIRED statement.  
Overlaying individual line plots of glucose concentration over time will be presented for each dose 
level.  
Spot Albumin/Creatinine Ratio: 
Spot albumin/creatinine ratio values were obtained from subjects with abnormal values at 
Baseline. Ratio values and changes from Baseline will be summarized descriptively for each study 
phase by visit up to the end of the Maintenance Phase. Paired t-tests comparing the Baseline 
results to each post-baseline visit in the Maintenance Phase will be performed for All dose groups 
combined, means of the differences between Baseline and post-baseline results and associated 
two-sided 95% CI and two-sided p-values from the tests will be displayed. The paired t-tests will 
be performed using SAS® PROC TTEST with PAIRED statement. 
Incidence of abnormal results (i.e. outside of the normal range) will be summarized for each study 
phase by visit (and at any visit during the study phase) and by dose group and for All dose groups 
combined.  
Shifts from Baseline from the normal range (Low, Normal, High and abnormal [low/high]) will be 
summarized for each study phase by dose group and visit.  
The mean ± SE will be plotted at each visit of Maintenance Phase by dose group and for All dose 
groups combined. 
7.8.2.8 
C-reactive Protein 
In addition to the ITT population, all summaries and analysis will be presented on the  MC 
population.  
C-reactive protein is considered as a CS comorbidities biomarker and will be summarized and 
analyzed as described in Section 8.8.2.1. In addition, the following summaries and plots will be 
produced: 
Incidence of abnormal results (i.e. outside of the normal range) will be summarized for each study 
phase by visit and/or dose group and for All dose groups combined.  
Shift from Baseline from the normal range (Low, Normal, High and abnormal [low/high]) will be 
summarized for each study phase by visit and/or dose group and for All dose groups combined.  


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 71 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
The mean ± SE will be plotted at each visit of Maintenance Phase for All dose groups combined 
and by dose group. 
7.8.3 
Exploratory Efficacy Endpoints and Analyses  
All summaries and analyses below will be presented for the ITT population.  For exploratory 
efficacy endpoints for the Extended Evaluation Phase that have secondary efficacy endpoint 
counterparts for the Maintenance Phase, the same univariate tests (e.g. paired t-test, Wilcoxon 
signed rank test) that will be used to analyze the secondary endpoints wil also be used to analyze 
the exploratory endpoints; however, the p-values for the exploratory efficacy endpoints are 
considered to be descriptive only. 
7.8.3.1 
Exploratory Urinary Free Cortisol Analyses 
The UFC response rates and UFC improvement rates at 9 and 12 months of dosing in the Extended 
Evaluation Phase will be summarized by dose group and for All dose groups combined as 
described in Section 8.8.2.2.1 and Section 8.8.2.2.2. There will be no imputation of missing data, 
and the response or improvement will be assessed regardless of dose increase. 
Mean, change from Baseline and percentage change from Baseline in mean UFC for the Extended 
Evaluation Phase will be similarly presented as described in Section 8.8.2.2.3. Shift in UFC 
normality categories from Baseline at 9 and 12 months of the Extended Evaluation Phase will be 
considered as mentioned in Section 8.8.2.2.5.  
7.8.3.2 
Exploratory Late Night Salivary and Serum Cortisol Levels Summaries 
Serum cortisol levels and mean LNSC levels at 9 and 12 months of dosing in the Extended 
Evaluation Phase including change from Baseline and percent change from Baseline will be listed 
and summarized descriptively by dose group and for All dose groups combined.  
The normalization of LNSC (i.e., percentage of subjects with LNSC ≤ ULN) over time in the 
Maintenance and Extended Evaluation Phases will be presented as a bar chart by dose group and 
all dose groups combined. 
Individual serum cortisol levels will be presented in data listings. 
7.8.3.3 
Exploratory Clinical Signs and Symptoms of Cushing’s Syndrome, Cushing 
Quality of Life and Beck Depression Inventory II Summaries  
Summaries will be presented at each visit in the Extended Evaluation Phase by signs/symptoms 
and grading for each dose group and for All dose groups combined. Change from Baseline 
summaries will be presented for clinical signs and symptoms of CS, QoL scores and BDI-II total 
score. 
Clinical signs and symptoms of CS in the Maintenance and Extended Evaluation Phases will be 
summarized graphically through individual subject-time profile of the preferred terms and 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 72 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
severity, time profile of the preferred terms and median severity, and percentage of subjects with 
an improvement from Baseline at Month 6 (or the last assessed visit in the Maintenance Phase) 
by mean UFC category at Month 6 (or the last assessed visit in the Maintenance Phase) and 
overall. 
7.8.3.4 
Exploratory Cushing’s Syndrome Comorbidities Biomarkers Summaries 
The change from Baseline in CS comorbidities biomarkers results at 9 and 12 months of dosing in 
the Extended Evaluation Phase will be summarized at each time point by dose group and for All 
dose groups combined. 
7.8.3.5 
Exploratory Oral Glucose Tolerance Test and Spot Albumin to Creatinine Ratio 
Summaries 
Change from Baseline in glucose values from the OGTT for pre-diabetics subjects at Baseline and 
spot albumin ratio values at 9 and 12 months will be summarized descriptively. 
7.8.3.6 
Exploratory C-reactive Protein Summaries 
Change from Baseline in CRP values will be summarized descriptively at 9 and 12 months of dosing 
in the Extended Evaluation Phase. 
7.8.3.7 
Clinical Benefit 
The proportion of subjects achieving Clinical Benefit (see Section 6.7.2) and Clopper-Pearson two-
sided 95% CIs for the Maintenance Phase and Extended Evaluation Phase will be displayed in 
tables and graphically by visit, dose group and for All dose groups combined for all subjects 
reaching the Maintenance Phase. 
The summary and graphical representation of the Clinical Benefit will be repeated using two 
alternative definitions of Clinical Benefit (Clinical Benefit regardless of dose increase and Clinical 
Benefit with partial UFC normalization, regardless of complete response status; see Section 6.7.2 
for their definitions). 
Only subjects with an abnormal value at Baseline for one or more of the 8 pre-specified CS 
comorbidities biomarkers (fasting glucose, HbA1c, SBP, DBP, total cholesterol, LDL-C, HDL-C, body 
weight) will be included in the analysis of Clinical Benefit, since one of the criteria for Clinical 
Benefit requires the presence of one or more abnormal values at Baseline. 
7.8.3.8 
Medication Changes 
Throughout the study, the Investigators record all medications taken by subjects and any changes. 
A new record is created to document a change either in dose or frequency or new drug. 
Medications with the same preferred term will be categorized as the same medication.  Using the 
start date of each record the medication changes will be segmented by study phase. 
• Dose increase: for a continuing medication, after the first dose of study drug, there is a  


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 73 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
      new record with a total daily dose that is above the total daily dose from the prior  
      medication record.     
• Dose decrease: for a continuing medication, after the first dose of study drug, there is a  
      new record with a total daily dose that is below the total daily dose from the prior  
      medication record.     
• New medication: a medication that started after the first dose of study drug and for  
      which no same medication was taken at Baseline.  
• Discontinued medication: a medication that has stopped after the first dose of the study  
      drug, and no more records of that drug indicating restarts are present. 
The above categories are not mutually exclusive. 
The number and percentage of subjects with medication changes for blood pressure, diabetes 
and cholesterol management in each phase of the study, will be summarized for each of the 
following possible categories.  
• Condition improving, 
• Condition worsening, 
• Study drug interaction, 
• Other (non-study) drug interaction, 
• Investigator decision, 
• Other. 
Summaries will be presented for each study phase by dose group and for All dose groups 
combined (i.e. considering all new medications started after the 1st dose of study drug).  
The relationship between change in co-medications (antihypertensive drugs, anti-diabetic drugs 
and cholesterol-lowering drugs) and change in the associated biomarkers of comorbidity of CS 
(SBP and DBP, fasting glucose, HbA1c, Total Cholesterol, HDL-C and LDL-C) will be investigated. 
For this purpose, the following by-subject profile will be provided within each study phase:  
On the top of the page the clinical assessment will be plotted per study day while on the 2nd half 
of the page, associated medications will be listed (includes name of the medication, start/stop 
date, total daily dose and unit as well as frequency and route of administration). 
• SBP and DBP vs antihypertensive drugs 
• Fasting Glucose vs. anti-diabetic drugs 
• HbA1c vs. anti-diabetic drugs 
• Total Cholesterol, HDL-C and LDL-C vs. anti-hypercholesterolemia drugs 
Use of anti-diabetic drugs will be summarized in a bar chart for All dose groups by drug class. Drug 
class will be one of the following: Biguanides (metformin), Insulins, Glinides, Sulfonamides, TZD, 
Gliptins and Gliflozins.  
The counts and percentages will also be presented in a supporting summary table. 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 74 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
7.8.3.9 
Clinical Signs of Hypercortisolism Assessed through Standardized Photographs 
An independent adjudication committee, composed of three clinician-investigator experts in CS 
will assess the subjects for changes in visible signs of hypercortisolism (moon face, plethora, 
supraclavicular and dorsal fat pads, striae, hirsutism, bruising and overall body habitus) by scoring 
standardized photographs. The scoring will be based on overall subjective impression of changes 
from Baseline to M3 (D90) visit, End of Maintenance Phase visit and End of Extended Evaluation 
Phase visit, as follows: obvious visible worsening, subtle visible worsening, no visible changes, 
subtle visible improvements, obvious visible improvements.  
Shift tables of the scores from Baseline will be presented by dose group and for All dose groups 
combined. The denominator of the percentages will be considered the number of subjects who 
consented to the photographs and for which the photographs were evaluated by the specialists 
at both Baseline and each of the corresponding visits.  
7.8.3.10 Intra-subject Within-visit Variability 
For each of the following assessments, for each subject, the SD will be calculated at each visit 
where more than one planned assessment is recorded in Maintenance and Extended Evaluation 
Phases. The SDs will be summarized for All dose groups combined.  
• 
UFC 
• 
LNSC 
• 
SBP and DBP 
• 
Abdominal girth 
7.8.4 
Other Exploratory Analysis   
Analysis of subject response in each of the categories defined below will be performed at all visits 
during the Maintenance Phase and the Extended Evaluation Phase.  
7.8.4.1 
Diabetes Mellitus Responders 
For the subpopulation of subjects meeting any of the following conditions at Baseline: (1) a 
confirmed diagnosis of diabetes mellitus and on anti-diabetic treatment, or (2) a fasting glucose 
of ≥126 mg/dL (7.0 mmol/L), or (3) a 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 (i.e. during 
OGTT), or (4) HbA1C ≥6.5% (48 mmol/mol), summary statistics of Diabetes mellitus responders 
will be provided. 
Diabetes mellitus responders are defined as (1) subjects with absolute HbA1C reduction of at least 
0.3 percentage points from Baseline without increases in dose(s) of continuing anti-diabetic 
medications or the addition of new anti-diabetic medication(s), OR (2) subjects with a total daily 
dose reduction of at least 50% of any continuing anti-diabetic medication, without new anti-
diabetic medication or an increase in dose of any anti-diabetic medication, OR (3) subjects not 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 75 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
treated with anti-diabetic medications at Baseline and with an HbA1C reduction of at least 0.3 
percentage points and who have not started taking new anti-diabetic medication. 
7.8.4.2 
Hypertensive Responders 
For the subpopulation of subjects with SBP of greater or equal to 140 mmHg (with or without 
antihypertensives) or normal BP and on antihypertensive medication at Baseline, summary 
statistics of hypertensive responders will be summarized. 
A hypertensive responder is defined as a subject with (1) a reduction in SBP or DBP of at least 2 
mmHg from Baseline. Responders must have also either maintained a stable dose OR had a 
reduction in dose OR withdrawal of continuing antihypertensive medications. If not treated with 
antihypertensive medication at Baseline they must not have been started on new 
antihypertensive medication. 
7.8.4.3 
Hypercholesterolemia Responders 
For the subpopulation of subjects with either of the following conditions met at Baseline (1) a 
LDL-C > 3.3 mmol/L (129 mg/dL) and not receiving statin therapy; or (2) LDL-C >2.6 mmol/L (100 
mg/dL) and receiving statins; summary statistics of hypercholesterolemia responders will be 
provided. 
Hypercholesterolemia responders are defined as (1) subjects with a relative reduction from 
Baseline in LDL-C of at least 24% and without a corresponding relative decrease in HDL-C of 
greater than 12% or an increase in dose of continuing cholesterol-lowering medication or the 
addition of new cholesterol-lowering medications, OR (2) subjects with a reduction of at least 50% 
of the total daily dose of any continuing cholesterol-lowering medication or withdrawal of 
cholesterol-lowering medications and LDL-C <3.3 mmol/L, OR (3) subjects not treated with 
cholesterol-lowering medication at Baseline with a relative reduction LDL-C of at least 24% from 
Baseline and did not add a new cholesterol-lowering medication. 
7.8.4.4 
Obesity Responders 
For the subpopulation of obese subjects at Baseline (BMI > 30), summary statistics of obesity 
responders will be provided. 
An obesity responder is defined as a subject with a relative decrease in body weight of 5% from 
Baseline OR with normalization of BMI (BMI ≤ 25) at the end of the Maintenance Phase.  
Concomitant use of weight-loss medications was excluded by protocol. Subjects who deviated 
from the protocol and used weight-loss medications at Baseline or during the study will not be 
considered obesity responders regardless of changes in body weight or BMI. 
7.8.4.5 
Metabolic Syndrome Responders 
For the subpopulation with metabolic syndrome at Baseline, summary statistics of metabolic 
syndrome responders will be provided.  The international harmonized definition of metabolic 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 76 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
syndrome (2009) will be used, as summarized here.  At least 3 of the following 5 criteria must be 
present to have the metabolic syndrome: 
1. Waist circumference: Men ≥ 102 cm; women ≥ 88 cm 
2. Serum fasting triglyceride ≥ 150 mg/dL (1.7 mmol/L) OR currently using one or more 
of the following drug classes: fibrates, niacin or high-dose omega-3 fatty acids 
3. Serum HDL-cholesterol < 40 mg/dL (1.0 mmol/L) in males; > 50 mg/dL (1.3 mmol/L) 
in females 
4. SBP ≥ 130 and/or DBP ≥ 85 mm Hg OR currently receiving antihypertensive drug 
therapy 
5. Serum fasting glucose ≥ 100 mg/dL (5.5 mmol/L) OR currently receiving anti-diabetic 
drug therapy. 
A metabolic syndrome responder is defined as a subject who met the definition of metabolic 
syndrome at Baseline as defined above and no longer meets the definition of metabolic syndrome 
at the end of the Maintenance Phase. 
 
 PHARMACOKINETIC/ PHARMACODYNAMIC ENDPOINTS AND 
ANALYSES 
7.9.1 
Pharmacokinetic Endpoints and Analyses  
Population PK endpoints and analyses will be discussed in a separate population PK/PD analysis 
plan. 
7.9.2 
Pharmacodynamic Endpoints and Analyses  
Population PD endpoints and analyses will be discussed in a separate population PK/PD analysis 
plan. 
  QUALITY OF LIFE OR PHARMACOECONOMIC ENDPOINTS AND 
ANALYSES 
For the QoL questionnaire see Section 6.7.2 and Section 8.8.2.5. 
 SAFETY DATA ENDPOINTS AND ANALYSES 
All Safety analyses will be performed on the ITT Population. In addition, selected safety summaries 
will be presented for the DT and MC populations, as described below. 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 77 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
7.11.1 Adverse Events 
All AEs will be coded using MedDRA dictionary and graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAEv4).  
All information on AEs will be listed by subject.  
All reported TEAEs will be summarized. 
All TEAEs will be assigned to only one study phase (Dose Titration, Maintenance or Extended 
Evaluation Phase) based on the start date of the phase and start date of the TEAE. TEAEs will be 
summarized per dose group and for All dose groups combined for each study phase and for the 
Maintenance and Extended Evaluation Phases combined.  TEAEs will also be summarized for All 
phases combined for All dose groups combined only. 
For the Dose Titration Phase, subjects will be summarized under each dose level they reached 
during the Dose Titration Phase, and a TEAE for a subject will be assigned to the last dose level 
the subject received on or before the start of the TEAE. For the Maintenance Phase, subjects will 
be summarized under their Therapeutic Dose. For the Extended Evaluation Phase, subjects will be 
summarized under each dose level they received during the Extended Evaluation Phase, and a 
TEAE for a subject will be assigned to the last dose level the subject received on or before the start 
of the TEAE. For the Maintenance and Extended Evaluation Phases combined, subjects will be 
summarized under their Therapeutic Dose. 
An overview of TEAE incidence rates by categories (see below) will be provided. In addition, the 
total number of events will be summarized. A unique event for a subject is defined as a unique 
combination of subject, system organ class, preferred term, AE start date, severity, and 
relationship to study drug. Clopper-Pearson two-sided 95% CIs of the incidence rates will be 
provided for All dose groups combined and for each of the TEAE categories below. 
The frequencies in these analyses, represented as percentages, will be calculated as the number 
of subjects reporting at least one AE in each dose group divided by the total number of subjects 
in each dose group at any time during the study phase.  
• 
TEAE 
o Any TEAE 
o Any study drug related (i.e. probable or definitely related as per the Investigator) 
TEAE 
o Any TEAE leading to study drug discontinuation 
o Any TEAE with worst severity of Severe 
o Any TEAE with worst severity of Moderate 
o Any TEAE with worst severity of Mild  
o Any non-serious TEAE of Special Interest 
 
• 
Serious TEAE 
o Any SAE 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 78 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
o Any study drug related SAE 
o Any SAE leading to study drug discontinuation 
o Any SAE with worst severity of Life Threatening 
o Any SAE with worst severity of Severe 
o Any SAE with worst severity of Moderate 
o Any SAE with worst severity of Mild 
o Any SAE leading to death 
o Any study drug related SAE leading to death 
o 
Any SAE of Special Interest. 
AEs of special interest, as defined per protocol, will be flagged in the eCRF by the Investigator and 
are: 
• 
Persistent QTc prolongation events, 
• 
Potential hepatic events, 
• 
Adrenal Insufficiency events. 
Note that AESIs are ultimately categorized by the Investigator, even if the Sponsor’s medical 
monitor does not agree with the assignment. 
The following category of AEs will be derived from the preferred terms. The list of preferred terms 
will be provided by the Cmed Medical Monitor and reviewed and approved by a Cortendo Study 
Physician. A separate summary table will be produced. 
• 
TEAEs potentially associated with abnormality of cardiac repolarization (syncope, 
dizziness, palpitations, etc.) 
The following summaries of TEAEs will be provided by System Organ Class and Preferred Term 
and by dose group and for All dose groups combined. The System Organ Classes and the Preferred 
Terms within each System Organ Class will be presented in order of decreasing frequency for All 
dose groups combined. 
• 
Incidence of TEAEs 
• 
Incidence of drug-related TEAEs 
• 
Incidence of TEAEs by worst severity 
• 
Incidence of TEAEs leading to study drug discontinuation 
• 
Incidence of drug-related TEAEs leading to study drug discontinuation 
• 
Incidence of TEAEs of special interest 
• 
Incidence of serious TEAEs  
• 
Incidence of serious TEAEs by worst severity 
A summary of TEAE by System Organ Class and Preferred Terms will be provided for events with 
an incidence rate of at least 5% for All dose groups combined (i.e. summarizing the most common 
AEs).  In addition, for this summary, Clopper-Pearson two-sided 95% CI will be provided for All 
dose groups combined.   


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 79 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
For any TEAE with an overall incidence > 10%, the following split by subgroups will be investigated: 
• 
Age (rounded median split),  
• 
Sex,  
• 
Disease duration (category) 
Subjects will be counted only once within each System Organ Class, Preferred Term and Severity.  
• 
If there is more than one AE within the same System Organ Class, the subject will be 
counted only once in that System Organ Class. 
• 
If there is more than one AE coded to the same Preferred Term within a System Organ 
Class, the subject will be counted only once in that System Organ Class and Preferred 
Term. 
• 
If there is more than one AE coded to the same Preferred Term within a System Organ 
Class, the subject will be counted only once in that System Organ Class and Preferred 
Term under the worst severity. Worst severity is ordered from most to least severe as 
follows:  Death, Life-threatening, Severe, Moderate, and Mild. 
If an AE severity is missing for a subject, its grade will be imputed as the worst grade reported for 
that subject (across all AEs) between mild, moderate, severe and life-threatening (i.e. excluding 
death).  
If there is any subject for which all of the AEs have a missing severity, then  the "Missing" category 
will be considered as the lowest/worst severity grade (i.e. below Mild).  
If the relationship for an AE is missing it will be assumed to be related to study drug in the 
summary tables. 
All AEs will be listed by subject; pre-existing conditions (i.e. AEs which are not treatment-
emergent) and TEAEs will be flagged.  
The following AEs will be listed: 
• 
All AEs 
• 
SAEs 
• 
Adverse events leading to study drug discontinuation 
• 
Adverse events leading to death  
• 
Adverse events of special interest 
An overview of TEAE table and a TEAE table by system organ class and preferred term will be 
produced for the DT population. There will no statistical tests of the TEAEs for the DT population. 
7.11.2 Clinical Laboratory Evaluations 
Laboratory analytes (hematology, blood chemistry, urinalysis, coagulation) values and change 
from Baseline will be summarized descriptively for each study phase by visit and/or dose group 
and for All dose groups combined. For Hematology, Blood Chemistry and Coagulation parameters 
these summaries will be repeated using the DT population. 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 80 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
For each analyte, incidence of abnormal results (i.e. outside of the normal range) will be 
summarized for each study phase by visit (and at any visit during the study phase) and/or dose 
group and for All dose groups combined. This summary by study phase will include unscheduled 
visits. A listing of all laboratory analytes and their corresponding normal ranges will be produced. 
For each analyte, shift from Baseline from the normal range (Low, Normal, High and Abnormal 
[low/high]) will be summarized for each study phase (including unscheduled visits) and by visit 
and/or dose group. For Hematology and Blood Chemistry analytes these summaries will be 
repeated using the DT population. 
In addition, for liver test analytes (Aspartate Aminotransferase [AST], Alanine Aminotransferase 
[ALT], Alkaline Phosphatase, Gamma-glutamyl Transferase [GGT] and Total Bilirubin), the results 
will be tabulated by study phase, visit (including unscheduled visits) and/or dose group and for All 
dose groups combined. A shift table will also be presented by study phase, visit and/or dose group 
and for All dose groups combined. The below categories will be used for incidence summaries and 
shift tables for LFTs (except Total Bilirubin): 
• 
Less than LLN (< LLN) 
• 
Within the normal range ([LLN; ULN]) 
• 
Greater than ULN and less than or equal to 3x ULN ((ULN; 3 x ULN]), 
• 
Greater than 3 x ULN and less than or equal to 5x ULN ((3 x ULN; 5 x ULN]), 
• 
Greater than 5 x ULN and less than or equal to 10x ULN ((5 x ULN, 10 x ULN]), 
• 
Greater than 10 x ULN (> 10 x ULN). 
For Total Bilirubin, the below categories will be used for incidence summaries and shift tables: 
• 
Less than LLN (< LLN) 
• 
Within the normal range ([LLN; ULN]) 
• 
Greater than ULN and less than or equal to 2 x ULN ((ULN; 2 x ULN]), 
• 
Greater than 2 x ULN (> 2 x ULN) 
The number of subjects with International Normalized Ratio (INR) >1.5 by study phase, visit, 
and/or dose group will also be summarized.  This will be repeated for the DT Population for the 
Dose Titration Phase only. 
Furthermore, box-and-whisker plots of results  by study phase, visit, and/or dose group and 
change from Baseline will also be produced for each LFT and electrolyte parameter. These box-
and-whisker plots will be repeated using the DT population.  
A matrix of eDISH plots for all ALT, AST, and Total Bilirubin results (regardless of time point) 
divided by their respective ULN will be plotted.   In eDISH plots the x- and y-axes are on a log/log 
scale and the LFT results are plotted as multiples of the ULNs of the LFTs. 
The following six individual-subject eDISH plots will be presented by study phase and for the Dose 
Titration Phase and Maintenance Phase combined:    
• 
Baseline ALT (expressed as x ULN) x Maximum Post-baseline ALT (expressed as x ULN) 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 81 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
• 
Maximum Post-baseline ALT (expressed as x ULN) x Maximum Post-baseline AST 
(expressed as x ULN) 
• 
Maximum Post-baseline ALT (expressed as x ULN) x Maximum Post-baseline Total 
Bilirubin (expressed as x ULN ) 
• 
Baseline AST (expressed as x ULN ) x Maximum Post-baseline AST (expressed as x ULN) 
• 
Maximum Post-baseline AST (expressed as x ULN) x Maximum Post-baseline Total 
Bilirubin (expressed as x ULN) 
• 
Baseline TBILI (expressed as x ULN) x Maximum Post-baseline Total Bilirubin (expressed 
as x ULN) 
For ALT, AST and Total Bilirubin, all post-baseline values during the study phase of interest will be 
included in determining the maximum post-baseline values for that study phase. 
Different symbols and colors will be used to distinguish the dose levels on the individual-subject 
scatterplots. 
Individual-subject line plots (or line plot matrices if possible) will be presented showing the time 
course of LFT values for all LFTs only for subjects where the maximum value of ALT or AST exceeds 
3 X ULN and 5 x ULN or the maximum value of Total Bilirubin exceeds 2 X ULN at anytime during 
the study.  
The time to the incidence of the maximum post-baseline value > 3 x ULN for each LFT (except 
Total Bilirubin) and > 2 x ULN for Total Bilirubin will be presented versus the probability of 
incidence as Kaplan-Meier curves by study phase and dose group.  The y-axis will present the 
Kaplan-Meier estimates of the cumulative probabilities of no event, and the x-axis will present the 
study day relative to the first dose of COR-003 in the study phase being presented.  A 
corresponding summary table of the Kaplan-Meier estimates for mean, median, and quartile 
times to incidence as well as cumulative probabilities of no event at specific study days of interest 
will be produced. 
All data will be listed in subject data listings and abnormal results will be flagged. 
7.11.3 Hormones and Biomarkers Laboratory Evaluations 
For certain hormones and biomarker laboratory parameters (triglycerides, LDL-C/HDL-C ratio, 
TSH, Free T4, IGF-1 and testosterone concentrations) values and change from Baseline will be 
summarized descriptively for each study phase by visit and/or dose group and for All dose groups 
combined.   
ACTH values and change from Baseline values will summarized descriptively for each study phase 
by visit and/or dose group and for All dose groups combined for all subjects combined and also 
for just subjects with an etiology of ACTH-dependent CS, subcategorized as CD only and ectopic 
ATCH only. This summary will be repeated for the DT and MC populations.  


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 82 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
For each analyte, the incidence of abnormal results (i.e. outside of the normal range) will be 
summarized for each study phase (and at any visit during the study phase) (including unscheduled 
visits) and by visit and by dose group and for All dose groups combined.  
For each analyte, shift from Baseline (Low, Normal, High and abnormal [low/high], defined by the 
normal range) will be summarized for each study phase (including unscheduled visits) and by visit 
and/or dose group and for All dose groups combined.  
7.11.4 Vital Signs 
Temperature, HR and three measurements of SBP and DBP were to have been collected at each 
visit.  
Vital sign (Height, HR, Sitting Blood Pressure [SBP and DBP], Body Temperature) values and 
changes from Baseline will be summarized descriptively for each study phase by visit and/or dose 
group and for All dose groups combined.  
Shifts from Baseline for each of the vital signs specified in Table 10 will be summarized for each 
study phase (including unscheduled visits) and by visit, dose group and for All dose groups 
combined.  
Table 10: Vital sign categories for shift tables 
Vital Sign 
Category 
Flag 
Heart Rate 
< 44 bpm 
Low (L) 
44-100 bpm 
Normal 
101-120 bpm 
High (H) 
>120 bpm 
Very High (VH) 
< 44 bpm or >100 bpm 
Abnormal (A) 
Systolic Blood Pressure 
< 90 mmHg 
Low (L) 
90-139 mmHg 
Normal 
140-169 mmHg 
High (H) 
≥170 mmHg 
Very High (VH) 
< 90 mmHg  or > 139 mmHg 
Abnormal (A) 
Diastolic Blood Pressure 
< 50 mmHg 
Low (L) 
50-89 mmHg 
Normal 
90-109 mmHg 
High (H) 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 83 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Vital Sign 
Category 
Flag 
≥ 110 mmHg 
Very High (VH) 
< 50 mmHg  or > 89 mmHg 
Abnormal (A) 
All vital signs will be listed by subject and visit and abnormal results as per criteria defined in Table 
10 will be flagged.  
As of Protocol Amendment 5, Ambulatory blood pressure (i.e. BP measured outside of clinic) is no 
longer measured; ambulatory BP data collected will be listed by subject and visit and not 
summarized. 
7.11.5 Electrocardiograms 
Quantitative ECG measurements (PR interval, QRS duration, HR, uncorrected QT interval, QT 
interval corrected using Bazett’s correction (QTcB interval), and QT interval corrected using 
Fridericia’s correction (QTcF interval) and changes from Baseline will be summarized descriptively 
by study phase, visit, and/or dose group. Paired t-tests comparing the Baseline results to each 
post-baseline visit will be performed for All dose groups combined, means of the differences 
between Baseline and post-baseline results and associated two-sided 95% CI and two-sided p-
values from the tests will be displayed. The paired t-tests will be performed using SAS® PROC 
TTEST with PAIRED statement. 
The number and percentage of subjects with notable PR interval, QRS duration, uncorrected QT 
interval, QTcB interval, and QTcF interval will be summarized for each study phase by dose group 
and visit (and at any visit during the study phase). Notable results are defined as per Table 11a.  
In addition, shifts from Baseline in overall interpretation (normal, abnormal not clinically 
significant and abnormal clinically significant) will be tabulated by study phase and dose group for 
each post-baseline visit and displayed.  
For All dose groups combined, two-sided p-values from the McNemar’s paired comparison test 
will be provided for the shift from normal to not clinically significant or clinically significant 
abnormal values. The McNemar’s tests will be performed using SAS® PROC FREQ with EXACT 
statement and MCNEM options. 
Box-and-whisker plots will be produced to graphically represent the QTcF interval results and 
changes from Baseline at each visit by dose group (Dose Titration and Maintenance/Extended 
Evaluation Phases will be separated). 
ECG interval values will be listed by subject and visit. Notable results will be flagged as per criteria 
defined in Table 11a and summarized by study phase, dose group, and visit (for the Maintenance 
and Extended Evaluation Phases). The clinical abnormalities based on the overall interpretation 
will also be flagged.  
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 84 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Table 11a: Notable ECG Criteria 
Parameter 
Criteria  
QTc, QTcB, QTcF 
> 450 msec 
> 480 msec 
> 500 msec 
> 30 msec from Baseline 
> 60 msec from Baseline 
PR 
≥ 50% increase from Baseline if Baseline < 200 ms 
≥ 25% increase from Baseline if Baseline ≥ 200 ms 
QRS 
≥ 50% increase from Baseline if Baseline < 110 ms 
≥ 25% increase from Baseline if Baseline ≥ 110 ms 
QTcF categories (L, M or H, as described in Table 11b) will be used to summarize QTc by worst 
(greatest) QTcF interval change from Baseline and worst (greatest) actual value per study phase 
by dose group and all dose groups combined for the ITT population and in the Dose Titration Phase 
for the DT population.  These categories will be used for descriptive summaries and listings. The 
summaries will include the Baseline mean and median QTcF values. 
Table 11b: QTcF Interval Values for Additional Analyses  
QTcF Interval 
Criterion (msec) 
Flag 
Change from Baseline 
<30 
Low (L) 
30-60 
Mid (M) 
>60 
High (H) 
Actual Value 
>450-480 
Low (L) 
>480-500 
Mid (M) 
>500 
High (H) 
7.11.6 Physical Examination Findings 
Clinically significant physical examination findings found after the first dose of COR-003 were to 
be reported as AEs by the Investigators and will be summarized as AEs.  


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 85 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
7.11.7 Other Safety Measures 
Pituitary diameter (mm) and pituitary volume (mm3) will be summarized at Baseline and by study 
phase (Maintenance and Extended Evaluation), by dose group and for All dose groups combined. 
The summary will be provided only for subjects with CD at Baseline. Change from Baseline will 
also be summarized. Pituitary volume will be derived as π/6 times maximum pituitary height x 
length x width in mm3 (V=π/6 x hlw). The maximum height (h) is the larger of the coronal height 
and sagittal height. The length (l) and width (w) are the sagittal length and coronal width, 
respectively. 
Results from pituitary MRI will be listed by subject and visit. 
 Subgroup Analysis   
Subgroup summaries/analysis will be performed on the ITT population using the following 
subgroups. For each individual subgroup, if a subject has missing/unknown results, the subject 
will be excluded from the subgroup summaries/analysis (for example, if the age of a subject is 
missing / unknown the subject will be excluded from the by-age summaries/analyses). Subgroup 
summaries will only be performed for a minimum subgroup size of at least 30% of the ITT 
population, unless otherwise specified. P-values from statistical tests will be considered as 
descriptive rather than inferential. The following subgroups will be considered for analysis.  
• 
Cushing’s Disease 
o With CD – Subjects with CD as recorded in the CRF at Baseline,  
o Without CD (any other form of CS) 
• 
Prior Therapy for CS (3 sets of mutually exclusive subgroups) 
o Therapy-naïve versus not therapy-naïve (any prior drug therapy or surgery for CS) 
o Prior drug therapy versus No prior drug therapy 
o Prior surgery versus No prior surgery (applicable only to CD subjects) 
• 
Prior Radiation Therapy 
o Subjects without previously received radiation therapy 
• 
Hypertensive Subjects  
o Subjects with diagnosed Hypertension at Baseline, according to CRF response 
o Subjects without diagnosed Hypertension at Baseline, according to CRF response 
• 
Diabetes Status at Baseline 
o Subjects without diagnosed prediabetes or diabetes 
o Pre-Diabetes Subjects, according to CRF response (inclusion criterion 9) 
o Diabetic Subjects, according to CRF response 
• 
Region 
o US 
o non-US 
• 
Sex 
• 
Age 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 86 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
o ≤ Median 
o 
> Median  
• 
Time since CS diagnosis (note: the categories may be changed if the sample sizes are not 
adequate for some of the subgroups.) 
o < 2 years 
o 2 to <10 years  
o ≥ 10 years  
• 
Baseline UFC by tertiles 
• 
Baseline LNSC by tertiles 
• 
Baseline ACTH by tertiles 
 
The endpoints to be analyzed by subgroup are defined below in Table 12.  
The  subgroup analysis of efficacy endpoints by visit during the Maintenance Phase by Baseline 
UFC tertiles will address the part of the primary objective on evaluating the range of effective 
doses in subjects with various levels of hypercortisolism, since the by-visit summaries present the 
results by the Therapeutic Dose groups.


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 87 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Table 12:  Analyses by subgroup 
Output 
Subgroup 
Cushing’s Disease 
Prior Therapy for CS 
Prior Radiation Therapy 
Hypertensive subjects 
Diabetes Status 
Region 
Sex 
Age 
Time since CS Diagnosis 
Baseline UFC  
Baseline LNSC  
Baseline ACTH 
Demographics and Baseline Characteristics 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Exposure and Compliance 
X 
 
 
 
 
X 
 
 
 
 
 
 
Summaries and Primary Analysis of Clinical Response 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Summaries and bar charts of UFC Response and Improvement  
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Summary of Change from Baseline in Mean UFC 
X 
 
 
 
 
 
 
 
 
 
 
 
Plots of Mean Change and Percentage Change from Baseline in 
Mean UFC 
X 
 
 
 
 
 
 
 
 
 
 
 
Summary of CS Comorbidities Biomarkers  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Summary of Change and Percent Change from Baseline CS 
Comorbidities Biomarkers  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Summary of Clinical Signs and Symptoms of CS 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 88 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 
Summary of Change from Baseline in Clinical Signs and Symptoms of 
CS 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Summary of Total Peripheral Edema Score by Visit 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Summary of Change from Baseline in Total Peripheral Edema Score 
by Visit 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Summary of Acne Global Score by Visit (female only) 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
Summary of Change from Baseline in Acne Global Score by Visit 
(female only) 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
Summary of Cushing QoL Total Score by Visit 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Summary of Change from Baseline in Cushing QoL Total Score by 
Visit 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Summary of Total BDI-II Score by Visit 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Summary of Change from Baseline in Total BDI-II Score by Visit 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Summary of Mean LNSC 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Summary of Change from Baseline in Mean LNSC 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Overall Summary of TEAEs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Incidence of TEAEs by System Organ Class and Preferred Term  
 
 
 
 
 
X 
X 
X 
 
X 
X 
X 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan 
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 89 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
8 Timing of Analysis and Reporting 
Final data analysis will be performed in two separate stages: (1) the end of the Maintenance Phase 
and (2) at the end of the Extended Evaluation Phase.    
The final analysis of safety is to be coincident with the last subject visit following completion of 
the Extended Evaluation Phase (i.e. following at least 12 months’ treatment at the Therapeutic 
Dose), including the Follow-up visit.  Interim analyses of safety are planned to coincide with timing 
for the primary analysis of efficacy (i.e. after the last subject has completed the Maintenance 
Phase) and for any unplanned interim efficacy analyses, in order to assess benefits and risks of 
treatment simultaneously.  
In addition, planned and unplanned safety analyses will be performed and reported on a limited 
basis in order to satisfy requirements of study oversight, for example to Institutional Review 
Boards and Competent Authorities. These limited analyses (e.g. common adverse reactions 
summary) will not be accompanied by assessments of potential benefits. The Data Safety 
Monitoring Board (DSMB) will review all SAEs and adverse events of special interest (AESIs) on a 
rolling basis and assess benefits and risk of therapy systematically at approximately 6-month 
intervals. These analyses are detailed separately in the DSMB SAP. 
Once all data are available for analysis of the primary endpoint, at the End of the Maintenance 
Phase, those data will be locked (Data lock 1).  There will be a second lock after the Extended 
Evaluation Phase when the study is completed. (Data lock 2)  
• 
End of Maintenance Phase Analysis: This analysis will be conducted after the last subject 
is assessed for efficacy after 6 months in the Maintenance Phase. The data will be locked 
for all visits prior to and including the End of Maintenance Phase visit (and Follow-up visit 
for early withdrawal or irradiated subjects). For the data collected on an ongoing basis 
(i.e. not linked to visits) the data will be cleaned / reconciled and reported, up to the End 
of the Maintenance Phase. All visits and events reported during the Maintenance Phase, 
including the primary analysis, will be reported once all subjects have completed the 
Maintenance Phase. In addition, all SAEs occurring during the Extended Evaluation Phase 
but recorded in the database prior to the End of Maintenance Phase Analysis will be 
preliminarily summarized for the End of Maintenance Analysis in a separate table. 
• 
End of Extended Evaluation Phase Analysis (also corresponds to the final analysis): This 
analysis will be conducted once all subjects have completed the Extended Evaluation 
Phase, including the Follow-up visit, and the database has been locked. All visits and 
events occurring during the Extended Evaluation Phase will be reported at the end of the 
study once all subjects have completed the Extended Evaluation Phase. 
After the End of Maintenance Phase Analysis, data entered at a visit level will remain locked; data 
entered in the log pages (e.g. AEs and Concomitant medications) will be unlocked to allow the 
Investigator to enter additional data (e.g. end date of AEs).  


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan 
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 90 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
The results generated at the end of the Maintenance Phase are the primary results of the study.  
The results generated at the end of the Extended Evaluation Phase provide supplementary 
information.  
In the unlikely event that new information that becomes available after the Maintenance Phase 
database lock potentially impacts locked data, it will be discussed in the final study report. 
A Data Review Meeting to determine protocol deviations and analysis populations will be held at 
the end of the Maintenance Phase. Protocol deviations occurring after the end of the 
Maintenance Phase will be reported in the End of Extended Evaluation Phase Analysis, but will 
not lead to exclusion from any of the analysis populations.  
Further details regarding the timing of reporting by study phase and the analysis populations are 
presented in Appendix 15.5. 
 DATA SAFETY MONITORING BOARD 
Safety and limited efficacy data are reviewed by an external, independent DSMB every 6 months, 
and serious AEs and AESIs are reviewed in near real-time. The primary function of the DSMB is to 
monitor the study and make recommendations to the Cortendo study team regarding study 
conduct in order to safeguard the well-being of subjects already in the study and those to be 
recruited. The DSMB is responsible for providing external oversight and is not involved in the day-
to-day conduct of the study. The DSMB will not review efficacy results outside of their mandate 
to monitor benefits and risks of ongoing study treatment and will not be involved in making 
recommendations or decisions based primarily on efficacy results (i.e. the DSMB does not advise 
on futility or early stopping for established efficacy).  
No interim analyses of efficacy are planned.   
A specific DSMB Charter and an associated SAP provide further details. 
9 List of Laboratory Analytes, Units and Precision  
Only the following analytes listed in Table 13 will be included in the summary tables, using the 
units and number of decimal points presented in the below table for the precision level. There is 
one exception. For HbA1c, the values will be summarized in tables and figures in conventional 
unit, ie, as %, with 1 decimal point for the precision level. The HbA1c values will be presented in 
the listings in both conventional and international units. 
 
 
 
 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan 
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 91 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Table 13: List of Laboratory parameters, units and precision level 
Category 
Analyte 
SI Unit 
Decimal point 
Biochemistry 
Urea Nitrogen 
mmol/L 
1 
Biochemistry 
Creatinine 
umol/L 
1 
CS Comorbidity 
Glucose 
mmol/L 
1 
Biochemistry 
Sodium 
mmol/L 
0 
Biochemistry 
Potassium 
mmol/L 
1 
Biochemistry 
Chloride 
mmol/L 
0 
Biochemistry 
Total CO2 
mmol/L 
0 
Biochemistry 
Calcium 
mmol/L 
2 
Biochemistry 
Magnesium 
mmol/L 
2 
Biochemistry 
Phosphate 
mmol/L 
2 
Biochemistry 
Uric Acid 
umol/L 
0 
Biochemistry 
Albumin 
g/L 
0 
Biochemistry 
Protein, Total 
g/L 
0 
Biochemistry 
AST (SGOT) 
U/L 
0 
Biochemistry 
ALT (SGPT) 
U/L 
0 
Biochemistry 
GGT 
U/L 
0 
Biochemistry 
Alkaline Phosphatase 
U/L 
0 
Biochemistry 
Total Bilirubin 
umol/L 
0 
Biochemistry 
Direct Bilirubin 
umol/L 
0 
CS Comorbidity 
Total Cholesterol 
mmol/L 
2 
CS Comorbidity 
LDL-C 
mmol/L 
2 
CS Comorbidity 
HDL-C 
mmol/L 
2 
Biochemical 
Marker 
LDL-C:HDL-C 
ratio 
2 
Biochemical 
Marker 
Triglycerides 
mmol/L 
2 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan 
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 92 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Category 
Analyte 
SI Unit 
Decimal point 
Hematology 
Platelet count 
GI/L 
1 
Hematology 
Red blood cell (RBC) 
TI/L 
1 
Hematology 
White blood cell (WBC) 
GI/L 
1 
Hematology 
Hemoglobin 
g/L 
1 
Hematology 
Hematocrit 
1 
1 
Hematology 
MCV 
FL 
1 
Hematology 
MCH 
pg 
1 
Hematology 
MCHC 
g/L 
1 
Hematology 
Abs. Neutrophils * 
GI/L 
2 
Hematology 
Abs. Lymphocytes 
GI/L 
2 
Hematology 
Abs. Monocytes 
GI/L 
2 
Hematology 
Abs. Eosinophils 
GI/L 
2 
Hematology 
Abs. Basophils 
GI/L 
2 
Urinalysis 
Specific Gravity 
 
3 
Urinalysis 
pH 
 
1 
Biochemical 
Marker 
LNSC 
nmol/L 
1 
Hormone 
TSH 
mu/L 
2 
Hormone 
Free T4 
pmol/L 
1 
Hormone 
FSH 
IU/L 
1 
Biochemical 
Marker 
Albumin/Creatinine 
Ratio 
mg/mmol Creat 
1 
Urinalysis 
Albumin Urine 
mg/L 
1 
Coagulation 
INR 
 
1 
Coagulation 
PT 
sec 
1 
Coagulation 
PTT 
sec 
1 
CS Comorbidity 
HbA1C 
mmol/mol 
1 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan 
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 93 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Category 
Analyte 
SI Unit 
Decimal point 
OGTT 
Glucose, 
plasma 
(fasting) 
mmol/L 
1 
Biochemical 
Marker 
Serum Cortisol 
nmol/L 
2 
Biochemical 
Marker 
ACTH 
pmol/L 
1 
Biochemical 
Marker 
CRP 
mg/L 
1 
Hormone 
IGF-1 
nmol/L 
2 
Hormone 
Testosterone, Total 
nmol/L 
2 
Hormone 
Testosterone, Free 
nmol/L 
2 
Hormone 
Testosterone, 
bioavailable 
nmol/L 
2 
Efficacy 
- 
Urinalysis 
Cortisol, 24-hour 
nmol/D 
1 
Efficacy 
- 
Urinalysis 
Mean Cortisol, 24-hour 
nmol/D 
1 
Efficacy 
- 
Urinalysis 
Creatinine Excretion** 
mmol/D 
1 
* Total 
** Urine Creatinine 
Abbreviations: OGTT = Oral Glucose Tolerance Test. 
10 Clarifications and Changes from Planned Analyses in the 
Protocol 
• 
Primary objective: To clarify, the term “normal UFC” in the primary objective is meant to 
correspond to mean 24-hour UFC ≤ ULN, which is what is stated in the definition of the 
primary efficacy endpoint. 
• 
In addition to the 8 CS comorbidities biomarkers that were pre-specified in the protocol, 
CRP, BMI and abdominal girth are also considered as CS comorbidities biomarkers. It 
should be noted that change from Baseline in CRP during the Maintenance Phase is 
already identified as a secondary efficacy endpoint. 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan 
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 94 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
• 
The secondary endpoints section of the protocol amendment 6 (page 34) states ‘low and 
high density lipoproteins’ as a CS comorbidity biomarker. This should read ‘low and high 
density lipoprotein-associated cholesterol’, therefore in Section 4.1 of this document 
these endpoints have been correctly defined.  
• 
The secondary endpoints section of the protocol amendment 6 (page 79) states that 
‘shifts from Baseline (with regards to laboratory normal range) in individual biochemical 
markers of CS comorbidities will be analyzed using a t-test paired comparison test at each 
scheduled visit’.  The shifts are included but not the t-test, which is not an appropriate 
test for categorical shifts. 
• 
The exploratory endpoints section of the protocol amendment 6 (page 36) defines the 
first criterion of clinical benefit as ‘Clinical response as indicated by UFC ≤ ULN’. In section 
4.1 of this document for clarity this criterion has been defined as ‘UFC response as 
indicated by UFC ≤ ULN’. 
• 
There will be two data locks for this study. For the first data lock, the primary analysis will 
be performed after the last subject reaches End of Maintenance Phase. For the End-of-
Maintenance Phase analyses: 
o Total study exposure will be by study phase, and no summary is planned over the 
entire study duration. 
o AEs will be summarized up to the End of the Maintenance Phase, and by study 
phase.  No summary is planned over the entire study duration. 
o The protocol references a singular model for CS comorbidity biomarkers. This 
model is split by Maintenance Phase and Extended Evaluation Phase. 
• 
The terms Clinical Response and Complete or Partial Response were renamed UFC 
Response and UFC Improvement, respectively, with the following exception. The term 
Clinical Response is still used to refer to the primary efficacy endpoint.  
• 
Definitions for DT, MC, PK and PD population were added. 
• 
The definition of PP population was modified to require that the subjects complete the 
Maintenance Phase and that only major protocol deviations that may affect  the primary 
efficacy assessment will be considered. 
• 
Expanded on the DSMB from what is provided in the protocol. 
• 
New section to describe the analysis of Prior Therapy for CS was added. 
• 
Imputation scheme revised to include: 
o Imputation rule added for subjects who withdrew from the study prior to the 
Maintenance Phase for longitudinal analyses.  
o Creation of a new imputation scheme to assess the impact of a dose increase on 
UFC response and UFC improvement  
• 
Model methodology: Added region (US vs.  non-US) to the longitudinal models, as the 
study is a multi-center study, and there may be possible regional differences in efficacy. 
• 
Additional statistical testing has been added for CRP 
• 
Exploratory analyses: 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan 
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 95 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
o Two alternative definitions of Clinical Benefit have been added and will be 
summarized.  They are:  Clinical Benefit regardless of dose increase and Clinical 
Benefit with partial UFC normalization. 
o Medication changes are split by study phase. 
o Hypercortisolism / Photograph data were also collected at M3 (D90) visit in 
addition to Baseline, End of Maintenance Phase visit and End of Extended 
Evaluation visit; this has been added to the analysis. 
• 
Clarified that safety signals captured at unscheduled visits will be included in shift tables 
completed at a study phase level. 
• 
New subgroups have been added to those specified in the protocol, as follows:  
o Cushing’s Disease 
o Region 
o Age 
o Sex 
o Baseline UFC 
o Baseline LNSC 
o Baseline ACTH 
• 
Clarified CI methodology for the AE analysis and analysis of response rates. 
• 
Included definition of clinically  meaningful improvement.  
• 
Added description of graphics to investigate co-medications intake and change in their 
associated CS comorbidities biomarkers for drugs controlling blood pressure, diabetics 
and cholesterol. 
• 
Added summary of tumor volume from MRI assessments. 
• 
Added exploratory analysis for intra-subject variability within-visit variability for UFC, 
LNSC, SBP, DBP and abdominal girth. 
• 
Dexamethasone suppression test (DST) listing is now a screening / disposition listing and 
not considered as safety data. 
• 
Added exploratory analyses for Diabetes Mellitus, Hypertensive, Hypercholesterolemia, 
Obesity and Metabolic Syndrom Responders. 
11 Tables, Figures And Listing Shells 
See separate document for the TFL shells. The TFL shell document will be prepared prior to the 
dry runs that occurred before the Maintenance Phase database lock.  Further changes in the 
templates may occur after review of the dry runs prior to the Maintenance Phase database lock. 
12 Document History 
Date 
Version 
Modified by 
Brief details of changes made to template 
DDMMMYYYY 
1.0 
XXXXX 
Initial final version. 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan 
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 96 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
13 References 
[1] Fleseriu M, Biller BMK, Findling J, Molitch M, Schteingart D, Gross C on behalf of the SEISMIC 
Study Investigators. Mifepristone, a Glucocorticoid Receptor Antagonist, Produces Clinical and 
Metabolic Benefits in Subjects with Cushing’s Syndrome. J Clin Endocrinol Metab 2012; 97: 2039-
2049. 
[2] Colao A, Petersenn S, Newell-Price J, Findling J, Gu F, Maldonado M, Schoenherr U, Mills D, 
Salgado R, and Biller B for the Pasireotide B2305 Study Group. A 12-Month Phase 3 Study of 
Pasireotide in Cushing’s Disease. N Engl J Med 2012; 366, 914-924. 
[3] Petersenn S, Newell-Price J, Finding JW, Gus F, Maldonado M, Sen K, Salgado LR, Colao A, and 
Biller BMK on behalf of the Pasireotide B2305 Study Group. High variability in baseline urinary 
free cortisol values in subjects with Cushing’s disease. Clin Endocrinol. 2013; 0: 1-9. 
[4] Hochberg, Y. (1988), A sharper Bonferroni procedure for multiple tests of significance, 
Biometrika, 75, p 800-803 
[5] Hahn, GJ and Meeker WQ. (1991). Statistical Intervals: A Guide for Practitioners, p 82-90. New 
York: John Wiley & Sons. 
14 Appendices 
 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 97 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 PROCEDURE SCHEDULE FOR SCREENING, DOSE TITRATION, MAINTENANCE AND EXTENDED 
EVALUATION PHASES 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 98 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
14.1.1 Table 14: Study Flow Chart for Screening, Dose Titration, Maintenance and Extended Evaluation Phases 
Assessments 
Screening Phase 
Dose 
Titration 
Phase1 
Maintenance Phase2 
Months 
Extended 
Eval Phase3 
 
FU 
Visit4 
Scrn5  Baseline6 
DL-1 
DL-2 
DL-3 
DL-4 
DL-5 
DL-6 
DL-7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End 
of 
MP 
M 9 
M 12 
Informed Consent 
X 
 
                                                          
1 The approximate interval between dose adjustments will be 18 days (±4 days) including reporting time for UFC levels and safety laboratory assessments. If 
additional UFC collections are required, the approximate interval between either dose adjustments or to transition to maintenance should be 30 days (±7 days) to 
allow for additional testing and reporting time.  DL0 is a lower dose of 150 mg once daily that may be used if the subject develops signs and/or symptoms of 
adrenal insufficiency at DL1 and is to be restarted on a reduced the dose after their resolution (see Protocol Section 6.3.3 and 6.2.4.2). 
2 Maintenance visits should occur every 30 days (±7 days). 
3 Extended Evaluation visits should occur every 90 days (±14 days). 
4 Subjects who complete the Extended Evaluation Phase (M12 Visit) and are not progressing into an expanded access program should return approximately 2 weeks 
after completion of treatment with COR-003 for the Follow-up Visit (and no later than 30 days). NOTE: The Follow-Up Visit is not required for subjects continuing 
into expanded access treatment.  
5 Screening procedure to be performed following ICF and PRIOR to washout (if necessary) 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 99 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Assessments 
Screening Phase 
Dose 
Titration 
Phase1 
Maintenance Phase2 
Months 
Extended 
Eval Phase3 
 
FU 
Visit4 
Scrn5  Baseline6 
DL-1 
DL-2 
DL-3 
DL-4 
DL-5 
DL-6 
DL-7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End 
of 
MP 
M 9 
M 12 
Eligibility 
(Check 
Inclusion/Exclusion Criteria) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
7
 and 
demography 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medication 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer 
drug/drug 
accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam & assessment of 
appearance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                                          
6 Baseline procedures should be performed within 14 days (± 7 days) of DL-1 visit. 
7 Medical history to include previous documentation of diagnosis of Cushing’s syndrome, and data on all previous LFTs, as medical records permit.  Medical 
histories should be updated at Baseline. 
8 Blood pressure, diabetes, cholesterol medications will be specifically reviewed. 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 100 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Assessments 
Screening Phase 
Dose 
Titration 
Phase1 
Maintenance Phase2 
Months 
Extended 
Eval Phase3 
 
FU 
Visit4 
Scrn5  Baseline6 
DL-1 
DL-2 
DL-3 
DL-4 
DL-5 
DL-6 
DL-7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End 
of 
MP 
M 9 
M 12 
Assessment 
of 
 
Signs 
& 
Symptoms form 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (BP and HR in 
triplicate and temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/height/body habitus 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abdominal Girth (in triplicate) 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
HIV / Hepatitis B and C blood 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Photographs 
(consenting 
subjects only) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
ECG – Local ECG machine 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                          
9 Assessment of Clinical Signs & Symptoms form (Protocol Appendix M) to be completed along with the physical exam once at each dose level during the Dose 
Titration Phase and at each visit during the Maintenance and Extended Evaluation Phases 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 101 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Assessments 
Screening Phase 
Dose 
Titration 
Phase1 
Maintenance Phase2 
Months 
Extended 
Eval Phase3 
 
FU 
Visit4 
Scrn5  Baseline6 
DL-1 
DL-2 
DL-3 
DL-4 
DL-5 
DL-6 
DL-7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End 
of 
MP 
M 9 
M 12 
ECG – Spaulding10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contact subject 1 week after a 
new dose 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Additional safety evaluations 11  
(e.g., day 7 [± 3 days]) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Late-night salivary cortisol (1 
night) 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
Late-night salivary cortisol (2 
nights) 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
                                                          
10 Spaulding ECGs will be obtained over a maximum of 5 minutes at Baseline and within approximately 1 – 2 h after drug administration at each dose level during 
Dose Titration Phase and monthly at each visit the Maintenance and Extended Evaluation Phases 
11 Additional safety assessments at higher dose levels to include:  AEs, vital signs, routine safety laboratory assessments (including LFTs), ECGs, and serum 
cortisol levels. 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 102 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Assessments 
Screening Phase 
Dose 
Titration 
Phase1 
Maintenance Phase2 
Months 
Extended 
Eval Phase3 
 
FU 
Visit4 
Scrn5  Baseline6 
DL-1 
DL-2 
DL-3 
DL-4 
DL-5 
DL-6 
DL-7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End 
of 
MP 
M 9 
M 12 
TSH / free T4 12 
X 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Pituitary MRI (CD only)  
 
X 13 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
FSH (women only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine βHCG, females 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety clinical laboratory 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR/PT/PTT 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HbA1c  
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
OGTT (pre-diabetics only) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
                                                          
12 TSH/free T4 to be measured at DL4 Visit during the Dose Titration Phase.  If, subjects reach their maximum dose before the DL4 visit during the Dose Titration 
Phase, they will have TSH/free T4 measured at the M1 visit of Maintenance Phase. 
13 Pituitary MRI at Baseline only for CD subjects and if not done in prior 6 months 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 103 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Assessments 
Screening Phase 
Dose 
Titration 
Phase1 
Maintenance Phase2 
Months 
Extended 
Eval Phase3 
 
FU 
Visit4 
Scrn5  Baseline6 
DL-1 
DL-2 
DL-3 
DL-4 
DL-5 
DL-6 
DL-7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End 
of 
MP 
M 9 
M 12 
Dexamethasone 
Suppression 
Test (DST) 
 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum cortisol 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ACTH 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
lipid 
measurements, 
triglycerides 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IGF-1  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spot 
urine 
for 
albumin/creatinine ratio  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot 
urine 
for 
albumin/creatinine 
ratio 
(If 
abnormal at baseline) 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
                                                          
14 DST will need to be available at Baseline if not previously performed and results available within the 2 months prior to start of Screening Phase 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 104 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Assessments 
Screening Phase 
Dose 
Titration 
Phase1 
Maintenance Phase2 
Months 
Extended 
Eval Phase3 
 
FU 
Visit4 
Scrn5  Baseline6 
DL-1 
DL-2 
DL-3 
DL-4 
DL-5 
DL-6 
DL-7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End 
of 
MP 
M 9 
M 12 
Serum testosterone, free/total  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Baseline signs & AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cushing QoL questionnaire 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
BDI-II instrument 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
24-h 
UFC/free 
cortisol/creatinine/ 
urinary 
volume (4 collections) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
24-h 
urinary 
free 
cortisol/creatinine/ 
volume 
(2 collections) 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 105 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Assessments 
Screening Phase 
Dose 
Titration 
Phase1 
Maintenance Phase2 
Months 
Extended 
Eval Phase3 
 
FU 
Visit4 
Scrn5  Baseline6 
DL-1 
DL-2 
DL-3 
DL-4 
DL-5 
DL-6 
DL-7 
M 1 
M 2 
M 3 
M 4 
M 5 
M 6 
End 
of 
MP 
M 9 
M 12 
24-h 
urinary 
free 
cortisol/creatinine/ 
volume 
(2 to 4 collections) 15 
 
 
X 11 
X 11 
X 11 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic sampling 
 
 
(X) 16 
(X)12 
(X)12 
(X)12 
(X)12 
(X)12 
(X)12 
(X)12 
(X)12 
 
 
 
 
 
 
 
 
                                                          
15 First 24-hour urine collection will be ~Day 10 (±1 day) followed by the second 24-hour collection (ideally on two consecutive days) after start of each dose level.  
If UFC ≤ULN, there will be 2 additional 24-hour urine collection to confirm UFC results. 
16 Each subject will provide PK samples from at least 2 dose levels during their participation in the study.  The sample collection time and the dose level will vary 
from subject-to-subject and will be determined by the Investigator.  See Protocol Section 6.2.8.1 for details. 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0  / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 106 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 IDENTIFYING WORST RESULTS FOR LABORATORY PARAMETERS, VITAL SIGNS, ABDOMINAL GIRTH AND 
ECG PARAMETERS 
 
Table 15.2.1: Worst results for the laboratory parameters 
 
Category 
Analyte 
SI Unit 
Abnormal 
result 
Worst result 
Biochemistry 
Urea Nitrogen 
mmol/L 
Low/high 
High 
Biochemistry 
Creatinine 
umol/L 
High 
High 
CS Comorbidity 
Glucose 
mmol/L 
Low/high 
Low 
Biochemistry 
Sodium 
mmol/L 
Low/high 
High 
Biochemistry 
Potassium 
mmol/L 
Low/high 
Low  
Biochemistry 
Chloride 
mmol/L 
Low 
Low 
Biochemistry 
Total CO2 
mmol/L 
High 
High 
Biochemistry 
Calcium 
mmol/L 
Low/high 
High 
Biochemistry 
Magnesium 
mmol/L 
Low 
Low 
Biochemistry 
Phosphate 
mmol/L 
Low 
Low 
Biochemistry 
Uric Acid 
umol/L 
High 
High 
Biochemistry 
Albumin 
g/L 
Low 
Low 
Biochemistry 
Protein, Total 
g/L 
Low/high 
Low 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0  / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 107 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Category 
Analyte 
SI Unit 
Abnormal 
result 
Worst result 
Biochemistry 
AST (SGOT) 
U/L 
High 
High 
Biochemistry 
ALT (SGPT) 
U/L 
High 
High 
Biochemistry 
GGT 
U/L 
High 
High 
Biochemistry 
Alkaline Phosphatase 
U/L 
High 
High 
Biochemistry 
Total Bilirubin 
umol/L 
High 
High 
Biochemistry 
Direct Bilirubin 
umol/L 
High 
High 
CS Comorbidity 
Total Cholesterol 
mmol/L 
High 
High 
CS Comorbidity 
LDL-C 
mmol/L 
High 
High 
CS Comorbidity 
HDL-C 
mmol/L 
Low 
Low 
Biochemical Marker 
LDL-C:HDL-C 
ratio 
High 
High 
Biochemical Marker 
Triglycerides 
mmol/L 
High 
High 
Hematology 
Platelet count 
GI/L 
Low/high 
Low 
Hematology 
Red blood cell (RBC) 
TI/L 
Low/high 
Low 
Hematology 
White blood cell (WBC) 
GI/L 
Low/high 
Low 
Hematology 
Hemoglobin 
g/L 
Low/high 
Low 
Hematology 
Hematocrit 
1 
Low/high 
Low 
Hematology 
MCV 
FL 
Low/high 
Low 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0  / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 108 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Category 
Analyte 
SI Unit 
Abnormal 
result 
Worst result 
Hematology 
MCH 
pg 
Low 
Low 
Hematology 
MCHC 
g/L 
Low/high 
Low 
Hematology 
Abs. Neutrophils * 
GI/L 
Low/high 
Low 
Hematology 
Abs. Lymphocytes 
GI/L 
Low/high 
High 
Hematology 
Abs. Monocytes 
GI/L 
High 
High 
Hematology 
Abs. Eosinophils 
GI/L 
High 
High 
Hematology 
Abs. Basophils 
GI/L 
High 
High 
Urinalysis 
Specific Gravity 
 
Low/high 
Low 
Urinalysis 
pH 
 
Low/high 
Low 
Biochemical Marker 
LNSC 
nmol/L 
Low 
Low 
Hormone 
TSH 
mu/L 
Low/high 
Low 
Hormone 
Free T4 
pmol/L 
Low/high 
High 
Hormone 
FSH 
IU/L 
Low/high 
High 
Biochemical Marker 
Albumin/Creatinine Ratio 
mg/mmol 
Creat 
Low/high 
High 
Urinalysis 
Albumin Urine 
mg/L 
High 
High 
Coagulation 
INR 
 
High 
High 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0  / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 109 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Category 
Analyte 
SI Unit 
Abnormal 
result 
Worst result 
Coagulation 
PT 
sec 
High 
High 
Coagulation 
PTT 
sec 
High 
High 
CS Comorbidity 
HbA1C 
mmol/mol 
High 
High 
OGTT 
Glucose, plasma (fasting) 
mmol/L 
High 
High 
Biochemical Marker 
Serum Cortisol 
nmol/L 
Low/high 
Low 
Biochemical Marker 
ACTH 
pmol/L 
Low/high 
High 
Biochemical Marker 
CRP 
mg/L 
High 
High 
Hormone 
IGF-1 
nmol/L 
High 
High 
Hormone 
Testosterone, Total 
nmol/L 
Low 
Low 
Hormone 
Testosterone, Free 
nmol/L 
Low 
Low 
Hormone 
Testosterone, bioavailable 
nmol/L 
Low 
Low 
* Total 
Abbreviations: OGTT = Oral Glucose Tolerance Test. 
 
 
 
 
 
 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0  / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 110 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Table 15.2.2: Worst results for the vital signs and abdominal girth 
 
Parameter 
SI Unit 
Abnormal result 
Worst result 
SBP 
mmHg 
Low/high 
High 
DBP 
mmHg 
Low/high 
High 
BMI 
kg/m2 
Low/high 
High 
Weight 
kg 
Low/high 
High 
Abdominal 
girth 
cm 
Low/high 
High 
 
Table 15.2.3: Worst results for the ECG parameters 
 
Parameter 
SI Unit 
Abnormal result 
Worst result 
Heart Rate 
bpm 
Low/high 
Low 
QT Interval 
msec 
High 
High 
QT Duration 
msec 
High 
High 
QTcB 
msec 
High 
High 
QTcF 
msec 
High 
High 
QRS Complex 
msec 
High 
High 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0  / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 111 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Parameter 
SI Unit 
Abnormal result 
Worst result 
QRS Duration 
msec 
High 
High 
QRS Axis 
deg 
High 
High 
PR Interval 
msec 
Low/high 
Low 
RR Interval 
msec 
Low/high 
Low 
RR Duration 
msec 
Low/high 
Low 
 
 VISIT WINDOWS 
Table 16: Visit Windows 
Study 
Phase 
Period 
Repeat# 
Relative 
Day 
Relative day from: 
Efficacy Visit 
Window (exclude 
vital signs, and MRI) 
Safety Visit 
Window (include 
vital signs, and 
MRI) 
Baseline 
Screening/ 
Baseline 
 
1 
First dose 
[-14; -1] 
Dose 
Titration 
Phase* 
DL1  
1 
1 
First dose 
Any data collected under DL1, repeat 1 
DL2 
1 
1 
First dose at DL2 (first time) 
Any data collected under DL2, repeat 1 
DL3 
1 
1 
First dose at DL3 (first time) 
Any data collected under DL3, repeat 1 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0  / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 112 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Study 
Phase 
Period 
Repeat# 
Relative 
Day 
Relative day from: 
Efficacy Visit 
Window (exclude 
vital signs, and MRI) 
Safety Visit 
Window (include 
vital signs, and 
MRI) 
DL4 – D1 
1 
1 
First dose at DL4 (first time) 
Any data collected under DL4 –D1, repeat 
1 
DL4 – D4-7 
1 
5 
First dose at DL4 (first time) 
Any data collected under DL4 – D4-7, 
repeat 1 
DL4- D14-16 
1 
15 
First dose at DL4 (first time) 
Any data collected under DL4 – D14 -16, 
repeat 1 
(cont.) 
 
 
 
 
DL3 
2 
1 
First dose at DL3 (second time) 
Any data collected under DL3, repeat 2 
DL4 – D1 
2 
1 
First dose at DL4 (second time) 
Any data collected under DL4 – D1, 
repeat 2 
(cont.) 
 
 
 
 
 
Maintenan
ce Phase** 
Month 1 
 
1 
First dose in Maintenance 
Phase 
UFC: Not Applicable 
LNSC: [-10, 14] 
Other parameters: 
[1;14] 
[1; 14] 
Month 2 
 
30 
First dose in Maintenance 
Phase 
[15; 49] 
[15; 49] 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0  / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 113 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Study 
Phase 
Period 
Repeat# 
Relative 
Day 
Relative day from: 
Efficacy Visit 
Window (exclude 
vital signs, and MRI) 
Safety Visit 
Window (include 
vital signs, and 
MRI) 
Month 3 
 
60 
First dose in Maintenance 
Phase 
[50; 79] 
[50; 79] 
Month 4 
 
90 
First dose in Maintenance 
Phase 
[80; 109] 
[80; 109] 
Month 5 
 
120 
First dose in Maintenance 
Phase 
[110; 139] 
[110; 139] 
Month 6 
 
150 
First dose in Maintenance 
Phase 
[140; 169] 
[140; 169] 
End of 
Maintenance 
Phase 
 
180 
First dose in Maintenance 
Phase 
[170; 200] 
[170; 200] 
Extended 
Evaluation 
Phase** 
Month 9 
 
270 
First day post Maintenance 
Phase 
[201; 315] 
[201; 315] 
Month 12 
 
360 
First day post Maintenance 
Phase 
[316; 400] 
[316; 400] 
Follow-up 
 
14 
From last dose date 
[1, 35] 
[1, 35] 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0  / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 114 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Study 
Phase 
Period 
Repeat# 
Relative 
Day 
Relative day from: 
Efficacy Visit 
Window (exclude 
vital signs, and MRI) 
Safety Visit 
Window (include 
vital signs, and 
MRI) 
* Study drug interruptions will be ignored when assigning a result in the Dose Titration Phase to the appropriate dose level. 
** If the subject discontinued early or was irradiated, data collected strictly post last dose, will be summarized / analyzed under 
Follow-up visit.  
Note: For ECGs, if for a given date for a subject, there are both a centrally read ECG from Spaulding and a local ECG on that same 
day, the ECG from Spaulding will be the one included when applying the visit windows.   


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 115 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 BDI-II SCORING INFORMATION 
 
Question 
   Response 
Answer 
Score 
Question 
Score 
1. 
Sadness 
 
 
 
I do feel sad. 
0 
 
 
I feel sad much of the time. 
1 
 
 
I am sad all the time. 
2 
 
 
I am so sad or unhappy that I can’t stand it. 
3 
 
2. 
Pessimism 
 
 
 
I am not discouraged about my future. 
0 
 
 
I feel more discouraged about my future than I used to be. 
1 
 
 
I do not expect things to work out for me. 
2 
 
 
I feel my future is hopeless and will only get worse. 
3 
 
3. 
Past Failure 
 
 
 
I do not feel like a failure. 
0 
 
 
I have failed more than I should have. 
1 
 
 
As I look back, I see a lot of failures. 
2 
 
 
I feel I am a total failure as a person. 
3 
 
4. 
Loss of Pleasure 
 
 
 
I get as much pleasure as I ever did from the things I enjoy. 
0 
 
 
I don’t enjoy things as much as I used to. 
1 
 
 
I get very little pleasure from the things I used to enjoy. 
2 
 
 
I can’t get any pleasure from the things I used to enjoy. 
3 
 
5. 
Guilty Feelings 
 
 
 
I don’t feel particularly guilty. 
0 
 
 
I feel guilty over many things I have done or should have done. 
1 
 
 
I feel quite guilty most of the time. 
2 
 
 
I feel guilty all of the time. 
3 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 116 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Question 
   Response 
Answer 
Score 
Question 
Score 
6. 
Punishment Feelings 
 
 
 
I don’t feel I am being punished. 
0 
 
 
I feel I may be punished. 
1 
 
 
I expect to be punished. 
2 
 
 
I feel I am being punished. 
3 
 
7. 
Self-Dislike 
 
 
 
I feel the same about myself as ever. 
0 
 
 
I have lost confidence in myself. 
1 
 
 
I am disappointed in myself. 
2 
 
 
I dislike myself. 
3 
 
8. 
Self-Criticalness 
 
 
 
I don’t criticize or blame myself more than usual. 
0 
 
 
I am more critical of myself than I used to be. 
1 
 
 
I criticize myself for all my faults. 
2 
 
 
I blame myself for everything bad that happens. 
3 
 
9. 
Suicidal Thoughts or Wishes 
 
 
 
I don’t have any thoughts of killing myself. 
0 
 
 
I have thoughts of killing myself, but I would not carry them out. 
1 
 
 
I would like to kill myself. 
2 
 
 
I would kill myself if I had the chance. 
3 
 
10. Crying 
 
 
 
I don’t cry any more than I used to. 
0 
 
 
I cry more than I used to. 
1 
 
 
I cry over every little thing. 
2 
 
 
I feel like crying, but I can’t. 
3 
 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 117 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Question 
   Response 
Answer 
Score 
Question 
Score 
11. Agitation 
 
 
 
I am no more restless or wound up than usual. 
0 
 
 
I feel more restless or wound up than usual. 
1 
 
 
I am so restless or agitated that it’s hard to stay still. 
2 
 
 
I am so restless or agitated that I have to keep moving or doing 
something. 
3 
 
12. Loss of Interest 
 
 
 
I have not lost interest in other people or activities. 
0 
 
 
I am less interested in other people or things than before. 
1 
 
 
I have lost most of my interest in other people or things. 
2 
 
 
It’s hard to get interested in anything. 
3 
 
13. Indecisiveness 
 
 
 
I make decisions about as well as ever. 
0 
 
 
I find it more difficult to make decisions than usual. 
1 
 
 
I have much greater difficulty in making decisions than I used to. 
2 
 
 
I have trouble making any decision. 
3 
 
14. Worthlessness 
 
 
 
I do not feel I am worthless. 
0 
 
 
I don’t consider myself as worthwhile and useful as I used to. 
1 
 
 
I feel more worthless as compared to other people. 
2 
 
 
I feel utterly worthless. 
3 
 
15. Loss of Energy 
 
 
 
I have as much energy as ever. 
0 
 
 
I have less energy than I used to have. 
1 
 
 
I don’t have enough energy to do very much. 
2 
 
 
I don’t have enough energy to do anything. 
3 
 
 
 
 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 118 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
Question 
   Response 
Answer 
Score 
Question 
Score 
16. Changes in Sleeping Pattern 
 
I have not experienced any change in my sleeping pattern. 
0 
 
 
I sleep somewhat more than usual. 
1 
 
 
I sleep somewhat less than usual. 
1 
 
 
I sleep a lot more than usual. 
2 
 
 
I sleep a lot less than usual. 
2 
 
 
I sleep most of the day. 
3 
 
 
I wake up 1–2 hours early and can’t get back to sleep. 
3 
 
17. Irritability 
 
 
 
I am no more irritable than usual. 
0 
 
 
I am more irritable than usual. 
1 
 
 
I am much more irritable than usual. 
2 
 
 
I am irritable all the time. 
3 
 
18. Changes in Appetite 
 
 
 
I have not experienced any change in my appetite. 
0 
 
 
My appetite is somewhat less than usual. 
1 
 
 
My appetite is somewhat greater than usual. 
1 
 
 
My appetite is much less than before. 
2 
 
 
My appetite is much greater than usual. 
2 
 
 
I have no appetite at all. 
3 
 
 
I crave food all the time. 
3 
 
19. Concentration Difficulty 
 
 
 
I can concentrate as well as ever. 
0 
 
 
I can’t concentrate as well as usual. 
1 
 
 
It’s hard to keep my mind on anything for very long. 
2 
 
 
I find I can’t concentrated on anything. 
3 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 119 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 
Question 
   Response 
Answer 
Score 
Question 
Score 
20. Tiredness or Fatigue 
 
 
 
I am no more tired or fatigued than usual. 
0 
 
 
I get more tired or fatigued more easily than usual. 
1 
 
 
I am too tired or fatigued to do a lot of the things I used to do. 
2 
 
 
I am too tired or fatigued to do most of the things I used to do. 
3 
 
21 
Loss of Interest in Sex 
 
 
 
I have not noticed any recent change in my interest in sex. 
0 
 
 
I am less interested in sex than I used to be. 
1 
 
 
I am much less interested in sex now. 
2 
 
 
I have lost interest in sex completely. 
3 
 
 
 
 
 
 
TOTAL SCORE (Sum of all responses) 
 
 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 120 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 STUDY ENDPOINTS BY POPULATION, PHASE AND TIMING OF ANALYSIS 
Table 17: Study endpoints by population, phase and timing of analysis 
 
 
Analysis Set 
Maintenance Phase Database Lock 
End of Study 
Database 
Lock 
All 
ITT 
DT 
M 
MC 
PP 
Baseline 
Dose 
Titration 
Phase 
Maintenance 
Phase 
Extended 
Evaluation 
Phase 
Extended 
Evaluation 
Phase 
Supportive Data 
Subject Disposition  
x 
x 
 
 
x 
x 
x 
x 
Summary of Populations 
x 
 
 
x 
Demographic and Baseline 
 
x 
x 
x 
x 
x 
x 
Protocol Deviations Leading to Exclusion 
from the PP Population  
 
x 
 
 
Medical History 
 
x 
x 
 
x 
 
 
 
 
 
 
Disease Characteristics  
 
x 
x 
 
x 
x 
Other Medical History  
 
x 
 
 
x 
x 
Prior Medications  
 
x 
 
 
x 
New and Continuing Medications 
 
x 
 
 
x 
x 
x 
x 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 121 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 
 
Analysis Set 
Maintenance Phase Database Lock 
End of Study 
Database 
Lock 
All 
ITT 
DT 
M 
MC 
PP 
Baseline 
Dose 
Titration 
Phase 
Maintenance 
Phase 
Extended 
Evaluation 
Phase 
Extended 
Evaluation 
Phase 
Prior CS Drug Therapy, Radiotherapy and 
Surgery 
 
x 
 
 
x 
Study Drug Exposure and Compliance  
 
x 
 
 
x 
x 
x 
x 
x 
Primary Endpoint 
Primary Analysis of UFC Response 
 
x 
 
x 
x 
x 
x 
Secondary Endpoints 
Other analyses of UFC Response and/or 
Improvement 
 
x 
 
 
x 
x 
x 
 
x 
x 
x 
Summaries and Plots of UFC Response and/or 
Improvement by Visit (and/or Dose, if 
applicable) 
 
x 
 
 
 
x* 
 
 
 
x* 
x 
x* 
 
 
 
x 
x 
 
 
Individual Plots of Change from Baseline to 
End of Maintenance Phase in UFC 
 
 
 
 
x 
 
 
 
x 
 
 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 122 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 
 
Analysis Set 
Maintenance Phase Database Lock 
End of Study 
Database 
Lock 
All 
ITT 
DT 
M 
MC 
PP 
Baseline 
Dose 
Titration 
Phase 
Maintenance 
Phase 
Extended 
Evaluation 
Phase 
Extended 
Evaluation 
Phase 
Plots of Effect of Dose Increases During the  
Maintenance Phase of UFC 
 
 
 
 
x 
 
 
 
 
 
 
Serum and LNSC 
 
x 
 
 
x 
x 
x 
x 
CS Comorbidities Biomarkers 
 
x 
 
 
x 
x 
x 
x 
Clinical signs and symptoms of CS 
 
x 
 
 
x 
x 
x 
Cushing Quality of Life Total Score 
 
x 
 
 
x 
x 
x 
x 
BDI-II Total Score 
 
x 
 
 
x 
x 
x 
x 
OGTT and Spot Albumin/Creatinine Ratio 
  
x 
 
 
x 
x 
x 
x 
Abnormal Spot Albumin/Creatinine Ratio  
  
x 
 
 
x 
x 
x 
Exploratory Endpoints 
Clinical Benefit Rate 
  
x 
 
 
x 
x 
Changes to Antihypertensive, Anti-diabetic, 
Cholesterol-lowering Medications  
  
x 
 
 
x 
x 
Hypercortisolism from Photographs Scores 
  
x 
 
 
x 
x 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 123 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 
 
Analysis Set 
Maintenance Phase Database Lock 
End of Study 
Database 
Lock 
All 
ITT 
DT 
M 
MC 
PP 
Baseline 
Dose 
Titration 
Phase 
Maintenance 
Phase 
Extended 
Evaluation 
Phase 
Extended 
Evaluation 
Phase 
Intra-subject Within Visit Variability for 
Applicable Efficacy Parameters 
  
x 
 
 
x 
x 
Other Exploratory Analysis 
Diabetes Mellitus Responders 
 
x 
 
 
 
 
 
 
x 
 
 
Hypertension Responders 
 
x 
 
 
 
 
 
 
x 
 
 
Hypercholesterolemia Responders 
 
x 
 
 
 
 
 
 
x 
 
 
Obesity Responders 
 
x 
 
 
 
 
 
 
x 
 
 
Safety Endpoints 
AEs 
 
x 
x^ 
 
x 
x 
x 
x 
Clinical Laboratory Assessments (changes 
from baseline) 
 
x 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Assessments (summary 
statistics, shift tables, plots) 
 
x 
 
x^ 
 
x 
x 
x 


 
Sponsor: CORTENDO 
Protocol: COR-2012-01 
Statistical Analysis Plan:  
Version 1.0 / 19JUN2018 
 
Author: Jean-Luc Beffy 
Page 124 of 124 
BMSOP111/F2 
Version Draft 
 
 
 
 
 
Analysis Set 
Maintenance Phase Database Lock 
End of Study 
Database 
Lock 
All 
ITT 
DT 
M 
MC 
PP 
Baseline 
Dose 
Titration 
Phase 
Maintenance 
Phase 
Extended 
Evaluation 
Phase 
Extended 
Evaluation 
Phase 
Hormones 
and 
Biomarkers 
Laboratory 
Evaluations 
 
x 
 
 
x 
x 
x 
ACTH 
 
x 
x 
 
x 
 
 
x 
x 
 
 
Vital Signs  
 
x 
 
 
x 
x 
x 
ECG Parameters 
 
x 
x^ 
 
x 
x 
x 
Tumor size and volume 
 
x 
 
 
x 
x 
x 
* Selected summaries only, see Section 8.8 for further details. 
^ Selected Summaries only, see Section 8.11 for further details.