Conditions: Hypogonadism
Keywords: Hypogonadism
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 117
Healthy volunteers: no

Brief summary:
Multicenter study consisting of two study periods as follows: a 90-day Treatment Period, with potential extension by 30 days for those patients requiring a dose increase, as determined by the treating physician. Participants receiving 122.5mg of NATESTO (5.5 mg of testosterone) per nostril twice daily may have an increased daily dose adjustment on Day 90, based on their hypogonadism symptoms.

Detailed description:
The primary objective of the study is to measure patient satisfaction with testosterone replacement therapy before (for non-naïve patients), during and after treatment with NATESTO.

The secondary objectives of this study are to evaluate the following:

* Improvement in hypogonadism symptoms;
* Patient treatment preference versus prior testosterone replacement therapy;
* Frequency of daily dose of NATESTO;
* Safety monitoring.

The population for this study is adult men 18-65 years of age inclusive, with primary or secondary hypogonadism, with historical documented total serum testosterone concentration of ≤300 ng/dL and the ability to provide informed consent. Eligible subjects include treatment-naïve, hypogonadal patients with a documented confirmation of hypogonadism, as well as patients previously treated with an alternate topical testosterone replacement therapy (TRT) for at least three months prior to selection. Participants currently receiving topical testosterone replacement therapy will be required to discontinue their current testosterone treatment before initiating treatment with NATESTO. The approximate total duration of study participation for participants completing the study will be up to 150 days (\~21 weeks).

This is a Phase 4, multicenter study consisting of two study periods as follows:

* A 90-day Treatment Period, extended to 120-days for those subjects requiring a dose increase, during which participants will receive 122.5 mg of NATESTO (5.5mg testosterone) per nostril twice daily (BID) for 90 days. At Day 90, the treating physician will assess the patient's hypogonadism symptoms, review patient's completed questionnaires and based on the Canadian Men's Health Foundation Multidisciplinary Guidelines as endorsed by both the Canadian Urological Association and the Canadian Society of Endocrinology and Metabolism1, decide if continuation at a higher dose frequency of three-times daily (TID) is required for efficacy. For TID patients, there will be a 30-day Treatment Extension during which participants whose symptoms were not adequately treated on a BID dose, will receive 122.5 mg of NATESTO TID (5.5mg testosterone) per nostril. At Day 120, the TID patient will return to the site for examination, discussion of symptoms with the physician and questionnaire completion. All patients will have their blood testosterone levels assessed at Day 90 and only TID patients at Day 120.
* Post-study follow-up: All study patients will be requested to follow up at Day 150 to confirm whether they continued therapy with NATESTO.

Patient selection will come as a result of a doctor's visit for routine controls, prescription renewal and by pre-selection by the physician from among hypogonadal patients currently receiving topical testosterone replacement therapies and willing to participate in a clinical trial with NATESTO, or as a result of an initial consultation for naïve patients.

At Visit 1, patients who agree to participate in the study will come to the site. They will provide written informed consent and undergo a complete physical examination, including a nasal examination, and medical history collection. Blood pressure, heart rate, weight, and height measurements (from which body mass index \[BMI\] will be determined) will also be performed. Blood will be drawn at a local lab for safety assessment. However, if these values have already been documented in their patient file from the preceding 6 months, then those values will be entered into the eCRF. Previous treatment for hypogonadism (drug and nondrug; daily dose) will be recorded, as well as other concomitant treatment with drug or nondrug therapies. Study questionnaires Treatment Satisfaction Questionnaire for Medication (TSQM) and quantitative Androgen Deficiency in the Aging Male (qADAM) will be reviewed and subjects will be given instructions for proper completion of the instruments. Patients will complete Part A of the Patient Preference and Use Questionnaire. Patients will also be provided with a prescription for a 90-day supply of the study medication, NATESTO, and a Study Drug Access Card that will be used for payment purposes at the patient's preferred pharmacy.

Non-naïve participants will be instructed to stop their current topical treatment at least one day and no more than 7 days prior to initiation of treatment with NATESTO. Patients should not take both medications simultaneously.

The open-label Treatment Period will consist of a maximum of 5 study visits: 2 visits will be done via telephone by the Study Coordinator (Visit 2, Day 30 and Visit 3, Day 60) and one clinic visit (Visit 4, Day 90), and a last clinic visit for patients who were placed on a TID dose (Visit 5, Day 120).

At Visit 2 (Day 30) and Visit 3 (Day 60), participants will be required to complete questionnaires (TSQM and qADAM) by telephone with the Study Coordinator, and will also be asked about any concurrent medications or AEs.

At Visit 4 (Day 90), the patient will return to the site. Any unreported adverse events will be recorded. Patients will undergo a basic physical examination including a nasal examination. Blood pressure, heart rate, weight, and height measurements (from which body mass index \[BMI\] will be determined) will be recorded. Hypogonadism symptoms will be assessed by the Investigator making reference to the qADAM questionnaire results, and the patient will complete the TSQM.

At Visit 4 (Day 90), if in the physician's judgment the patient is adequately treated with twice daily (BID) NATESTO, the physician will decide whether the patient a.) should return to their previous therapy; b.) remain on NATESTO; or c.) consider a new treatment option. The physician will provide the patient with a prescription for the treatment chosen. The BID patients will have a blood draw taken at a local laboratory for safety assessment and to assess their testosterone level. This will constitute the END OF TREATMENT for BID subjects. These adequately controlled patients will complete Part B (for Non-naïve) or Part C (for Naïve) of the Patient Preference and Use Questionnaire.

At Visit 4 (Day 90), if the physician's judgement is that the twice daily (BID) dose of NATESTO was not adequate to treat the patient's symptoms and believes that the patient will benefit from a higher dose, then a prescription will be given to the patient for three times daily (TID) NATESTO. The Study Drug Access Card will be used for payment purposes at the patient's preferred pharmacy. These patients moving to TID will have a blood draw taken at a local laboratory to assess safety as well as their testosterone level. The patient will schedule Visit 5 (Day 120) at this time.

At Visit 5 (Day 120 for TID patients only), any unreported adverse events will be recorded. Patients will undergo a basic physical examination including a nasal examination. Blood pressure, heart rate, weight, and height measurements (from which body mass index \[BMI\] will be determined) will be recorded. The patients will have a blood draw taken at a local laboratory for safety assessment and to assess their testosterone level. In addition to TSQM and qADAM questionnaires, subjects will also complete Part B (for Non-naïve) or Part C (for Naïve) of the Patient Preference and Use Questionnaire. The physician will decide whether the patient a.) should return to their previous therapy; b.) remain on NATESTO; or c.) consider a new treatment option. The physician will provide the patient with a prescription for the treatment chosen.

At Visit 6 (Day 150), all study patients will be asked by telephone whether they are still taking NATESTO and why (or why not).

Arms:
arm 1: NATESTO Testosterone Nasal Gel administered intranasally to patients with no prior TRT experience. Multiple-dose dispenser will be used for gel deposition into the nasal cavity. The dispenser is a finger-actuated, non-pressurized dispensing system designed to deliver 122.5mg of NATESTO (5.5mg testosterone) per actuation.

For BID administration, NATESTO 22 mg/day of testosterone. For the subset of patients that continue on TID, NATESTO 33 mg/day of testosterone. arm 2: NATESTO Testosterone Nasal Gel administered intranasally to patients who had prior TRT. Multiple-dose dispenser will be used for gel deposition into the nasal cavity. The dispenser is a finger-actuated, non-pressurized dispensing system designed to deliver 122.5mg of NATESTO (5.5mg testosterone) per actuation.

For BID administration, NATESTO 22 mg/day of testosterone. For the subset of patients that continue on TID, NATESTO 33 mg/day of testosterone.

Interventions: intervention 1: NATESTO Testosterone Nasal Gel
Intervention descriptions: intervention 1: Participants will be instructed to administer 5.5 mg of testosterone (1 actuation) per nostril of NATESTO Testosterone Nasal Gel once in the morning and once in the evening (at least 6 hours apart), preferably at the same time each day for a total daily dose of 22 mg/day of testosterone. Patients should be instructed to completely depress the pump 1 time in each nostril to receive the total dose.

For three times daily (after Visit 4 \[Day 90\] if symptoms not adequately managed by a BID dose), NATESTO will be administered intranasally once in the morning, once in the afternoon and once in the evening (approximately 6-8 hours apart), preferably at the same time each day for a total daily dose of 33 mg/day of testosterone.

Protocol document:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL  
 
A 150-DAY, PROSPECTIVE, PHASE 4, OPEN-LABEL STUDY, 
EVALUATING PATIENT SATISFACTION AND SYMPTOM 
IMPROVEMENT WHEN TREATING MALE HYPOGONADISM WITH 
TESTOSTERONE NASAL GEL (Natesto™) (MY-T STUDY)  
Investigational Product: Testosterone nasal gel 4.5% w/w (Natesto™) 
Protocol Number: NAT-2016-01 
 
Sponsor: 
 
Acerus Pharmaceuticals Corporation 
2486 Dunwin Drive 
Mississauga 
ON L5L 1J9 
Canada 
 
Telephone: 1-905-817-8191 
Facsimile: 1-905-569-1809 
 
Protocol Amendment:  
Version 5.0 
February 13, 2018 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Acerus Pharmaceuticals Corporation except to the extent that disclosure would be 
required by law and for the purpose of evaluating and/or conducting a clinical study for Acerus 
Pharmaceuticals Corporation. You are allowed to disclose the contents of this document only to 
your Institutional Review Board (IRB) and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Acerus Pharmaceuticals Corporation and that it may not be further 
disclosed to third parties. 




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SYNOPSIS 
 
TITLE: A 150-Day, Prospective, Phase 4, Open-Label Study, Evaluating Patient Satisfaction 
and Symptom Improvement when Treating Male Hypogonadism with Testosterone Nasal Gel 
(Natesto™) (My-T Study) 
 
PROTOCOL NUMBER: NAT-2016-01 
 
INVESTIGATIONAL PRODUCT: Testosterone Nasal Gel 4.5% w/w (Natesto™) 
 
PHASE: 4 
 
INDICATION: Adult male hypogonadism (primary and secondary) 
 
OBJECTIVES: 
 
The primary objective of the study is to measure patient satisfaction with testosterone 
replacement therapy before (for non-naïve patients), during and after treatment with NATESTO.  
 
The secondary objectives of this study are to evaluate the following: 
• Improvement in hypogonadism symptoms; 
• Patient treatment preference versus prior testosterone replacement therapy; 
• Frequency of daily dose of NATESTO;  
• Safety monitoring. 
 


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POPULATION: 
 
The population for this study is adult men 18-65 years of age inclusive, with primary or secondary 
hypogonadism, with historical documented total serum testosterone concentration of ≤300 ng/dL 
/ ≤10.4nmol/L and the ability to provide informed consent.  Eligible subjects include treatment-
naïve, hypogonadal patients with a documented confirmation of hypogonadism, as well as 
patients previously treated with an alternate topical testosterone replacement therapy (TRT) for 
at least three months prior to selection.  
 
Participants currently receiving topical testosterone replacement therapy will be required to 
discontinue their current testosterone treatment before initiating treatment with NATESTO.  
 
 
Study Duration 
The approximate total duration of study participation for participants completing the study will 
be up to 150 days (~21 weeks). 
 
 
This is a Phase 4, multicenter study consisting of two study periods as follows: 
 
• A 90-day Treatment Period, extended to 120-days for those subjects 
requiring a dose increase, during which participants will receive 
122.5 mg of NATESTO (5.5mg testosterone) per nostril twice daily 
(BID) for 90 days.  At Day 90, the treating physician will assess the 
patient’s hypogonadism symptoms, review patient’s completed 
questionnaires and based on the Canadian Men’s Health Foundation 
Multidisciplinary Guidelines as endorsed by both the Canadian 
Urological Association and the Canadian Society of Endocrinology and 
Metabolism1, decide if continuation at a higher dose frequency of three-
times daily (TID) is required for efficacy. For TID patients, there will be 
a 30-day Treatment Extension during which participants whose 
symptoms were not adequately treated on a BID dose, will receive 
122.5 mg of NATESTO TID (5.5mg testosterone) per nostril. At Day 
120, the TID patient will return to the site for examination, discussion of 
symptoms with the physician and questionnaire completion.  All patients 
will have their blood testosterone levels assessed at Day 90 and only TID 
patients at Day 120.  
• Post-study follow-up: All study patients will be requested to follow up at 
Day 150 to confirm whether they continued therapy with NATESTO. 
 
Patient Screening 
 
Patient selection will come as a result of a doctor’s visit for routine controls, prescription 
renewal and by pre-selection by the physician from among hypogonadal patients currently 


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receiving topical testosterone replacement therapies (TRT) and willing to participate in a 
clinical trial with NATESTO, or as a result of an initial consultation for naïve patients.    
 
Eligible patients will receive information about NATESTO and the Informed Consent Form 
(ICF), and can contact the site to clarify any questions before deciding to participate in the trial. 
 
At Visit 1, patients who agree to participate in the study will come to the site. They will provide 
written informed consent and undergo a complete physical examination, including a nasal 
examination, and medical history collection. Blood pressure, heart rate, weight, and height 
measurements (from which body mass index [BMI] will be determined) will also be performed. 
Blood will be drawn at a local lab for safety assessment. However, if these values have already 
been documented in their patient file from the preceding 6 months, then those values will be 
entered into the eCRF. Previous treatment for hypogonadism (drug and nondrug; daily dose) 
will be recorded, as well as other concomitant treatment with drug or nondrug therapies. Study 
questionnaires Treatment Satisfaction Questionnaire for Medication (TSQM) and quantitative 
Androgen Deficiency in the Aging Male (qADAM) will be reviewed and subjects will be given 
instructions for proper completion of the instruments.  All patients will complete qADAM, and 
non-naïve patients will complete the TQSM. Patients will also complete Part A of the Patient 
Preference and Use Questionnaire. Patients will be provided with a prescription for a 90-day 
supply of the study medication, NATESTO, and a Study Drug Access Card that will be used for 
payment purposes at the patient’s preferred pharmacy. 
 
Non-naïve participants will be instructed to stop their current topical treatment at least one day 
and no more than 7 days prior to initiation of treatment with NATESTO. Patients should not 
take both medications simultaneously. 
  
 
Treatment Period 
 
The open-label Treatment Period will consist of a maximum of 5 study visits: 2 visits will be 
done via telephone by the Study Coordinator (Visit 2, Day 30; and Visit 3, Day 60) and one 
clinic visit (Visit 4, Day 90), and a last clinic visit for patients who were placed on a TID dose 
(Visit 5, Day 120).  
 
 
At Visit 2 (Day 30) and Visit 3 (Day 60), participants will be required to complete 
questionnaires (TSQM and qADAM) by telephone with the Study Coordinator, and will also be 
asked about any concurrent medications or AEs.   
 
At Visit 4 (Day 90), the patient will return to the site. Any unreported adverse events will be 
recorded.  Patients will undergo a basic physical examination including a nasal examination. 
Blood pressure, heart rate, weight, and height measurements (from which body mass index 
[BMI] will be determined) will be recorded. Hypogonadism symptoms will be assessed by the 
Investigator making reference to the qADAM questionnaire results, and the patient will 
complete the TSQM.   
 


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At Visit 4 (Day 90), if in the physician’s judgment the patient is adequately treated with twice 
daily (BID) NATESTO, the physician will decide whether the patient a.) should return to their 
previous therapy; b.) remain on NATESTO; or c.) consider a new treatment option. The 
physician will provide the patient with a prescription for the treatment chosen. The BID patients 
will have a blood draw taken at a local laboratory for safety assessment and to assess their 
testosterone level. This will constitute the END OF TREATMENT for BID subjects. These 
adequately controlled patients will complete Part B (for Non-naïve) or Part C (for Naïve) of the 
Patient Preference and Use Questionnaire.   
  
At Visit 4 (Day 90), if the physician’s judgement is that the twice daily (BID) dose of 
NATESTO was not adequate to treat the patient’s symptoms and believes that the patient will 
benefit from a higher dose, then a prescription will be given to the patient for three times daily 
(TID) NATESTO.  The Study Drug Access Card will be used for payment purposes at the 
patient’s preferred pharmacy. These patients moving to TID will have a blood draw taken at a 
local laboratory to assess safety as well as their testosterone level.   The patient will schedule 
Visit 5 (Day 120) at this time. 
 
At Visit 5 (Day 120 for TID patients only), any unreported adverse events will be recorded. 
Patients will undergo a basic physical examination including a nasal examination. Blood 
pressure, heart rate, weight, and height measurements (from which body mass index [BMI] will 
be determined) will be recorded. The patients will have a blood draw taken at a local laboratory 
for safety assessment and to assess their testosterone level. In addition to TSQM and qADAM 
questionnaires, subjects will also complete Part B (for Non-naïve) or Part C (for Naïve) of the 
Patient Preference and Use Questionnaire. The physician will decide whether the patient a.) 
should return to their previous therapy; b.) remain on NATESTO; or c.) consider a new 
treatment option.  The physician will provide the patient with a prescription for the treatment 
chosen. 
 
Post-study Follow-Up  
 
At Visit 6 (Day 150), all study patients will be asked by telephone whether they are still taking 
NATESTO and why (or why not).   
 
See Appendix A, Schedule of Procedures, page 57. 
 
 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
 
Study Drug: 
Testosterone nasal gel 4.5% w/w ( NatestoTM) 
Pharmaceutical form: 
Gel for intranasal administration 
Content: 
Active ingredient: testosterone 
Excipients: silicon dioxide, castor oil, and oleoyl 
polyoxylglycerides 
Mode of administration: 
Intranasal 
Storage conditions: 
Controlled Room Temperature (15-30ºC) 
 


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NATESTO is administered intranasally by the participant. A multiple-dose dispenser will be 
used for gel deposition into the nasal cavity. The dispenser is a finger-actuated, non-pressurized 
dispensing system designed to deliver 122.5mg of NATESTO (5.5mg testosterone) per 
actuation.  The key components of the multiple-dose dispenser include a cap, barrel, pump, and 
actuator, which are composed of polypropylene, and a piston, which is composed of 
polyethylene. 
The dispenser capacity is 11g which provides for 30 doses (60 actuations; 1 dose = one actuation 
per nostril) of NATESTO after priming, sufficient for 15 days with twice-daily (BID) 
administration.  For BID administration, NATESTO should be applied in the morning and in 
the evening (preferably at the same time each day) for a total daily testosterone dose of 22 
mg/day of testosterone.  For the subset of patients that continue on TID, NATESTO will be 
administered in the morning, in the afternoon and in the evening (approximately 6-8 hours 
apart), preferably at the same time each day, for a total daily testosterone dose of 33 mg/day of 
testosterone.    
 
EFFICACY VARIABLES: 
 
Primary efficacy is the self-reported patient satisfaction with treatment that will be assessed by 
the Treatment Satisfaction Questionnaire for Medication (TSQM), a validated, 9-item 
instrument with domains for Effectiveness, Convenience and Global Satisfaction.  The change 
in satisfaction will be determined by the difference in values at Visit 4 (Day 90) relative to Visit 
1 for adequately controlled BID patients; and values at Visit 5 (Day 120) relative to Visit 1 for 
patients up-titrated to TID. 
 
Secondary efficacy variables are: 
• For naïve patients the same efficacy assessment as stated above will be extended to 
being relative to Visit 2 – naïve patients cannot be assessed relative to Visit 1 as they 
will not have been taking any medication. 
• Improvement in hypogonadism symptoms as measured by quantitative Androgen 
Deficiency in Aging Males (qADAM) questionnaire: patient-reported outcome 
measure to evaluate symptoms of hypogonadism: a 10-item hypogonadism symptom 
severity instrument. 
• Patient preference of therapy as measured by the Treatment Preference questionnaire. 
• NATESTO dosing frequency. 
 
Exploratory analyses will include analysis of the monthly change of the primary or secondary 
efficacy global and domain measures over the treatment period.  Patient’s responses from the 
post-study follow-up will be tabulated. 
 
 
 


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SAFETY VARIABLES: 
 
Safety assessments will include adverse events, vital signs (blood pressure, heart rate, and 
temperature), physical examination parameters and total testosterone measurements (if 
required), hematocrit, lipid profile (total cholesterol, LDL, HDL and triglycerides), hemoglobin, 
and liver function tests (liver enzyme levels). 
 
STATISTICAL ANALYSES: 
 
The intent-to-treat (ITT) population will consist of all participants who receive study drug and 
have a valid post-dose efficacy measurement. The safety population will consist of all 
participants who receive at least one dose of study drug. The primary and secondary efficacy 
analyses will be based on the ITT population and the safety analyses will be based on the safety 
population. 
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities. A general summary of the adverse events and serious adverse events for each 
treatment group will be presented by the overall number of adverse events, the severity, and the 
relationship to study drug. The incidence of adverse events will be summarized by system organ 
class, preferred term, and treatment group. Vital signs will also be summarized by visit and by 
treatment group along with the change from baseline. Other safety measurements will be 
summarized and listed if deemed necessary. 
Sample Size Determination 
A sample size of approximately 100 participants will be selected to provide a sufficient number 
of participants for the analysis.  No more than 25 naïve patients will be allowed in the study.  
Since this is an observational study, no formal sample size calculation will be performed.  
Interim analysis and sample size re-estimation may be performed after results are acquired from 
50 and 75 patients.  
 
 
SITES: Approximately 10 sites in Canada. 
 
SPONSOR: (hereafter referred to as Acerus) 
Acerus Pharmaceuticals Corporation 
2486 Dunwin Drive 
Mississauga 
ON L5l 1J9 
Canada 
 
Telephone: 1-905-817-8191 
Facsimile:  1-905-569-1809 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE ...........................................................................................................2 
TABLE OF CONTENTS ....................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................... 12 
1 
INTRODUCTION AND BACKGROUND INFORMATION ..................... 13 
1.1 
Background ................................................................................................... 13 
1.2 
Summary of Clinical Studies ......................................................................... 15 
1.3 
Rationale ........................................................................................................ 20 
1.4 
Risk/Benefit ................................................................................................... 21 
2 
STUDY OBJECTIVES AND HYPOTHESES ............................................. 22 
3 
STUDY DESIGN ........................................................................................... 23 
3.1 
Summary of Study Design ............................................................................. 23 
3.2 
Study Indication(s) ........................................................................................ 26 
4 
STUDY POPULATION ................................................................................ 27 
4.1 
Inclusion Criteria .......................................................................................... 27 
4.2 
Exclusion Criteria ......................................................................................... 27 
5 
STUDY PROCEDURES ............................................................................... 29 
5.1 
Assessment Schedule ..................................................................................... 29 
5.1.1 
Patient Screening ............................................................................................. 29 
5.1.2 
Treatment Period ............................................................................................. 30 
5.1.3 
Post Study Follow Up (Day 150). .................................................................... 32 
5.1.4 
Early Termination Visit ................................................................................... 33 
5.2 
Study Procedures........................................................................................... 33 
5.2.1 
Medical, Surgical, and Family History............................................................. 33 
5.2.2 
Demographics ................................................................................................. 33 
5.2.3 
Vital Signs ...................................................................................................... 34 
5.2.4 
Physical Examination ...................................................................................... 34 
5.2.5 
Height and Weight .......................................................................................... 34 
5.2.6 
Total Testosterone Test ................................................................................... 34 
5.2.7 
Blood Test ....................................................................................................... 34 
6 
TREATMENT AND RESTRICTIONS ........................................................ 35 
6.1 
Treatment ...................................................................................................... 35 
6.1.1 
Treatment Regimen, Dosage, and Duration ..................................................... 35 
6.1.2 
Treatment Assignment..................................................................................... 35 
6.2 
Study Restrictions ......................................................................................... 36 


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6.2.1 
Concomitant Medications ................................................................................ 36 
6.2.2 
Participant Restrictions .................................................................................... 36 
6.3 
Important Added Safety Considerations ...................................................... 37 
6.3.1 
Endocrine and Metabolism .............................................................................. 37 
6.3.2 
Genitourinary .................................................................................................. 37 
6.3.3 
Hepatic ............................................................................................................ 37 
6.3.4 
Hematologic .................................................................................................... 37 
6.3.5 
Respiratory ...................................................................................................... 37 
6.3.6 
Sexual Function ............................................................................................... 37 
7 
INVESTIGATIONAL PRODUCT ............................................................... 38 
7.1 
Clinical Study Material ................................................................................. 38 
7.2 
Pharmaceutical Formulation ........................................................................ 38 
7.3 
Labeling and Packaging ................................................................................ 38 
7.4 
Dispensing Procedures and Storage Conditions........................................... 38 
7.4.1 
Dispensing Procedures .................................................................................... 38 
7.4.2 
Storage Conditions .......................................................................................... 38 
8 
EFFICACY ASSESSMENTS ....................................................................... 39 
9 
SAFETY ASSESSMENTS ............................................................................ 40 
9.1 
Adverse Events .............................................................................................. 40 
9.2 
Serious Adverse Events (SAEs)..................................................................... 43 
9.3 
Serious Adverse Event Reporting-Procedure for Investigators .................. 43 
10 
TREATMENT DISCONTINUATION/PARTICIPANT WITHDRAWALS
 ........................................................................................................................ 45 
11 
STATISTICS ................................................................................................. 46 
11.1 
Analysis Populations ..................................................................................... 46 
11.2 
Statistical Methods ........................................................................................ 46 
11.2.1 
General Considerations ................................................................................... 46 
11.3 
Efficacy .......................................................................................................... 47 
11.3.1 
Primary Analysis ............................................................................................. 47 
11.3.2 
Secondary Analysis ......................................................................................... 47 
11.3.3 
Exploratory Analysis ....................................................................................... 48 
11.4 
Safety ............................................................................................................. 48 
11.5 
Sample Size Determination ........................................................................... 48 
12 
DATA MANAGEMENT AND RECORD KEEPING ................................. 49 
12.1 
Data Management ......................................................................................... 49 
12.1.1 
Data Handling ................................................................................................. 49 
12.1.2 
Computer Systems........................................................................................... 49 
12.1.3 
Data Entry ....................................................................................................... 49 
12.1.4 
Medical Information Coding ........................................................................... 49 
12.1.5 
Data Validation ............................................................................................... 49 


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12.2 
Record Keeping ............................................................................................. 50 
13 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................... 50 
14 
QUALITY CONTROL AND QUALITY ASSURANCE ............................. 50 
15 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE .............. 51 
16 
PUBLICATION POLICY ............................................................................. 51 
17 
STUDY ADMINISTRATIVE INFORMATION ......................................... 51 
17.1 
Protocol Amendments ................................................................................... 51 
17.2 
Address List ................................................................................................... 51 
17.2.1 
Sponsor ........................................................................................................... 51 
17.2.2 
Contract Research Organization ...................................................................... 51 
17.2.3 
Drug Safety ..................................................................................................... 52 
18 
REFERENCES .............................................................................................. 53 
19 
SUPPLEMENT ............................................................................................. 57 
19.1 
Investigator’s Agreement .............................................................................. 57 
APPENDIX A: SCHEDULE OF PROCEDURES ........................................................... 58 
APPENDIX B: DRUG ADMINISTRATION PROCEDURES ....................................... 59 
APPENDIX C: TSQM....................................................................................................... 62 
APPENDIX D: qADAM .................................................................................................... 65 
APPENDIX E:  Patient Preference & Use Questionnaire ............................................... 66 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AUC 
 
Area under the curve 
BID 
 
Twice daily 
BMI 
 
Body mass index 
Cavg 
 
Average concentration 
CFB 
 
Change from baseline 
CI  
 
Confidence interval 
Cmax 
 
Maximum concentration 
CRA 
 
Clinical research associate 
DHEA 
 
Dehydroepiandrosterone 
DHT 
 
Dihydrotestosterone 
DIN 
 
Drug Identification Number 
DM 
 
Data management 
DRE 
 
Digital rectal examination 
ECC 
 
Environmental challenge chamber 
ECG 
 
Electrocardiogram 
eCRF 
 
Electronic case report form 
EDC 
 
Electronic data capture 
GnRH 
 
Gonadotropin-releasing hormone 
h  
 
Hour(s) 
ICF 
 
Informed consent form 
IRB 
 
Institutional Review Board  
ITT 
 
Intent-to-treat 
LOCF 
 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
NumberPDE5 Phosphodiesterase 5 
PK 
Pharmacokinetic 
PP 
Per-protocol 
PSA 
Prostate specific antigen 
qADAM 
Quantitative Androgen Deficiency in the Aging Male 
SAE 
Serious adverse event 
SD 
Standard deviation 
SHBG 
Sex hormone-binding globulin 
TBS-1 
NATESTO code used for clinical trials 
TID 
Three times daily 
t1/2 
Half-life 
Tmax 
Time to maximum concentration 
TRT 
Testosterone replacement therapy 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
TU 
Testosterone undecanoate 
µL 
Microlitre 
w/w 
Weight by weight 
 


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1 
INTRODUCTION AND BACKGROUND INFORMATION 
NATESTO is a bioadhesive testosterone gel for intranasal application developed 
by Acerus Pharmaceuticals SRL and approved by Health Canada on January 6, 
2016 (DIN 02450550).  NATESTO is indicated for testosterone replacement 
therapy in adult males for conditions associated with a deficiency or absence of 
endogenous testosterone (hypogonadism). Prior studies have demonstrated that 
NATESTO restores normal serum total testosterone levels when administered 
two or three times daily with relatively few side effects. The purpose of this study 
is to evaluate patient satisfaction with the use of NATESTO, as compared to their 
satisfaction with previously used topical TRT. The study will consist of a 
Treatment Period up to 120 days in duration; with a follow-up telephone call 30 
days later.  
1.1 
Background 
Testosterone, the active ingredient in NATESTO, is an endogenous androgen 
necessary for normal male growth and development. Through nuclear receptors 
located throughout the body, testosterone influences the transcription of genes 
involved in statural growth, protein anabolism, bone remodeling, immune 
modulation, hematopoiesis, and lipid metabolism. Via conversion to 
dihydrotestosterone (DHT), testosterone also maintains adult male secondary sex 
characteristics. Deficiency leads to male hypogonadism with a clinical 
presentation determined by the age of onset and the duration and severity of 
deficit. In adults, symptoms vary widely, ranging from depression and cognitive 
decline to infertility and osteopenia.  
 
Hypogonadism is classified as primary (due to decreased production of androgens 
in the testes) or secondary (due to dysfunction of the hypothalamic-pituitary-
gonadal axis). Data from different groups have shown that testosterone secretion 
follows a diurnal pattern with a peak at approximately 0800 h to 0900 h and a 
nadir between 2000 h and 2100 h.2-4 It is believed that episodic testosterone 
secretion is required for the normal operation of the neuroendocrine axis that 
governs testicular function.5-7 
  
Immediately after its chemical isolation and synthesis in 1935, testosterone was 
introduced into clinical medicine and used for the treatment of hypogonadism. It 
was initially given by compressing the medication into pellets, which were then 
administered subcutaneously. In the 1950s, longer-acting intramuscular 
formulations became the preferred therapeutic modality. Orally effective 
testosterone undecanoate (TU) was added 20 years later. By the mid1990s, 
transdermal testosterone patches were introduced into clinical practice. 
Transdermal testosterone gel, currently the most frequently prescribed 
preparation, became available in 2000. 
 
Testosterone has a well-established profile with over 50 years of accumulated 
clinical experience. Numerous placebo-controlled studies have demonstrated that 
testosterone replacement therapy is efficacious in treating symptoms of 


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hypogonadism. These studies have been summarized in a number of recent meta-
analyses.8-10 Testosterone has been shown to improve sexual function (both libido 
and erectile function) in older men. Hypogonadal men treated with testosterone 
before receiving a phosphodiesterase 5 (PDE5) inhibitor have experienced 
improvement in the quality of erections.11-12 In some cases, testosterone has 
reversed erectile dysfunction in participants who fail to respond to PDE5 
inhibitors.13 Testosterone administered in low doses to men with borderline 
hypogonadism increases muscle mass and decreases fat mass.14-15 At higher 
doses, in men with serum total testosterone less than 12 nmol/L, testosterone has 
been shown to improve strength.9-10 In a recent large study (N=322 men over 
50 years of age), TU improved sexual function, increased lean body mass, 
decreased body fat mass, and increased bone mineral density at both the hip and 
the spine.16 Another large study (N=237 healthy men between 60 to 80 years of 
age with total testosterone levels below 13.7 nmol/L) showed that TU decreased 
body fat and increased muscle mass.17 Additional data also suggests that 
testosterone improves cognition and mood and may be useful in treating some 
participants with Alzheimer’s disease.18-22 
 
There are well known risks associated with the use of testosterone. Testosterone 
administration is not recommended in participants with a history of prostate or 
breast cancer, an unevaluated prostate nodule or induration, hematocrit >54%, 
severe lower urinary tract symptoms, uncontrolled or poorly controlled 
congestive heart failure, or a prostate specific antigen (PSA) >4 ng/mL. 
Testosterone is a teratogen and extensive data is available on its reproductive and 
developmental effects. As expected for a hormonally active compound, literature 
demonstrates excess testosterone exposure increases the incidence of prostate, 
endometrium, breast, and liver tumors. 
 
Despite the variety of current testosterone formulations available for treatment of 
male hypogonadism, several significant disadvantages remain. Some of the 
preparations (oral TU and scrotal patches) elevate DHT levels or the 
DHT:testosterone ratio beyond the normal physiologic range. Long-acting 
injection formulations result in high initial testosterone levels that can remain 
supraphysiologic for distinct periods of time, leading to wide fluctuations in 
systemic androgen levels. These fluctuations are thought to be responsible for the 
mood lability many men experience during treatment with the injection and TU 
formulations. Excessive erythrocytosis, especially in older participants, has also 
been observed with injection preparations. Patches frequently cause skin irritation 
and allergic contact dermatitis. Gel preparations have caused unintentional 
exposures in household contacts, which can be significantly detrimental to 
developing fetuses and young children.23-27 Buccal formulations frequently cause 
gum irritation and taste alterations.28 
 
In 2002, it was theorized that the intranasal route could provide an alternate 
method of administration of testosterone. Animal experiments showed that 
intranasal testosterone was minimally metabolized in the nose and offered 


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excellent bioavailability.29-30 Two local tolerance studies in rats and rabbits 
(study 208040401 and study 208040402) following single- and repeat-dose 
administrations showed that NATESTO was well tolerated. In another study 
(study 208040403), NATESTO was classified as a non-irritant using the Hen’s 
Egg Test-Chorioallantoic Membrane evaluation. In a 3-month study conducted in 
rabbits (study 22712040417), doses of 0.093 mg/kg, 0.550 mg/kg, and 
1.867 mg/kg (1, 5, and 10 times the proposed clinical dose of intranasal 
testosterone gel, respectively) resulted in no abnormal histopathologic changes in 
the nasal turbinates, brain, testes, heart, kidneys, and lungs. Centrilobular 
glycogenic vacuolation in the liver was marginally greater in the high dose 
testosterone group compared to the untreated control.31 
 
1.2 
Summary of Clinical Studies 
Similar to other androgen replacement therapies, the evaluation of the efficacy of 
NATESTO has been based on pharmacokinetic (PK) studies. NATESTO is 
referred to as TBS-1 or Nasobol (code for clinical trials) in this section. Clinical 
experience with NATESTO includes the following 6 completed studies: 
• A Phase 1/2, 3-period study (TST-PKP-01-MAT/04) conducted in 
8 hypogonadal men evaluating the PK profile after administration of 
3 different single doses of 3.8% TBS-1; 
• A Phase 2, parallel-group, open-label study (TST-DF-02-MAT/05) 
conducted in 21 hypogonadal men comparing the PK profile and 
tolerability of 3 different doses of 3.8% TBS-1; 
• A 
Phase 
2, 
4-period, 
parallel-group, 
open-label 
study 
(Nasobol-01-2009) conducted in 57 hypogonadal men comparing the 
PK profile and tolerability of 3 different doses of 3.2% TBS-1 versus 
Androderm® 5.0 mg patch; and 
• A Phase 2, parallel-group, open-label study (TBS-1-2010-01) 
conducted in 22 hypogonadal men comparing the PK profile and 
tolerability of 3 different doses of 4.0% and 4.5% TBS-1.  
• A Phase 2, open-label, randomized, cross-over study (TBS-1-2011-04) 
conducted in 18 health men suffering from seasonal allergic rhinitis.  
4.5% TBS-1 11.0 mg TID was administered in 3-treatment states for a 
3-period cross-over separated by a 4-day washout period.     
• A Phase 3, 90-day, randomized, dose-ranging study (TBS-1-2011-03), 
including potential dose titration, evaluating the efficacy and safety of 
intranasal 4.5% TBS-1 in the treatment of male hypogonadism with 
sequential safety extension periods of 90 and 180 days. 
 
 
 
 
 


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TST-PKP-01-MAT/04 
TST-PKP-01-MAT/04 was a Phase 1/2, open-label, 3-period study conducted in 
8 hypogonadal men to determine the PK profile of testosterone after varying 
doses of 3.8% w/w TBS-1. Each participant received single doses of 7.6 mg, 15.2 
mg, and 22.8 mg of TBS-1 separated by 24 hour washout periods. Blood samples 
to determine the PK profile, including the maximum concentration (Cmax), and 
half-life (t1/2) for serum total testosterone and DHT, were collected just before 
each dose and at regular time intervals after each dose.  
 
Results from study TST-PKP-01-MAT/04 showed that testosterone was well 
absorbed after TBS-1 administration. The Cmax values for total testosterone were 
all within the normal reference range for healthy young males (739 ng/dL, 
925 ng/dL, and 952 ng/dL for the 7.6 mg, 15.2 mg, and 22.8 mg groups, 
respectively). The time to maximum concentration (Tmax) was 1 to 2 hours after 
administration, which is significantly shorter than the Tmax for gels and patches, 
indicating a rapid absorption of testosterone from the nasal cavity. The 
testosterone was cleared from the serum with a t1/2 of approximately 10 hours. 
The concentration of DHT remained low over the observation period. None of the 
participants experienced a serious adverse event (SAEs). No adverse events were 
considered to be related to the study drug.  
 
TST-DF-02-MAT/05 
TST-DF-02-MAT/05 was a Phase 2, randomized, parallel, open-label study 
conducted in 21 hypogonadal men to identify the optimum daily dose of 3.8% 
w/w TBS-1. Each participant in the 3 treatment groups received 7.6 mg of 
testosterone administered via TBS-1 for 2 weeks. The first treatment group 
received TBS-1 twice daily (BID) at 0800 h and 1400 h (total daily dose of 
15.2 mg); the second treatment group received TBS-1 twice daily (BID) at 0800 h 
and 2000 h (total daily dose of 15.2 mg); and the third treatment group received 
TBS-1 three times daily (TID) at 0800 h, 1400 h, and 2000 h (total daily dose of 
22.8 mg). Blood samples to determine the PK profile, including the average 
concentration (Cavg) and Cmax for serum total testosterone and DHT, were 
collected. 
 
Results from study TST-DF-02-MAT/05 showed that the mean Cavg for serum 
total testosterone remained within the physiologic range in all 3 treatment groups. 
However, the 95% confidence interval remained entirely within the physiologic 
range only in the TID treatment group. The Cmax values exceeded the physiologic 
range in 3 participants (1 participant from each treatment group) but only for a 
very brief period of time (minutes). The Cavg of DHT did not exceed the upper 
limit of the physiologic range. In total, 36 adverse events were observed but none 
were considered drug related. No participant had an SAE. 
 
 
 


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Nasobol-01-2009 
Nasobol-01-2009 was a Phase 2, randomized, 4-group, 4-period, open-label, 
crossover study conducted in 57 hypogonadal men comparing the efficacy and 
tolerability of 3 different doses of 3.2% w/w TBS-1 versus Androderm 5.0 mg 
patch. All participants were administered the 5.0 mg Androderm patch and TBS-
1 at doses of 8.0 mg BID, 11.0 mg BID, and 14.0 mg BID. TBS-1 was prepared 
as 127 µL, 174 µL, and 222 µL for the 8.0 mg, 11.0 mg, and 14.0 mg doses, 
respectively. Each treatment was given for a 7-day period after which the 
participants rotated to 1 of the 3 other treatment groups. After 28 days (4 periods), 
all groups had rotated through each of the 4 treatment groups. Blood samples to 
determine the PK profile, including the Cavg and Cmax for serum total testosterone 
and DHT, were collected at the end of each period. 
 
All 3 TBS-1 treatment groups showed appreciable increases in serum testosterone 
levels above Baseline and sizeable increases in area under the curve (AUC) for 
serum total testosterone with increasing TBS-1 dose. After Day 7 of treatment, 
the serum total testosterone Cavg was within the normal range in 79.6% of 
participants treated with the Androderm 5.0 mg patch, 52% of participants treated 
with 14.0 mg TBS-1 BID, 36.5% of participants treated with 11.0 mg TBS-1 BID, 
and 49.1% of participants treated with 8.0 mg TBS-1 BID. The serum total 
testosterone Cmax values tended to be lower and the AUC values tended to be 
higher following Androderm administration compared to TBS-1 administration. 
The increase in serum total testosterone values following TBS-1 treatment in the 
3 escalating doses was not linear. This finding suggested that the larger gel 
volumes (174 µL and 222 µL) were too great to be consistently absorbed in the 
nasal cavity. Serum DHT profiles were similar with all doses of TBS-1 compared 
to Androderm and all treatment groups had DHT levels within the normal range.  
 
All treatments were well tolerated by participants. No participant had an SAE and 
no participant discontinued due to an adverse event. In total, 56 adverse events 
were reported, 22 of which were related to study drug. Two of these adverse 
events were moderate in severity. Nasal complaints such as dryness, discomfort, 
congestion, inflammation, and epistaxis reported in the TBS-1 group were 
transient and mild in intensity.  
 
TBS-1-2010-01 
TBS-1-2010-01 was a Phase 2, randomized, parallel-group, open-label study 
conducted in 22 hypogonadal men comparing the efficacy and tolerability of 
4.0% w/w and 4.5% w/w TBS-1 at 3 different doses. Participants were 
randomized to 1 of the following 3 treatment groups for 7 days:  
• Group A: 10.0 mg 4.0% w/w TBS-1 TID (total daily dose of 30.0 mg), 
• Group B: 13.5 mg 4.5% w/w TBS-1 BID (total daily dose 27.0 mg), or 
• Group C: 11.25 mg 4.5% w/w TBS-1 TID (total daily dose of 33.75 mg).  


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Blood samples to determine the PK profile, including the Cavg and Cmax for serum 
total testosterone and DHT, were collected after 7 days of treatment in each group. 
 
Serum total testosterone Cavg values within the normal range were achieved in 
87% of participants in Group A, 100% of participants in Group B, and 85% of 
participants in Group C. No participant had a serum total testosterone Cmax >1800 
ng/dL. Serum DHT and estradiol Cavg values remained within the normal range 
in all treatment groups. All 3 TBS-1 doses were well tolerated by participants. No 
participant had an SAE and no participant discontinued due to an adverse event. 
In total, there were 8 adverse events, 2 of which were considered drug related. All 
events were of mild or moderate severity. 
 
TBS-1-2011-04 Study 
 
Study TBS-1-2011-04 was a randomized, crossover study conducted in healthy 
men who suffer from seasonal allergic rhinitis.  Participants received 4.5% w/w 
TBS-1 when they were asymptomatic, symptomatic and untreated, and 
symptomatic and treated with oxymetazoline nasal spray. The symptomatic state 
was induced by exposure to Dactylis glomerata pollen in an environmental 
challenge chamber (ECC).   
 
The objectives of the study were (1) to evaluate whether intranasal application of 
testosterone is a reliable route of administration during naturally occurring nasal 
inflammation, such as allergic rhinitis; and (2) to investigate the potential 
interaction of TBS-1 with the common over-the-counter nasal decongestant 
spray, oxymetazoline (Nasivin®), in the presence of swelling of the nasal mucosa, 
as it occurs during allergic rhinitis.  Drug interaction was assessed from the 
relative bioavailability of Baseline-corrected serum testosterone concentrations 
and determination of bioequivalence. 
 
Participants each received TBS-1 11.0 mg TID for 1 day, while in each of the 
3 treatment states: the asymptomatic state, the symptomatic and untreated state, 
and the symptomatic and treated with oxymetazoline state.  TBS-1 doses were 
administered at 0700, 1300, and 2100 hours.  Treatment periods were separated 
by a 4-day washout period. 
 
A reliable increase in serum testosterone was observed in patients with 
symptomatic allergic rhinitis, however serum total testosterone concentrations were 
decreased by 21 to 24%. A 2.6% decrease in mean AUC(0-24) and 3.6% decrease in 
mean Cmax of total testosterone was observed in males with symptomatic seasonal 
rhinitis when treated with oxymetazoline 30 minutes prior to TBS-1 compared to 
when left untreated. Oxymetazoline did not impact the absorption of testosterone 
when concomitantly administered with TBS-1. 
 
 
 
 


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TBS-1-2011-03 Study 
 
Study TBS-1-2011-03 was a Phase 3, open-label, randomized, parallel 2-group, 
dose-ranging study, including dose-titration, evaluating clinical efficacy, PK, and 
safety endpoints in hypogonadal men.  The study period was up to 58 weeks and 
included a screening period, and a 90-day treatment period followed by 
2 sequential safety extension periods of 90 and 180 days. 
 
Participants were randomized to receive 11.0 mg (5.5 mg per nostril) of 4.5% w/w 
TBS-1 BID (22.0 mg daily) or TID (33.0 mg daily) with potential daily dose 
adjustment on Day 45 for patients in the BID treatment group as determined by 
the titration assessment conducted on Day 30. 
 
Inclusion criteria included men with primary or secondary hypogonadism and a 
morning 
serum 
testosterone 
level 
of 
<300 ng/dL; 
a 
normal 
otorhinolaryngological nasal endoscopy examination; a normal prostate 
examination; and a serum prostate specific antigen (PSA) ≤4.0 ng/mL.  The study 
was conducted at 39 centers in the US. 
 
The primary objective of this pivotal Phase 3 study was to determine the efficacy 
of TBS-1, administered as BID or TID intranasal doses of 11.0 mg (5.5 mg per 
nostril), as demonstrated by an increase in the 24 hour Cavg of serum total 
testosterone to the normal range (300 and 1050 ng/dL) in 75% of male 
patients treated for hypogonadism. 
 
At Day 90 in the ITT population, 90% (95% CI – 83% - 97%) of patients on the 
TBS-1 TID regimen and 71% (95% CI = 62% - 79%) of patients on the BID 
regimen had Cavg in the normal total testosterone range.  
   
Number and Percentage of Patients by Serum Total Testosterone Cavg 
Category at Day 90 – ITT Population and Per Protocol Population– 
Treatment Period 
 
Serum Total Testosterone Cavg in 
Normal Range on Day 90 
ITT Population 
(N = 303) 
Per-Protocol Population 
(N = 237) 
TBS-1 BID  
71% 
75% 
N' 
122 
102 
95% CI for frequency [1] 
(62, 79) 
(66, 83) 
TBS-1 BID/TID  
63% 
63% 
N' 
82 
68 
95% CI for frequency [1] 
(53, 74) 
(52, 75) 
TBS-1 TID 
90% 
91% 
N' 
69 
67 
95% CI for frequency [1] 
(83, 97) 
(84, 98) 
TBS-1 Combined TID 
76% 
77% 


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Serum Total Testosterone Cavg in 
Normal Range on Day 90 
ITT Population 
(N = 303) 
Per-Protocol Population 
(N = 237) 
N' 
151 
135 
95% CI for frequency [1] 
(69, 82) 
(70, 84) 
Note: N' is the number of participants who had a Cavg at Day 90. % = n/N'. 
1. The CI for the frequency was approximated by a binomial distribution within each treatment. 
 Cavg = average concentration; CI = confidence interval; ITT = Intent-to-Treat;  
 
All populations (ITT [both based on patients with assessments on Day 90 and on 
LOCF] and PP Populations) met the primary efficacy endpoint success criterion 
for the TID regimen.  The PP Population met the primary efficacy endpoint 
success criterion also for the BID regimen.  The ITT Population at Day 90, and at 
Day 90 LOCF, was very close to meeting the primary efficacy endpoint success 
criterion for the BID regimen, at 71% and 72%, respectively.  The requirement 
that the lower 95% CI be not less than 65% was met.  The lower bound of the 
95% CI for both TBS-1 treatment groups overall was 68% for the ITT Population 
and 71% for the PP Population. 
 
In addition, 88.6% of the ITT population had mean testosterone Cmax at Day 90 
below 1500 ng/dL (Supplemental Table 1).  Nine (3.3%) subjects had Cmax 
between 1800 and 2500 ng/dL. One subject showed a Cmax >2500 ng/dL 
(3570 ng/dL); this subject, presumably did not discontinue concomitant 
finasteride treatment prior to the study as evidenced by increased testosterone 
AUC and an unusually low DHT/T ratio as a result of the inhibition of 5a-
reductase that blocks conversion of testosterone to DHT. No safety concerns were 
identified for this subject. 
 
Number and Percentage of Subjects with Serum Total Testosterone Cmax Values in 
Selected Ranges at Day 90 of the Treatment Period by Treatment and Population 
 
Population 
Number, 
Cmax Value 
TBS-1 BID 
(n = 141) 
TBS-1 TID 
(n = 162) 
Total 
(N = 303) 
ITT 
n 
122 
151 
273 
Cmax ≤1500 ng/dL, n (%) 
107 (87.7) 
135 (89.4) 
242 (88.6) 
Cmax ≥1800 to ≤2500 ng/dL, n (%) 
6 (4.9) 
3 (2.0) 
9 (3.3) 
Cmax >2500 ng/dL, n (%) 
1 (0.8) 
0 
1 (0.4) 
PP 
n 
102 
135 
237 
Cmax ≤1500 ng/dL, n (%) 
91 (89.2) 
120 (88.9) 
211 (89.0) 
Cmax ≥1800 to ≤2500 ng/dL, n (%) 
5 (4.9) 
2 (1.5) 
7 (3.0) 
Cmax >2500 ng/dL, n (%) 
0 
0 
0 
 
 
1.3 
Rationale 
Although controversy for specific treatment criteria exists, clinical investigations 
have shown that testosterone replacement in symptomatic male hypogonadism is 
generally safe and well tolerated.28 Testosterone treatment has positive effects on 
sexual function and, in some cases, can reverse total failures to respond to PDE5 


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inhibitors.11-13 Testosterone also increases muscle mass, decreases fat mass, 
improves strength, increases bone mineral density, and may improve mood and 
cognition.16-22 
 
Injection site reactions, frequent rashes, and medication transference remain 
significant disadvantages for participants treated with current therapies. Gels and 
patches provide continuous testosterone exposure with levels in the mid or high 
physiologic range depending on the dose applied. Injection forms of testosterone 
cause high levels during the first weeks that then gradually decline. It has been 
suggested that continuous exposure to testosterone might cause down-regulation 
of receptors and desensitization of target cells. 
 
NATESTO is applied within a matter of seconds, readily absorbed and rapidly 
elevates serum testosterone levels during the first 2 hours after application. With 
a t1/2 of approximately 10-100 min, it is quickly cleared from the circulation. 
Through carefully timed administration of NATESTO, it is expected that the 
normal physiologic increase that is seen in eugonadal men can be mimicked.33-35  
 
As the intranasal route of administration is novel for TRTs, the goal of this study 
is to investigate self-reported satisfaction with treatment with NATESTO in men 
with hypogonadism either previously treated with other topical TRTs or naïve to 
testosterone treatment. 
  
1.4 
Risk/Benefit 
Participants participating in this study are at risk for the side effects common to 
all formulations of testosterone. Adverse events for which there is evidence of 
association with testosterone administration include: erythrocytosis, detection of 
subclinical prostate cancer, growth of metastatic prostate cancer, worsening of 
acne, oily skin, and reduced sperm production and fertility. There is also weak 
evidence of association with testosterone administration for the following 
uncommon adverse events: gynecomastia, male pattern balding, growth of breast 
cancer, and induction or worsening of obstructive sleep apnea. Clinical evidence 
also shows that testosterone supplementation increases prostate volume and PSA 
levels leading to a higher frequency of prostate biopsies in participants treated 
with testosterone.13  
 
In addition to risks inherent to all testosterone administration, participants 
receiving NATESTO in prior clinical studies have experienced mild nasal 
symptoms including rhinorrhea, nasal discomfort, epistaxis and scab. None of 
these adverse events were indicative of any major nasal tolerability issues.  
 
Potential benefits for participants participating in this study include improvement 
of the signs and symptoms associated with hypogonadism as outlined above.  
NATESTO provides a hands-free means of administration, reducing the risks of 
transference.  


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2 
STUDY OBJECTIVES AND HYPOTHESES 
The primary objective of the study is to measure patient satisfaction with 
testosterone replacement therapy before, during and after treatment with 
NATESTO.  
 
The secondary objectives of this study to evaluate the following: 
• Improvement in hypogonadism symptoms; 
• Patient treatment preference versus prior testosterone replacement 
therapy; 
• Frequency of daily dose of NATESTO; and 
• Safety monitoring. 
 
Exploratory objectives will include analysis of the rate of change of the primary 
or secondary efficacy measures over the treatment period be that 90 days for 
patients on NATESTO BID or 120 days for patients on NATESTO TID.   
 
 


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3 
STUDY DESIGN 
3.1 
Summary of Study Design 
Approximately 100 participants (25 treatment-naïve and 75 previous topical TRT 
users) will be enrolled at approximately 10 investigative sites in Canada. 
 
• This is a Phase 4, multicenter study consisting of two study periods 
as follows: a 90-day Treatment Period, with potential extension by 
30 days for those patients requiring a dose increase, as determined 
by the treating physician.  Participants receiving 122.5mg of 
NATESTO (5.5 mg of testosterone) per nostril twice daily may have 
an increased  daily dose adjustment on Day 90, based on their 
hypogonadism symptoms; 
• A one-day Study Completion Period: Patient will return to the site 
for examination, discussion of symptoms with physician and 
questionnaire completion.  Serum testosterone levels will be 
determined for all patients on Day 90 (BID dose) and on Day 120 
for the TID patients.   
• Post-study follow-up: All study patients will be followed up at Day 
150 after the Treatment Phase to determine if they have continued 
using NATESTO and why (or why not?).  
 
Patient selection will come as a result of a doctor’s visit for routine controls, 
prescription renewal and by pre-selection by the physician from among 
hypogonadal patients currently receiving topical testosterone replacement 
therapies and willing to participate in a clinical trial with NATESTO, or as a result 
of an initial consultation for naïve patients.    
Eligible patients will receive information about NATESTO and the Informed 
Consent Form. The maximum total duration of study participation for participants 
completing the study will be 150 days (~21 weeks). 
During Treatment Period visits are to occur on the scheduled visit date ± 3 days.   
The population for this study is adult men 18-65 years of age inclusive with 
primary or secondary hypogonadism, with historical documented total serum 
testosterone concentration of ≤300 ng/dL / 10.4 nmol/L and the ability to provide 
informed consent.  Participants may include naïve hypogonadal patients (up to 
25) with a confirmation of hypogonadism diagnosis and non-naïve patients, who 
have previously been treated with an alternate topical testosterone replacement 
therapy (TRT) for at least three months prior to screening.  
 
Non-naïve participants will be instructed to stop their current topical treatment at 
least one day and no more than 7 days prior to initiation of treatment with 
NATESTO.  
 


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Patient Screening 
 
Patient selection will come as a result of a doctor’s visit for routine controls, 
prescription renewal and by pre-selection by the physician from among 
hypogonadal patients currently receiving topical testosterone replacement 
therapies and willing to participate in a clinical trial with NATESTO, or as a result 
of an initial consultation for naïve patients.    
 
At Visit 1, patients who agree to change their current topical TRT to NATESTO 
will provide written informed consent and undergo a complete physical 
examination, including a nasal examination, and the patient’s medical history will 
be documented. Blood pressure, heart rate, weight, and height measurements 
(from which body mass index [BMI] will be calculated) will also be performed. 
Patients will undergo a blood draw at a local laboratory for assessment of 
hematocrit, lipid profile (total cholesterol, LDL, HDL and triglycerides), 
hemoglobin and liver function tests (liver enzyme levels). However if the patient 
already has these values documented in their patient file from the preceding 6 
months, then those values can be entered into the eCRF and a fresh test will not 
be required. Previous treatment for hypogonadism (drug and nondrug) will be 
recorded, as well as other concomitant treatment with drug or nondrug therapies.  
 
Study questionnaires (TSQM and qADAM) will be reviewed and all subjects will 
be given instructions for proper completion of the instruments. Non-naïve 
patients will complete both questionnaires. All patients will complete Part A of 
the Patient Preference and Use Questionnaire. 
 
All patients will be instructed to complete TSQM and qADAM questionnaires by 
telephone, with the Study Coordinator on Day 30 and Day 60; at the same time 
concomitant drugs and AEs will be queried. 
 
All patients will be trained on the proper administration of NATESTO. They will 
receive their 90-day prescription for NATESTO and be asked to obtain the drug 
at the pharmacy within the next three days. Non-naïve participants will be 
instructed to stop their current topical testosterone therapies at least one day and 
up to 7 days prior to initiation of treatment with NATESTO. 
 
Patients will be instructed to contact the site to report any adverse events 
experienced.  Patients will schedule their Day 90 visit at Visit 1.  
 
 
 


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Treatment Period 
The open-label Treatment Period will consist of up to 5 site or telephone visits: 
Visit 1 site visit as study initiation; Visit 2 (Day 30) via telephone with Study 
Coordinator, Visit 3 (Day 60) via telephone with Study Coordinator, Visit 4 (Day 
90) as a site visit and, for patients on NATESTO TID, a Visit 5 (Day 120) as a 
site visit 
 
Visit 2 and Visit 3 
 
On Day 30 and Day 60 participants will be required to complete questionnaires 
(TSQM and qADAM) by telephone with the Study Coordinator; at the same time 
the coordinator will query concurrent medications and any AEs, and verbally 
confirm the patients are taking their NATESTO as prescribed.  At the discretion 
of the Investigator, participants may be required to complete a site visit if they 
experience an adverse event that is considered to require a physician assessment. 
 
Visit 4 
 
At Visit 4, Day 90, all patients will return to the site. Hypogonadism symptoms 
will be assessed by the Investigator with the qADAM questionnaire results being 
used for reference. If required, BID dose of NATESTO will be increase to TID at 
the discretion of the physician.  
 
Any previously unreported adverse events and concomitant medications will be 
recorded. Patients will undergo a basic physical examination including a nasal 
examination. Blood pressure, heart rate, weight, and height measurements (from 
which body mass index [BMI] will be determined) will be recorded. In addition 
to TSQM and qADAM questionnaires, subjects will also complete the Treatment 
Preference questionnaire. All patients will also be required to provide a blood 
sample for the total testosterone measurement at the local lab. The blood sample 
will need to be taken 20 minutes to 2 hours after the morning dose of NATESTO. 
In addition sufficient blood will be drawn for assessment of hematocrit, lipid 
profile (total cholesterol, LDL, HDL and triglycerides), hemoglobin, and liver 
function tests (liver enzyme levels). The BID patients who are adequately 
controlled will complete Part B (for Non-naïve) or Part C (for Naïve) of the 
Patient Preference and Use Questionnaire. 
 
The physician will question the patient about their symptoms. If this assessment 
indicates that symptoms persist and the patient requires additional benefit from a 
higher dose of testosterone, the physician may ask the patient if he is willing to 
continue treatment at three times daily (TID) for an additional 30 days and answer 
questionnaires thereafter.  In the affirmative, the patient will receive a prescription 
for three additional dispensers and treatment with NATESTO will be continued 
for another 30 days. An appointment will be scheduled for Visit 5 to occur at Day 
120 of treatment.  
 


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For patients assessed to be adequately controlled on BID this will mark the end 
of study and the physician will decide whether the patient a.) should return to 
their previous therapy; b.) remain on NATESTO; or c.) consider a new treatment 
option. The physician will provide the patient with a prescription for the treatment 
chosen. 
 
Visit 5.  
TID patients will come to the site to complete qADAM, TSQM and Part B (for 
Non-naïve) or Part C (for Naïve) of the Patient Preference and Use Questionnaire. 
Any previously unreported adverse events and concomitant medications will be 
recorded. Patients will undergo a basic physical examination including a nasal 
examination. Blood pressure, heart rate, weight, and height measurements (from 
which body mass index [BMI] will be calculated) will be recorded. Patients will 
also be required to provide a blood sample for the total testosterone measurement 
at the local lab. The blood sample will need to be taken 20 minutes to 2 hours 
after the morning dose of NATESTO. In addition sufficient blood will be drawn 
for assessment of hematocrit, lipid profile (total cholesterol, LDL, HDL and 
triglycerides), hemoglobin, and liver function tests (liver enzyme levels). 
 
This will mark the end of study for the TID patients and the physician will decide 
whether the patient a.) should return to their previous therapy; b.) remain on 
NATESTO; or c.) consider a new treatment option. The physician will provide 
the patient with a prescription for the treatment chosen. 
 
 
Patient follow-up. 
 
Visit 6 
 
All study patients will be contacted by phone three months (Day 150 +/- 3 days) 
after they have concluded the study to confirm whether they continued therapy 
with NATESTO after completing the study.   
 
A detailed schedule of procedures is provided in Appendix A.  
 
3.2 
Study Indication(s) 
The indication for this study is the treatment of a deficiency or absence of 
endogenous testosterone (hypogonadism).  
 
 


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4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
Participants who meet all of the following inclusion criteria will be eligible for 
participation in the study: 
1. Hypogonadal male between 18 and 65 years of age, inclusive; 
2. Able to understand and provide signed informed consent; 
3. Have documented total serum testosterone levels ≤300 ng/dL / 10.4 
nmol/L; for non-naïve patients this can be any previous documented 
value in their medical history; for naïve patients this will be two 
documented values within the last 6 months; 
4. Are currently being treated with any form of a topical testosterone 
replacement therapy for at least three months, or are treatment-
naive.  
 
4.2 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from 
participation in the study: 
1. In the opinion of the Investigator, significant intercurrent disease of 
any type, in particular liver, kidney, heart disease, stroke, or 
psychiatric illness; 
2. History of pituitary or hypothalamic tumors or history of any 
malignancy (including breast and prostate cancers) excluding basal 
cell or squamous cell carcinoma of the skin curatively treated by 
surgery; 
3. Prostatomegaly or history of abnormal PSA levels (>10.0 ng/mL).  
If PSA is >10 ng/mL, a recent negative biopsy must be documented 
(within the last 12 months); 
4. History of nasal disorders, nasal or sinus surgery, nasal fracture 
within the previous 6 months or nasal fracture that caused a deviated 
anterior nasal septum surgery, mucosal inflammatory disorders, 
specifically Sjogren’s syndrome;  
5. Use of any form of intranasal medication delivery other than 
periodic short-term (less than 3 days) use of sympathomimetic 
decongestants; 
6. History of severe adverse drug reactions to testosterone therapies;  
7. History or current evidence of abuse of alcohol or any drug 
substance; 
8. Current 
treatment 
with 
other 
androgens 
(e.g., 
dehydroepiandrosterone [DHEA]), anabolic steroids, or other sex 
hormones; 


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9. Treatment with estrogens, gonadotropin-releasing hormone (GnRH) 
agonists, or growth hormone within the previous 12 months; 
10. Treatment with drugs that interfere with the metabolism of 
testosterone, such as anastrozole, clomiphene, dutasteride, 
finasteride, 
flutamide, 
ketoconazole, 
spironolactone, 
or 
testolactone; 
11. Poor compliance history; 
12. Participation in any other research study during the conduct of this 
study or 30 days prior to the initiation of this study.  
13. Any prior exposure to NATESTO. 
 
 


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5 
STUDY PROCEDURES 
5.1 
Assessment Schedule  
See Appendix A, Schedule of Procedures, on page 57.  
 
5.1.1 
Patient Screening  
Patient selection will come as a result of a doctor’s visit for routine controls, 
prescription renewal and by pre-selection by the physician from among 
hypogonadal patients currently receiving topical testosterone replacement 
therapies and willing to participate in a clinical trial with NATESTO, or as a result 
of an initial consultation for naïve patients.    
Naïve patients will require confirmation within the last 6 months of 
hypogonadism by ensuring that serum testosterone concentrations have been 
measured in the morning on at least two separate days and that these serum 
testosterone levels concentrations are below the normal range. 
 
Patients will be informed about the trial and given a copy of the ICF to review. 
 
Visit 1 (Day 0) 
The following procedures will be performed at Visit 1: 
• Evaluate inclusion/exclusion criteria and confirm patient eligibility; 
• Obtain signed informed consent form;  
• Register participant in the study using data management (DM) 
system; 
• Record the date of hypogonadism diagnosis; 
• Obtain medical, surgical, and family history; including any adverse 
events in the preceding 30 days; 
• Record demographics; 
• Record concomitant medications; 
• Obtain height and weight, and determine BMI; 
• Obtain vital sign measurements (heart rate, blood pressure, and 
temperature); 
• Perform physical examination including a nasal examination; 
• For naïve patients document the two serum testosterone values from 
within the last 6 months. 
• Undergo a blood draw at a local laboratory for assessment of 
hematocrit, lipid profile (total cholesterol, LDL, HDL and 
triglycerides), hemoglobin, liver function tests (liver enzyme 
levels). However if the patient already has these values documented 


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in their patient file from the preceding 6 months, then those values 
can be entered into the eCRF and a fresh test will not be required. 
• Complete qADAM questionnaires (all patients) and TSQM (non-
naïve patients only); and complete Patient Preference and Use 
questionnaire Part A. 
• Provide participant with training and instructions for study drug 
administration and 90-day prescription for NATESTO, along with a 
Study Drug Access Card; 
• Instruct participant to obtain NATESTO from pharmacy within 3 
days using their Study Drug Access Card.   
• Naïve participants can initiate treatment with NATESTO 
immediately, but no more than 7 days after Day 0 (Visit 1). 
• Non-naïve participants will be instructed to stop their current 
topical testosterone therapies and wait at least one day, but no 
more than 7 days prior to initiating  treatment with NATESTO;   
• Instruct participants that on Day 30 (Visit 2) and Day 60 (Visit 3), 
they will be contacted by the Study Coordinator via telephone to 
complete TSQM and qADAM questionnaires and be asked about 
any adverse events and concomitant medications;  
• Instruct participant to contact the site to report any adverse event 
experienced during the treatment period.   
• Schedule Visit 4 (Day 90). 
 
 
5.1.2 
Treatment Period  
 
Visit 2 (Day 30) 
 The following procedures will be performed at Visit 2: 
• Telephone call by Study Coordinator to complete TSQM and 
qADAM questionnaires, confirm patient compliance with 
NATESTO  (is the patient taking NATESTO as prescribed) and 
query concomitant medications and AEs 
Visit 3 (Day 60) 
The following procedures will be performed at Visit 3: 
• Telephone call by Study Coordinator to complete TSQM and 
qADAM questionnaires, confirm patient compliance with 
NATESTO (is the patient taking NATESTO as prescribed) and 
query concomitant medications and AEs. 


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Visit 4 (Day 90) 
All patients will be required to complete Visit 4.   
The following procedures will be performed at Visit 4: 
• Assess and record adverse events; 
• Record concomitant medications; 
• Height and Weight 
• Obtain vital sign measurements (heart rate, blood pressure, and 
temperature); 
• Perform physical examination including a nasal examination;  
• Ask patient to complete TSQM, qADAM; and for those patients 
adequately controlled on BID complete Part B (for Non-naïve) or 
Part C (for Naïve) of the Patient Preference and Use Questionnaire; 
• Assess patient’s hypogonadism symptoms, primarily by questioning 
the patient about their level of energy (tiredness) and interest in sex 
life; 
• Register participant completion of the study in the DM system, if 
symptoms are properly managed at BID dose;  
 
• The physician will decide whether the patient a.) should return to 
their previous therapy; b.) remain on NATESTO; or c.) consider a 
new treatment option. The physician will provide the patient with a 
prescription for the treatment chosen. 
 
• Request serum total testosterone measurement at local lab along 
with blood draw for assessment of hematocrit, lipid profile (total 
cholesterol, LDL, HDL and triglycerides), hemoglobin, liver 
function tests (liver enzyme levels).  
 
For patients who do not respond clinically to a BID Dose: 
 
• Provide a 30-day TID drug prescription, if the patient’s symptoms 
are not adequately managed and extend treatment period to Day 120 
with NATESTO. 
• Instruct patient to increase daily NATESTO dose to TID, if 
necessary (e.g. patient does not feel better as compared to the start 
of treatment with NATESTO); 
• Instruct participant to contact the site to report any adverse event 
experience during the treatment period.   
• Schedule Day 120 (Visit 5).  


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Visit 5 (Day 120) 
Only patients prescribed NATESTO TID will be required to complete Visit 5. 
The following procedures will be performed at Visit 5: 
• Assess and record adverse events; 
• Record concomitant medications; 
• Height and Weight 
• Obtain vital sign measurements (heart rate, blood pressure, and 
temperature); 
• Perform physical examination including a nasal examination;  
• Ask patient to complete TSQM, qADAM and to complete Part B 
(for Non-naïve) or Part C (for Naïve) of the Patient Preference and 
Use Questionnaire. 
• Assess patient’s hypogonadism symptoms, primarily by questioning 
the patient about their level of energy (tiredness) and interest in sex 
life; 
• Register participant completion of the study in the DM system; 
 
• The physician will decide whether the patient a.) should return to 
their previous therapy; b.) remain on NATESTO; or c.) consider a 
new treatment option. The physician will provide the patient with a 
prescription for the treatment chosen. 
 
• Request serum total testosterone measurement at local lab along 
with blood draw for assessment of hematocrit, lipid profile (total 
cholesterol, LDL, HDL and triglycerides), hemoglobin, liver 
function tests (liver enzyme levels). 
 
 
 
5.1.3 
Post Study Follow Up (Day 150).  
 
All patients will be required to complete the Post Study Follow Up.  
 
• Patient will contacted by phone to determine if they have continued 
on NATESTO (Y/N). If they have discontinued, ask when 
approximately, and why. 
 


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5.1.4 
Early Termination Visit 
For participants who withdraw from the study prematurely, an Early Termination 
Visit should if possible be scheduled. See Section 10, Treatment 
Discontinuation/Participant Withdrawals.   
The following procedures will be performed at the Early Termination Visit: 
• Assess and record adverse events; 
• Record concomitant medications; 
• Height and Weight 
• Obtain vital signs measurements (heart rate, blood pressure, and 
temperature); 
• Perform physical examination including a nasal examination; 
• Instruct participant to restart prior testosterone medication (if 
applicable); 
• Register participant discontinuation from the study in the DM 
system; 
• Request serum total testosterone measurement at local lab along 
with blood draw for assessment of hematocrit, lipid profile (total 
cholesterol, LDL, HDL and triglycerides), hemoglobin, liver 
function tests (liver enzyme levels). 
 
Ask patient to complete TSQM, qADAM and to complete Part B (for Non-naïve) 
or Part C (for Naïve) of the Patient Preference and Use Questionnaire. 
 
5.2 
Study Procedures 
5.2.1 
Medical, Surgical, and Family History 
Medical history information will be collected from all participants during the 
Visit 1, Day 0. Medical history will include hypogonadism history, family history 
and details regarding all illnesses and allergies, date(s) of onset, status of current 
condition, and smoking, drug and alcohol use. Additional information to be 
collected includes past surgical and medical procedures as well as medications. 
 
5.2.2 
Demographics 
Demographic information will be collected from all participants during the Visit 
1, Day 0. Demographic information will include day, month, and year of birth, 
race and gender. 
 


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5.2.3 
Vital Signs 
Vital signs will be measured during Visit 1, Day 0, and Visit 4, Day 90 and Visit 
5, Day 120 (for TID subjects), and at Early Termination, if applicable. Vital signs 
will include heart rate, blood pressure, and temperature. 
 
5.2.4 
Physical Examination 
A physical examination including a nasal examination will be performed during 
the Visit 1 (Day 0), at Visit 4 (Day 90) and Visit 5 (Day 120) [only for TID] or at 
Early Termination, if applicable. The physical examination must include general 
appearance, skin, and specific head and neck, heart, lung, abdomen and 
extremities. 
 
5.2.5 
Height and Weight 
Height and weight will be measured during the Visit 1, Day 0 and Visit 4, Day 
90 and Visit 5, Day 120 (for TID subjects), and at Early Termination, if applicable. 
Measurement of weight should be performed with the participant dressed, coat 
and shoes removed and bladder empty.  
 
5.2.6 
Total Testosterone Test 
Total Testosterone measurement will be performed for patients who are assessed 
to be effectively controlled on BID after Visit 4 (Day 90); and for patients on the 
higher dose frequency (TID) after Visit 5 (Day 120) at the local laboratory. Blood 
sample will need to be taken 20 minutes to 2 hours after the morning dose of 
NATESTO. 
 
5.2.7 
Blood Test 
Blood will be drawn at a local laboratory for assessment of hematocrit, lipid 
profile (total cholesterol, LDL, HDL and triglycerides), hemoglobin and liver 
function tests (liver enzyme levels) at Visit 1 (all subjects), Visit 4 (all subjects) 
and Visit 5 (TID subjects). However, if at Visit 1, the patient already has these 
values documented in their patient file from the preceding 6 months, then those 
values can be entered into the eCRF and a fresh test will not be required. 
 
 
 
 


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6 
TREATMENT AND RESTRICTIONS 
6.1 
Treatment 
6.1.1 
Treatment Regimen, Dosage, and Duration 
All study participants who meet the entry criteria will be assigned to NATESTO 
twice daily administration (BID). Patients will be provided with a prescription for 
90 days of the study medication, NATESTO, and a Study Drug Access Card 
which will be used for payment purposes. Patients can fill their prescription using 
the Study Drug Access Card at their preferred pharmacy. The site will contact the 
patient on Day 4 to record the date of the first dose of NATESTO. 
 
Participants will be instructed to administer 5.5 mg of testosterone (1 actuation) 
per nostril of NATESTO once in the morning and once in the evening (at least 6 
hours apart), preferably at the same time each day for a total daily dose of 22 
mg/day of testosterone.  Patients should be instructed to completely depress the 
pump 1 time in each nostril to receive the total dose.  
 
For three times daily (after Visit 4 [Day 90] if symptoms not adequately managed 
by a BID dose), NATESTO will be administered intranasally once in the morning, 
once in the afternoon and once in the evening (approximately 6-8 hours apart), 
preferably at the same time each day for a total daily dose of 33 mg/day of 
testosterone.   
 
The maximum total duration of study participation for participants will be up to 
150 days (~21 weeks).  
 
6.1.2 
Treatment Assignment  
6.1.2.1 
Identification Number 
Participant identification numbers will consist of 6 digits. The first 3 digits will 
be the 3-digit site number assigned to the Investigator and the second 3 digits will 
be the 3-digit participant number.  
 
The participant identification number will be used to identify the participant 
throughout the study and will be entered on all documentation. A participant 
identification number will not be assigned to more than 1 participant. If a 
participant is not eligible to receive treatment, or if a participant discontinues from 
the study, the participant identification number cannot be assigned to another 
participant. At Visit 1, site personnel will register the participant in the EDC 
system. 
 
At Visit 1 (Day 0), qualified participants who meet all of the inclusion criteria 
and none of the exclusion criteria will receive a prescription for 90 days of open-
label NATESTO along with a Study Drug Access Card. The participant will be 
instructed to obtain NATESTO from pharmacy within 3 days using their Study 
Drug Access Card.  Non-naïve participants will be instructed to stop their current 


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topical testosterone therapies at least one day and up to 7 days prior to initiation 
of treatment with NATESTO. The patient will contact the site by telephone to 
indicate the date of their first dose. The Investigator, or designee, will enter the 
participant’s first dose record in the EDC system to confirm the start of the study 
treatment.  
 
6.2 
Study Restrictions 
6.2.1 
Concomitant Medications 
Any medications administered during the study must be documented in the EDC 
system. Participants must not have taken any investigational medication within 
30 days prior to screening. Participants cannot participate in any other clinical 
study involving an investigational agent while participating in this study. 
Testosterone medications that are part of the participant’s regimen at screening 
will be discontinued for the duration of the study.  
 
Participants undergoing current treatment with other androgens (ie, DHEA), 
anabolic steroids, other sex hormones, or drugs that interfere with the metabolism 
of testosterone (i.e., anastrozole, clomiphene, dutasteride, finasteride, flutamide, 
ketoconazole, spironolactone, and testolactone), will be excluded from the study. 
Participants treated within the past 12 months prior to Screening with estrogens, 
GnRH agonists, or growth hormone will also be excluded.  
 
Administration of any other intranasal medication, other than oxymetazoline-
containing nasal sprays (e.g., Dristan 12-Hour Nasal Spray) for a short duration 
(no more than 3 days) is prohibited during the study.  
 
6.2.2 
Participant Restrictions 
Participants should be instructed not to blow their nose or sniff for 1 hour after 
intranasal administration of NATESTO.  
 
If a participant with a history of allergic rhinitis develops an exacerbation of 
rhinitis during the study, continued application of study drug will be permitted, 
provided the symptoms are mild according to the Investigator’s assessment. Mild 
symptoms require sporadic treatment for control and are generally characterized 
by normal sleep, no impairment of activities of daily living, and no troublesome 
symptoms. 
 
Participants with moderate and severe allergic rhinitis symptoms that cause an 
impairment of sleep and/or activities of daily living and that require daily 
treatment should be instructed to temporarily discontinue study drug application 
until symptoms improve. If these symptoms last longer than 72 hours or if longer 
treatment is required, participants will be evaluated for discontinuation from the 
study. The same restrictions will apply to participants with rhinitis of viral 
etiology during the study (i.e. influenza). 


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6.3 
Important Added Safety Considerations 
 
6.3.1 
Endocrine and Metabolism 
All diabetic patients (Type 1 and Type 2) should be followed carefully and the 
insulin or oral hypoglycemic dosage adjusted accordingly as testosterone may 
have a glucose lowering effect. The patient’s endocrinologist should be advised 
of their participation in the My-T trial. 
 
6.3.2 
Genitourinary 
If a patient presents with progressive difficulty with urination or a change in 
voiding habits, then PSA and a Digital Rectal Examination should be undertaken 
and evaluated accordingly.  
 
6.3.3 
Hepatic 
NATESTO is not known to produce serious hepatic adverse events associated 
with some orally active androgens. Nonetheless patients should be asked about 
any signs or symptoms of hepatic dysfunction (e.g. jaundice) and the clinician 
should also review the results of the blood safety values for liver enzymes. If any 
indication of serious hepatic adverse effects are suggested, the patient should be 
discontinued on NATESTO while the cause is evaluated. 
 
6.3.4 
Hematologic 
Increases in hematocrit, reflective of increases in red blood cell mass, may 
require discontinuation of NATESTO. The hematocrit value obtained at Day 90 
for all patients and Day 120 for TID patients should be compared to the baseline 
value. If the hematocrit becomes elevated, NATESTO should be stopped until 
the hematocrit decreases to acceptable levels.  
 
6.3.5 
Respiratory 
NATESTO may potentiate sleep apnea, particularly for any patients with obesity. 
 
6.3.6 
Sexual Function 
NATESTO may cause patients to develop gynecomastia, priapism or excessive 
sexual stimulation, and also oligospermia may occur after prolonged exposure to 
NATESTO. 
 


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7 
INVESTIGATIONAL PRODUCT 
7.1 
Clinical Study Material 
NATESTO will be provided in multiple-dose dispensers by way of a prescription 
filled at the patient’s preferred pharmacy.  Placebo gel multiple-dose dispensers 
will be provided directly to the Investigator sites, which will only be used for the 
training of site personnel and participants.  
 
7.2 
Pharmaceutical Formulation 
The study drug NATESTO, to be used in this trial, was approved on January 6, 
2016 by Health Canada. It is provided in a multiple-dose dispenser with each 
finger-initiated actuation dispensing 122.5 mg of 4.5% w/w testosterone gel. The 
active ingredient is testosterone. The inactive ingredients are silicon dioxide, 
castor oil, and oleoyl polyoxylglycerides. Testosterone belongs to the 
pharmacologic class of androgens. The empirical formula of testosterone is 
C19H28O2 and its molecular weight is 288.4 Da.  
 
 
7.3 
Labeling and Packaging 
A multiple-dose dispenser will be used for gel deposition into the nasal cavity. 
The dispenser is a finger-actuated dispensing system designed to deliver 122.5 
mg of NATESTO (5.5 mg of testosterone) per actuation from a non-pressurized 
dispenser into the nasal cavity. The dispenser is designed to administer 30 doses 
(60 actuations; one dose equals one actuation to each nostril) of NATESTO after 
priming. The key components of the multiple-dose dispenser include a barrel, 
base, pump, and actuator, which are composed of polypropylene, and a piston, 
which is composed of polyethylene. 
 
All study drug dispensers will be labeled according to regulatory requirements 
for marketed products in Canada.  
7.4 
Dispensing Procedures and Storage Conditions 
7.4.1 
Dispensing Procedures 
Patients will be prescribed a 90 day supply of the study medication, NATESTO, 
and a Study Drug Access Card for payment purposes. Patients can fill their 
prescription using the Study Drug Access Card at their preferred pharmacy. 
 
All participants will be trained on proper administration of NATESTO. See 
Appendix B for priming and drug administration instructions.  
 
7.4.2 
Storage Conditions  
NATESTO is stored at room temperature (15º to 30°C). It should be kept in a safe 
place out of the reach and sight of children and pets. 


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After multiple-dose dispensers are primed, they should be kept with the dust cap 
securely in place. Gel that remains on the tip of the actuator should be wiped away 
using a clean, dry swab. 
 
8 
EFFICACY ASSESSMENTS 
Primary efficacy is the self-reported patient satisfaction with treatment that will 
be assessed by the TSQM, Treatment Satisfaction Questionnaire for Medication, 
a validated, 9-item instrument with domains for Effectiveness, Convenience and 
Global Satisfaction.  The change in satisfaction will be determined by the 
difference in values at Visit 4 (Day 90) relative to Visit 1; and values at Visit 5 
(Day 120) relative to Visit 1 for patients up-titrated to TID. 
 
 
Secondary efficacy variables are:  
 
• For naïve patients the same efficacy assessment as stated above will be 
extended to being relative to Visit 2 – naïve patients cannot be assessed 
relative to Visit 1 as they will not have been taking any medication. 
• Improvement in hypogonadism symptoms as measured by quantitative 
Androgen Deficiency in the Ageing Male (qADAM), a 10-item patient-
reported outcome measure to evaluate the symptom severity of 
hypogonadism.  
• Patient preference of therapy as measured by the Treatment Preference 
questionnaire. 
• NATESTO dosing frequency assigned at Visit 4. 
 
Exploratory analyses will include analysis of the monthly change of the primary 
or secondary efficacy measures, including global and domain specific analyses, 
over the treatment period.   
 


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9 
SAFETY ASSESSMENTS 
Safety assessments will include adverse events, clinical laboratory measurements 
of serum testosterone levels, vital sign measurements, and physical examination. 
 
9.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. An adverse 
event can therefore be any unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the 
investigational medicinal product. All adverse events, including observed or 
volunteered problems, complaints, or symptoms, are to be recorded on the 
appropriate eCRF.  
 
Adverse events, which include clinical laboratory test variables, will be 
monitored from the time of informed consent until study participation is 
complete. Participants should be instructed to report any adverse event that they 
experience to the Investigator and to contact the site between study visits to report 
any adverse events experienced. Beginning with Visit 1 (Day 0) Investigators 
should assess for adverse events at each visit and record the event on the 
appropriate adverse event eCRF. Adverse events that occur prior to treatment will 
be recorded as pre-treatment events.  
 
Wherever possible, a specific disease or syndrome rather than individual 
associated signs and symptoms should be identified by the Investigator and 
recorded on the eCRF. However, if an observed or reported sign or symptom is 
not considered a component of a specific disease or syndrome by the Investigator, 
it should be recorded as a separate adverse event on the eCRF.  
 
Any medical condition that is present when a participant is screened or present at 
Baseline that does not deteriorate should not be reported as an adverse event. 
However, medical conditions or signs or symptoms present at Baseline that 
change in severity or seriousness at any time during the study should be reported 
as an adverse event. 
 
Clinically significant abnormal laboratory findings or other abnormal 
assessments that are detected during the study or are present at Baseline and 
significantly worsen will be reported as adverse events. The Investigator will 
exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
All abnormal laboratory values considered clinically significant by the 
Investigator must be recorded on the adverse event page of the eCRF. Significant 
abnormal laboratory values occurring during the clinical study will be followed 
until repeat tests return to normal, stabilize, or are no longer clinically significant. 


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The Investigator will rate the severity (intensity) of each adverse event as mild, 
moderate, or severe, and will also categorize each adverse event as to its potential 
relationship to study drug using the categories of Definitely Unrelated, Unlikely, 
Possible, Probable, or Definitely Related. 
 
Assessment of Severity 
Severity will be assessed under the following scale: 
Mild – An event that is usually transient in nature and generally not interfering 
with normal activities. 
 
Moderate – An event that is sufficiently discomforting to interfere with normal 
activities. 
 
Severe – An event that is incapacitating with inability to work or do usual 
activity or inability to work or perform normal daily activity. 
 
Assessment of Causality 
The relationship of an adverse event to the administration of the study drug is to 
be assessed according to the following definitions: 
 
Definitely Unrelated 
Should be reserved for those events which occur prior to administration of study 
drug (e.g. washout) or for those events which cannot be even remotely related to 
study participation. 
 
Unlikely  
Event with a time to drug intake that makes a relationship improbable (but not 
impossible). Disease or other drugs provide plausible explanations for the event. 
 
Possible 
The suspected adverse event may or may not follow a reasonable temporal 
sequence from administration of study drug but seems to be the type of reaction 
that cannot be dismissed as unlikely. The event could have been produced or 
mimicked by the participant’s clinical state or by other modes of therapy 
concomitantly administered to the participant. 
 
Probable 
The suspected adverse event follows a reasonable temporal sequence from 
administration of study drug, abates upon discontinuation of the medication, and 
cannot be reasonably unexplained by the known characteristics of the 
participant’s clinical state. 
 
 
 


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Definitely Related 
Should be reserved for those events which have no uncertainty in their 
relationship to administration of study drug. 
 
The following factors should also be considered: 
• The temporal sequence from study drug administration; 
o The event should occur after the study drug is given. The length 
of time from study drug exposure to event should be evaluated in 
the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases; 
o Each report should be evaluated in the context of the natural 
history and course of the disease being treated and any other 
disease the participant may have. 
• Concomitant medication; 
o The other medications the participant is taking or the treatment the 
participant receives should be examined to determine whether any 
of them might be recognized to cause the event in question. 
• Known response pattern for this class of study drug; 
o Clinical and/or preclinical data may indicate whether a particular 
response is likely to be a class effect. 
• Exposure to physical and/or mental stresses; and 
o The exposure to stress might induce adverse changes in the 
recipient and provide a logical and better explanation for the event. 
• The pharmacology and PK of the study drug. 
o The known pharmacologic properties (absorption, distribution, 
metabolism, and excretion) of the study drug should be 
considered. 
 
Suspected Adverse Reaction- Any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of 
investigational new drug safety reporting, “reasonable possibility” means there is 
evidence to suggest a causal relationship between the drug and the adverse event. 
 
Unexpected Adverse Events- An unexpected adverse event is an adverse event 
either not previously reported or where the nature, seriousness, severity, or 
outcome is not consistent with the current Investigator’s Brochure. Additionally, 
unexpected adverse events include those that are mentioned in the Investigator’s 
Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug but not specifically mentioned as 
occurring with the particular drug under investigation. 


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9.2 
Serious Adverse Events (SAEs) 
An adverse event or suspected adverse reaction is considered serious if, in the 
view of either the Investigator or Sponsor, it results in any of the following 
outcomes:  
• Death; 
• A life-threatening adverse event; 
o NOTE: An adverse event or suspected adverse event is considered 
“life-threatening” if, in the view of either the Investigator or 
Sponsor, its occurrence places the participant at immediate risk of 
death. It does not include an event that, had it occurred in a more 
severe form, might have caused death. 
• Requires hospitalization or prolongation of existing hospitalization; 
o NOTE: In general, hospitalization for treatment of a pre-existing 
condition(s) that did not worsen from Baseline is not considered 
an adverse event and should not be reported as an SAE. 
• A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; 
• A congenital anomaly/birth defect; or 
• An important medical event. 
o NOTE: Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered an 
SAE when, based upon appropriate medical judgment, they may 
jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient 
hospitalizations, or the development of drug dependency. 
 
9.3 
Serious Adverse Event Reporting-Procedure for Investigators 
Initial Reports 
All SAEs occurring from the time of informed consent through until Visit 4, Day 
90 (BID patients) or Visit 5, Day 120 (TID patients) or the last administration of 
study drug must be reported to the Sponsor within 24 hours of the knowledge of 
the occurrence (this refers to any adverse event that meets any of the 
aforementioned serious criteria). Serious adverse events that the Investigator 
considers related to study drug occurring after the treatment period will also be 
reported to the Sponsor. 
 
To report the SAE, the reporter must complete the Serious Adverse Event Report 
Form. When the form is completed and signed by the Investigator, the form will 


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be transmitted to Acerus c/o Innomar Strategies Inc., within 24 hours of 
awareness of the event. Reports are reviewed during normal business hours.  
 
 
Safety Contact Information: Acerus c/o Innomar Strategies Inc. 
 
Tel:  1-844-850-1642 
Facsimile: 1-877-597-6344  
e-mail: AcerusPV@innomar-strategies.com 
 
The Investigator is required to submit SAE reports to the Institutional Review 
Board (IRB) in accordance with local requirements. All Investigators involved in 
studies using the same investigational product will receive any investigative new 
drug Safety Reports for onward submission to their local IRB as required.  
 
Follow-Up Reports 
The Investigator must continue to follow the participant until the SAE has 
subsided or until the condition becomes chronic in nature, stabilizes (in the case 
of persistent impairment) or the participant dies. Within 24 hours of receipt of 
follow-up information, the Investigator must submit a new Serious Adverse Event 
Report Form stating that this is a follow-up to a previously reported SAE using 
the same contact details as above. Any supporting documentation (e.g., laboratory 
test reports, hospital discharge summary, or autopsy reports) may be attached to 
the Serious Adverse Event Report Form after removal of any identifying 
participant information (e.g., participant name, or initials). 
 
 
 
 


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10 
TREATMENT DISCONTINUATION/PARTICIPANT WITHDRAWALS 
Participants may be discontinued from the study at any time, at the discretion of 
the Investigator or request of the patient. The Sponsor or their representative 
should be notified if a participant is discontinued because of an adverse event or 
laboratory abnormality. Participants must be followed until the adverse event or 
laboratory abnormality is resolved. 
 
A participant may be withdrawn for any of the following reasons:  
• Participant withdraws consent or requests discontinuation from the study 
for any reason; 
• Sponsor discontinues the study; 
• Occurrence of a clinical or laboratory adverse event, either serious or 
non-serious, at the discretion of the Investigator; 
• Need to initiate therapy with an excluded concomitant medication;  
• Increase in serum PSA concentration >1.4 ng/mL above Baseline; 
• Increase in hematocrit to >54%; or 
• Any medical condition or personal circumstance that, in the opinion of the 
Investigator, exposes the participant to risk by continuing in the study or 
precludes adherence to the protocol. 
Participants who are withdrawn from the study should complete all procedures 
described for Early Termination (see Section 5.1.4). Every attempt must be made 
to have the participant return for the Early Termination Visit.  
 
 


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11 
STATISTICS 
11.1 
Analysis Populations 
All Participants: This consists of all participants who signed the informed consent 
form. 
 
Intent-to-Treat (ITT) : Participants who receive at least one dose of study drug 
and have  a valid post-dose efficacy measurement.; this analysis set will serve as 
the basis for the primary analysis of efficacy.  
 
Safety Population: All participants who received at least one dose of the study 
drug.  This analysis set will be used for all assessments of safety and also some 
sensitivity analyses with respect to efficacy. 
 
Per-Protocol (PP) Population: This will consist of all ITT participants who 
complete the 90-day Treatment Period without any major protocol deviations.  
Selected efficacy analyses may be repeated for the per-protocol population to 
confirm the robustness of the results for the ITT population.  
 
11.2 
Statistical Methods 
 
11.2.1 
General Considerations 
 
Analyses (including the primary and secondary) will be performed on the 
complete study population and stratified by dose level). Further subgrouping may 
be considered. 
 
The statistical analyses will be reported using validated summary tables, figures, 
and data listings generated with SAS Version 9.2 or higher.   
 
Data from all assessments, whether scheduled or unscheduled, will be listed by 
participant and visit.  
 
Continuous variables will be summarized with means, %CV, standard deviations 
(SDs), medians, minimums and maximums.  For change from Baseline (CFB), 
individual differences of the scheduled post Baseline value to the Baseline value 
will be summarized. Categorical variables will be summarized by counts and by 
percentage of participants in corresponding categories.  Percentages will be based 
on the overall N for the analysis set used unless otherwise specified.  
 
 
 
 


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11.3 
Efficacy 
11.3.1 
Primary Analysis 
 
The primary objective of this study is to measure patient satisfaction with 
testosterone replacement therapy before, during and after treatment with 
NATESTO.   Patient satisfaction with treatment will be measured by TSQM 
(Treatment Satisfaction Questionnaire for Medication) Version 9, a 9 item 
validated instrument. TSQM domains include – Effectiveness, Convenience, 
Global Satisfaction. Point values will be assigned to each answer in the 
questionnaire according to Appendix C.  
 
Domain scores will be the sum of the points of each question making up the 
domain.  The scores for each domain will be summarized with descriptive 
statistics at Baseline and Day 90, and the change from Baseline at Day 90 for BID 
patients; similarly at Baseline and Day 120 for TID patients.  Mean domain scores 
at Baseline and Day 90 for BID patients, and Day 120 for TID patients will be 
compared using ANOVA methods; any missing data points will be assessed using 
LOCF methodology and other statistical analyses as deemed appropriate.  
 
11.3.2 
Secondary Analysis 
 
The secondary objectives of this study are to evaluate the following: 
• Improvement in hypogonadism symptoms; 
• Patient treatment preference versus prior testosterone replacement 
therapy; 
• Frequency of daily dose of NATESTO;  
   
Improvement in hypogonadism symptoms will be measured by the qADAM, a 
10 point validated instrument.  Point values will be assigned to each answer in 
the questionnaire according to Appendix D.   The scores for each qADAM item 
will be summarized with descriptive statistics at Baseline and Day 90 
(BID)/Day 120 (TID), and the change from Baseline at Day 90 (BID)/Day120 
(TID). Patient treatment preference versus prior testosterone replacement 
therapy will be measured by the Treatment Preference questionnaire.  Mean 
item scores at Baseline and Day 90(BID)/Day 120(TID) for these instruments 
will be compared using ANOVA methods. 
 
Frequency of daily dosing with NATESTO will be summarized and descriptive 
statistics provided. 
 
These analyses will be performed using the ITT population. 
 


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11.3.3 
Exploratory Analysis 
 
Exploratory analyses will include analysis of the rate of change of the primary or 
secondary efficacy measures over the treatment period, including the eventual 
extension.   
 
11.4 
Safety 
Adverse events will be coded using the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA). A general summary of the adverse events 
and SAEs for each treatment group will be presented by the overall number of 
adverse events, the severity and the relationship to study drug. The incidence of 
treatment emergent adverse events will be summarized by system organ class and 
preferred term. The total testosterone laboratory data for both the BID and TID 
patient populations will be summarized and descriptive statistics provided. Vital 
signs will also be summarized by visit and by treatment group along with the 
change from Baseline. The clinical findings in the physical examination will be 
summarized at each scheduled visit. Other safety measurements will be 
summarized and/or listed, if necessary. 
 
11.5 
Sample Size Determination 
A sample size of approximately 100 participants will be selected to provide a 
sufficient number of participants for the analysis. Since this is an observational 
study, no formal sample size calculation will be performed.  Interim analysis and 
sample size re-estimation may be performed after results are acquired from 50 
and 75 patients.  
 


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12 
DATA MANAGEMENT AND RECORD KEEPING 
12.1 
Data Management 
12.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the clinical research 
associate (CRA) during monitoring visits. The CRAs will verify data recorded in 
the EDC system with source documents. All corrections or changes made to any 
study data must be appropriately tracked in an audit trail in the EDC system. An 
eCRF will be considered complete when all missing, incorrect, and/or inconsistent 
data has been accounted for. 
 
12.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
 
12.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All study-
site personnel must log into the system using their secure user name and password 
in order to enter, review, or correct study data. These procedures must comply with 
the Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other 
appropriate international regulations. All passwords will be strictly confidential. 
 
12.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of MedDRA for adverse events and 
• World Health Organization Drug Dictionary for concomitant medications. 
 
12.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental 
validation performed via review of the downloaded data, will be applied to the data 
in order to ensure accurate, consistent, and reliable data. Data identified as 
erroneous, or data that are missing, will be referred to the investigative site for 
resolution through data queries. 
 
The eCRFs must be reviewed and deemed complete and correct by an Investigator 
who signed the protocol. 
 
 
 
 


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12.2 
Record Keeping 
Records of participants, source documents, monitoring visit logs, eCRFs, regulatory 
documents, and other Sponsor correspondence pertaining to the study must be kept 
in the appropriate study files at the site. Source data is defined as all information in 
original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the evaluation and 
reconstruction of the clinical study. Source data are contained in source documents 
(original records or certified copies). These records will be retained in a secure file 
for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, Acerus must be notified in writing and be given the 
opportunity to further store such records. 
 
13 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator and research institution agree that Acerus, its representatives, 
regulatory authorities and the IRB will have the right, both during and after the 
clinical study, to review and inspect pertinent medical records related to the clinical 
study. 
 
14 
QUALITY CONTROL AND QUALITY ASSURANCE 
CMX Research Inc., (CMX) as the agent for Acerus for Study Protocol NAT-2016-
1, will perform quality control and quality assurance checks for this trial. Before the 
enrollment of any participant in this study, CMX personnel will review with the 
Investigator and site personnel the following documents: protocol, Product 
Monograph, eCRFs and procedures for their completion, informed consent process, 
and the procedure for reporting SAEs. Site visits will be performed by the CMX 
CRAs and/or other Acerus representatives. During these visits, information 
recorded on the eCRFs will be verified against source documents and requests for 
clarification or correction may be made. After the eCRF data is entered by the site, 
CMX will review the data for safety information, completeness, accuracy, and 
logical consistency. Computer programs that identify data inconsistencies may be 
used to help monitor the clinical study. If necessary, requests for clarification or 
correction will be sent to Investigators. 
 
By signing the protocol, CMX and Acerus agree to be responsible for implementing 
and maintaining quality control and quality assurance systems with written standard 
operating procedures to ensure that studies are conducted and data are generated, 
documented, and reported in compliance with the protocol and accepted standards 
of Good Clinical Practice. 
 
 


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15 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve human 
participants. Compliance with this standard provides public assurance that the 
rights, safety, and wellbeing of study participants are protected, consistent with the 
principles that have their origin in the Declaration of Helsinki, and that the clinical 
study data are credible.  
 
16 
PUBLICATION POLICY 
Acerus is responsible for preparing a fully integrated report in cooperation with the 
Investigators and CMX. 
 
17 
STUDY ADMINISTRATIVE INFORMATION 
17.1 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be communicated to the Investigator by CMX or Acerus. All 
protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been 
approved by the IRB and Health Canada as required, unless immediate 
implementation of the change is necessary for participant safety. In this case, the 
situation must be documented and reported to the IRB within 5 working days. 
 
17.2 
Address List 
17.2.1 
Sponsor 
Matthew Gronski, PhD 
Senior Manager, Clinical Affairs 
Acerus Pharmaceuticals Corporation 
2486 Dunwin Drive 
Mississauga 
ON L5l 1J9,  
Tel: 1-905-817-8191 
Fax:  1-905-569-1809 
 
 
17.2.2 
Contract Research Organization 
CMX Research Inc. 
2 – 416 North Service Road East 
Oakville, Ontario, L6H 5R2 
Tel: 905-338-1078 
Fax:  905-338-0054 
 


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17.2.3 
Drug Safety 
 
All serious adverse events and abnormal laboratory values associate with the study 
should be reported within 24 hours of receipt at the Investigator site to:  
 
Acerus Pharmaceuticals Corp. 
c/o Innomar Strategies Inc. 
3470 Superior Court East Oakville, Ontario L6L 0C4 
E-mail: AcerusPV@innomar-strategies.com 
Tel:  1-844-850-1642  
Fax:  1-877-597-6344 
 


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18 
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testosterone gels. J Sex Med 2005;2(2):278. 
 
26. Merhi ZO, Santoro N. Postmenopausal virilization after spousal use of topical 
androgens. Fertil Steril 2007;87(4):976.e13-5. 
 
27. Bhowmick SK, Ricke T, Rettig KR. Sexual Precocity in a 16-Month-Old Boy 
Induced by Indirect Topical Exposure to Testosterone. Clinical Pediatrics 
2007;46(6):540-543. 
 
28. Bhasin S, Cunningham GR, Hayes FJ, et al. Androgens in Men Guideline 
Task Force. Testosterone therapy in adult men with androgen deficiency 
syndromes: An Endocrine Society clinical practice guideline. J Clin 
Endocrinol Metab 2010;95(6):2536-2559. 
 
29. Ko KT, Needham TE, Zia H. Emulsion formulations of testosterone for 
nasal administration. J Microencapsul 1998;15(2):197-205. 
 
30. Hussain AA, Al-Bayatti AA, Dakkuri A, Okochi K, Hussain MA. 
Testosterone 17beta-N,N-dimethylglycinate hydrochloride: A pro-drug with 
a potential for nasal delivery of testosterone. J Pharm Sci 
2002;91(3):785-789. 
 
31. Mowat, V. Histopathology Report: 3 months toxicity study according to the 
FDA pre-IND 70,512. CONFARMA FRANCE SARL, sponsored by Mattern 
Pharmaceuticals AG Stans, (2005) 1-6. 
 
32. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on 
serum total and free testosterone levels in healthy men. Baltimore 
Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724-731. 
 


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33. Ohdo S. Chronopharmacology focused on biological clock. Drug Metab 
Pharmacokin 2007;22(1):3-14. 
 
34. Kriegsfeld LJ, Silver R. The regulation of neuroendocrine function: timing 
is everything. Horm Behav 2006;49(5):557-574. 
 
35. Lincoln GA, Andersson H, Loudon A. Clock genes in calendar cells as the 
basis of annual timekeeping in mammals- a unifying hypothesis. 
J Endocrinol 2003;179(1):1-13. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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19 
SUPPLEMENT 
19.1 
Investigator’s Agreement 
By signing below I agree that: 
 
I have read this protocol and agree to conduct this study in accordance with the 
design and specific provision of this protocol.  I will make a reasonable effort to 
complete the study within the time designated. I will provide copies of this 
protocol and access to all information furnished by Acerus Pharmaceuticals 
Corporation to study personnel under my supervision. I will discuss this material 
with them to ensure they are fully informed about the study product and study 
procedures. I will let them know that this information is confidential and 
proprietary to Acerus Pharmaceuticals Corporation and that it may not be further 
disclosed to third parties. I understand that the study may be terminated or 
enrollment suspended at any time by Acerus Pharmaceuticals Corporation with 
or without cause, or by me if it becomes necessary to protect the best interests of 
the study participants. 
 
I agree to conduct this study in full accordance with Health Canada Regulations, 
Institutional Review Board Regulations, and International Conference on 
Harmonization Guidelines for Good Clinical Practice. 
 
 
 
 
 
 
_____________________________ 
 
____________________ 
Investigator’s Signature  
 
 
Date 
 
 
 
_____________________________ 
Investigator’s Name 


 
 
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APPENDIX A: SCHEDULE OF PROCEDURES 
Study Phase 
Treatment Period 
 
 
Treatment 
Start 
Efficacy Analysis 
Post Study 
Follow Up 
Early 
Withdrawal/ 
Termination 
 
 
 
 
 
 
Day 0 
 
 
 
 
 
 
Day 30 
+/- 3 days 
 
 
 
 
 
Day 60 
+/- 3 days  
End of 
Study: 
BID 
Patients 
 
Day 90 
+/- 3 days  
End of 
Study: 
TID 
Patients 
 
Day 120 
+/- 3 days  
 
 
 
 
 
Day 150 
+/- 3 days 
 
Visit 
1 
2 
3 
4a 
5b 
6 
 
Location/Type 
clinic 
telephone 
telephone 
clinic 
 
clinic 
 
telephone 
clinic 
Study Procedures: 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
Medical history 
x 
 
 
x 
x 
 
 
Demographics 
x 
 
 
 
 
 
 
Physical examination +  nasal exam 
x 
 
 
x 
x 
 
x 
Height and weight 
x 
 
 
x 
x 
 
x 
Vital signs (HR, BP, and 
temperature) 
x 
 
 
x 
x 
 
x 
Serum total testosterone plus safety 
labs 
xc 
 
 
x 
xd 
 
x 
Participant training on NATESTO 
administration 
x 
 
 
 
 
 
 
Provide Study Drug Access Card 
for NATESTO  
x 
 
 
 
 
 
 
Provide Pharmacy Prescription  
x 
 
 
xg 
 
 
 
Potential study drug daily dose 
increase to TID 
 
 
 
x 
 
 
 
TSQM 
xe 
x 
x 
x 
x 
 
x 
qADAM 
xf 
x 
x 
x 
x 
 
x 
Patient Preference + Use 
x 
 
 
x 
x 
 
x 
Concomitant medications 
x 
x 
x 
x 
x 
 
x 
Assess adverse events 
x 
x 
x 
x 
x 
 
x 
Assess voluntary treatment 
continuation 
 
 
 
 
 
x 
 
 
a. All subjects are required to complete Visit 4  
b.  Only subjects assigned to NATESTO TID are required to complete Visit 5 
c.  Naïve patients will require confirmation of hypogonadism by serum testosterone within the last 6 months 
d.  Only patients who continued on TID  
e.  TSQM to be completed by non-naïve patients only 
f.  qADAM to be completed by all patients 
g.  Patients who are assigned to NATESTO TID will be provided with a new Pharmacy Prescription increasing their dosage to TID 
 


 
 
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APPENDIX B: DRUG ADMINISTRATION PROCEDURES 
 
PROCEDURE FOR MULTIPLE-DOSE DISPENSER PRIMING (to be performed by the site 
coordinator prior to the first use only): 
 
Before use of the applicator for the first time, it is necessary to prime the applicator 
pump.  
 
How to prime the applicator pump:  
Hold the applicator over a sink, turn it upside down (invert) and slowly press the pump and 
release 10 times (See Figure 1A).  
 
(Figure 1A) 
All the gel that comes out when the pump is primed should be rinsed down the sink with warm 
water.  
If there is any gel on the tip of the actuator after priming, wipe the tip with a clean, dry tissue. 
If any gel gets on your hands, it is recommended to wash your hands with warm water and 
soap. 
 
PROCEDURE FOR MULTIPLE-DOSE DISPENSER (Participant Instructions): 
 
Applying the nasal gel with the applicator: 
Step 1:  Blow your nose. 
Step 2:  Remove the applicator cap. 
Step 3:  While looking in the mirror, put your right first (index) finger on the pump of your 
actuator and slowly slide the tip of the actuator up into your left nostril until your finger on the 
pump touches the bottom of your nose (See Figure A). 
 
(Figure A) 


 
 
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Step 4:  Gently tilt the actuator so that the hole in the tip touches the lateral (side) wall of your 
nostril. This will make sure that the gel is delivered in the correct place (See Figure B). 
 
 
(Figure B) 
 
 
Step 5:  With the actuator in place, slowly push the pump down until it stops and remove the 
actuator from your nose. 
Step 6:  While looking in the mirror, put your left first (index) finger on the pump of your 
actuator and slowly slide the tip of the actuator up into your right nostril until your finger on 
the pump touches the bottom of your nose (See Figure C). 
 
 
(Figure C) 
 
Step 7:  Gently tilt the tip of the actuator so that the hole in the tip touches the lateral (side) 
wall of your nostril.  This will make sure that the gel is delivered in the correct place (See 
Figure D). 
 
 


 
 
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(Figure D) 
 
Step 8:  Slowly push down on the pump until it stops and remove the actuator from your nose. 
Step 9:  Wipe the tip of the actuator with a clean, dry tissue. 
Step 10: Replace the cap. 
Step 11: Press your nostrils together just below the middle of your nose (bridge) and lightly 
rub them together (See Figure E). 
 
 
(Figure E) 
 
 
 


 
 
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APPENDIX C: TSQM 
 
TSQM-9 
Abbreviated Treatment Satisfaction Questionnaire for Medication 
 
Instructions:  Please take some time to think about your level of 
satisfaction or dissatisfaction with the medication you are taking in 
this clinical trial.  We are interested in your evaluation of the 
effectiveness, side effects, and convenience of the medication over 
the last two to three weeks, or since you last used it.  For each 
question, please place a single check mark next to the response that 
most closely corresponds to your own experiences. 
 
1. How satisfied or dissatisfied are you with the ability of the medication to 
prevent or treat your condition?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
2. How satisfied or dissatisfied are you with the way the medication relieves your 
symptoms?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
 
 
 
 
 
 


 
 
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3. How satisfied or dissatisfied are you with the amount of time it takes the 
medication to start working?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
 
4. How easy or difficult is it to use the medication in its current form?  
□1   Extremely Difficult 
□2   Very Difficult 
□3   Difficult 
□4   Somewhat Easy 
□5   Easy 
□6   Very Easy 
□7   Extremely Easy 
 
5. How easy or difficult is it to plan when you will use the medication each time?  
□1   Extremely Difficult 
□2   Very Difficult 
□3   Difficult 
□4   Somewhat Easy 
□5   Easy 
□6   Very Easy 
□7   Extremely Easy 
 
6. How convenient or inconvenient is it to take the medication as instructed?  
□1   Extremely Inconvenient 
□2   Very Inconvenient 
□3   Inconvenient 
□4   Somewhat Convenient 
□5   Convenient 
□6   Very Convenient 
□7   Extremely Convenient 
 
 
 
 
 
 
 


 
 
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7. Overall, how confident are you that taking this medication is a good thing for 
you?  
□1   Not at All Confident 
□2   A Little Confident 
□3   Somewhat Confident 
□4   Very Confident 
□5   Extremely Confident 
 
8. How certain are you that the good things about your medication outweigh the 
bad things?  
□1   Not at All Certain 
□2   A Little Certain 
□3   Somewhat Certain 
□4   Very Certain 
□5   Extremely Certain 
 
9. Taking all things into account, how satisfied or dissatisfied are you with this 
medication?  
□1   Extremely Dissatisfied 
□2   Very Dissatisfied 
□3   Dissatisfied 
□4   Somewhat Satisfied 
□5   Satisfied 
□6   Very Satisfied 
□7   Extremely Satisfied 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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APPENDIX D: qADAM 
 
 
 
 
 
 


 
 
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APPENDIX E:  PATIENT PREFERENCE & USE QUESTIONNAIRE 
 
 
 
OVERVIEW 
 
• Patients will undertake the questionnaire as follows: 
 
o All patients will complete PART A at Visit 1 (Day 0) 
o Patients who were assessed to be controlled on BID will complete PART B if 
Non-naïve and PART C if Naïve at Visit 4 (Day 90)  
o Patients who were up-titrated to TID will complete PART B if Non-naïve and 
PART C if Naïve at Visit 5 (Day 120) 
 
• The Study Coordinator is to enter the Patient Study Number for the patient on their 
questionnaire 


 
 
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Part A: ALL PATIENTS at Study Initiation 
 
1. Patient Study Number (to be entered by Study Coordinator)  
_________________________ 
2. Age (years)   
 
 
 
 
 
 
_________________________ 
3. City, Province  
 
 
 
 
 
 
_________________________ 
4. Date 
 
 
 
 
 
 
 
_________________________ 
 
 
5. Read the list of symptoms below, indicate if you have experienced each symptom (in the Y/N column) and how important it is for you to 
treat that symptom. 
 
My low-testosterone symptoms include …. 
Do you or did you 
experience these 
symptoms?  
(Y/N) 
If yes, please rate how important this symptom was to you. 
(put an x in the appropriate column) 
Very 
Important 
 Important 
Somewhat 
Important 
Not Important  
at all 
Low sex drive 
 
 
 
 
 
Difficulty achieving or maintaining an erection 
 
 
 
 
 
Increased body fat 
 
 
 
 
 
Decreased muscle/strength 
 
 
 
 
 
Fatigue (tiredness)/loss of energy 
 
 
 
 
 
Decreased physical activity/vitality 
 
 
 
 
 
Loss of facial, underarm and/or pubic hair 
 
 
 
 
 
Decline in general feeling of well-being 
 
 
 
 
 
Depression (feeling unhappy)/depressed mood 
 
 
 
 
 
Mood changes/irritability 
 
 
 
 
 
Inability to concentrate 
 
 
 
 
 
difficulty falling asleep/staying asleep 
 
 
 
 
 
 
 
6. Of the above symptoms please tell us which is the most important symptom for you : ________________________________________ 
 
 


 
 
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7. Read each statement and indicate how important each of the following considerations are to you when selecting your testosterone 
treatment.  
 
My Testosterone Therapy (TRT) …….. 
If yes, please rate how important this aspect is to you. 
(put an x in the appropriate column) 
Very 
Important 
 Important 
Somewhat 
Important 
Not Important  
at all 
restores my testosterone levels to the normal range  
 
 
 
 
relieves my symptoms 
 
 
 
 
has no/few side effects 
 
 
 
 
Is easy to administer/use  
 
 
 
 
is affordable 
 
 
 
 
is recommended by my physician  
 
 
 
 
is recommended by my friends/family 
 
 
 
 
should be at the lowest dose of testosterone that provides symptom relief 
 
 
 
 
minimizes the risk of transference to women and/or children  
 
 
 
 
 
 
 
8. Were you ever prescribed a testosterone replacement therapy prior to this study?  
 Yes – Please continue and answer questions 9-13 below.  
 No – Please stop here and return the questionnaire to the Study Coordinator 
 
 
 


 
 
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9. Answer  the following questions: 
 
Family 
Doctor 
Urologist 
Endocrinologist 
Other 
Specialist 
(specify type) 
Not 
Applicable 
Which doctor did you see first regarding your symptoms? 
 
 
 
 
 
Which doctor first diagnosed your low testosterone condition? 
 
 
 
 
 
Which doctor asked you to do a blood test to confirm the diagnosis 
of low testosterone? 
 
 
 
 
 
Which doctor gave your first prescription for testosterone therapy? 
 
 
 
 
 
Which doctor now prescribes your testosterone treatment? 
 
 
 
 
 
 
 
 
10.  Answer Yes or No to the following questions 
 
YES 
NO 
Don’t Know 
Were you asked to undertake a blood test for your testosterone level 
 
 
 
Did you research low testosterone and possible treatment options prior to visiting your physician?  
 
 
 
Did you ask your physician/specialist to prescribe a specific product for low testosterone? 
 
 
 
If yes, did your physician prescribe the specific testosterone product you asked for? 
 
 
 
Did you ever interrupt your testosterone therapy for any reason after you were placed on a therapy?      
 
 
 
 
 
11. For your previous testosterone replacement therapy (TRT) list the brand(s) and approximate length of time you used each one  
TRT Brand 
(e.g. Axiron, Androgel, Androderm, 
Testim ) 
Length of Time Used (approx.) 
(put an x in the appropriate column) 
0-3 months 
3-6 months 
6-12 months 
1-2 years 
2+ years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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12. If you listed more than one prescription TRT brand above, indicate the reason(s) why you switched from one product to another. 
________________________________________________________________________________________________________________ 
__________________________________________________________________________________________________________________
______________________________________________________________________________________________________________ 
 
13. If you ever paused or interrupted therapy for a period of time, can you explain why?  
________________________________________________________________________________________________________________ 
________________________________________________________________________________________________________________ 
________________________________________________________________________________________________________________ 
 
 


 
 
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Part B: At Study Completion for Non-naïve Patients 
1. Patient Study Number (to be entered by Study Coordinator)  
_________________________ 
2. Age  
 
 
 
 
 
 
_________________________ 
3. City, Province 
 
 
 
 
 
_________________________ 
4. Date 
 
 
 
 
 
 
_________________________ 
 
5. Are you aware that the testosterone from gels or solutions that are normally applied to the skin (i.e. shoulders, upper arms, etc.) can 
accidentally get onto and through the skin of women and children, causing undesirable side effects, such as early puberty or masculinization 
(hair growth, voice changes)? 
 Yes 
 No 
 
6. Is being on the lowest effective dose of testosterone important to you? 
 Yes 
 No 
 
7. Please indicate if you agree or disagree with the following statements.  (Check one box per line). 
General Statements 
Strongly 
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
Not 
applicable 
NATESTO restores my testosterone levels back to a normal range 
 
 
 
 
 
 
NATESTO relieves my symptoms 
 
 
 
 
 
 
NATESTO has no/few side effects 
 
 
 
 
 
 
NATESTO is easy to administer/use 
 
 
 
 
 
 
NATESTO is the lowest dose of testosterone that will provide symptom relief 
 
 
 
 
 
 
NATESTO cannot be transferred to women and/or children 
 
 
 
 
 
 
NATESTO is affordable 
 
 
 
 
 
 
 
 


 
 
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Use Statements 
Strongly 
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
Not 
applicable 
NATESTO is easier to use than my previous testosterone therapy  
 
 
 
 
 
 
NATESTO is less messy than my previous testosterone therapy  
 
 
 
 
 
 
NATESTO takes less time to use than my previous therapy 
 
 
 
 
 
 
I can take NATESTO at home without visiting my doctor 
 
 
 
 
 
 
The time it takes to use  NATESTO is acceptable/convenient 
 
 
 
 
 
 
Symptom Statements 
Strongly 
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
Not 
applicable 
NATESTO alleviates my symptoms better than my previous therapy 
 
 
 
 
 
 
NATESTO increased my sex drive 
 
 
 
 
 
 
NATESTO helps in achieving and/or maintaining an erection 
 
 
 
 
 
 
NATESTO reduced my body fat 
 
 
 
 
 
 
NATESTO increased my muscle/strength 
 
 
 
 
 
 
NATESTO increased my energy level  
 
 
 
 
 
 
 
 
 
 
 
NATESTO increased my physical activity level/vitality 
 
 
 
 
 
 
NATESTO reduced my loss of facial, underarm and/or pubic hair 
 
 
 
 
 
 
NATESTO improved my general feeling of well-being  
 
 
 
 
 
 
NATESTO helped me feel less depressed 
 
 
 
 
 
 
NATESTO helped  me to feel less irritable 
 
 
 
 
 
 
NATESTO improved my concentration 
 
 
 
 
 
 
NATESTO improved my ability to fall asleep/stay asleep 
 
 
 
 
 
 
Preference Statements 
Strongly 
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
Not 
applicable 
I prefer NATESTO over other testosterone therapies 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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8.  How much would you be willing to pay out-of-pocket for NATESTO if your health insurance does not cover the full amount or you do not have 
health insurance?  (Select one) 
 Up to $25 per month 
 Up to $50 per month 
 Up to $75 per month 
 Up to $100 per month 
 Up to $150 per month 
 I would not pay anything out-of-pocket for NATESTO 
 
9.  If NATESTO cost you exactly the same as the product you were using before joining the study, would you choose to switch to NATESTO? 
 Yes 
 No 
 Undecided 
 
10. What do you like about NATESTO?  
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
________________________________________________________________________________________________________ 
 
11. What do you dislike about NATESTO? 
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
________________________________________________________________________________________________________ 
 
12. Following this study, do you plan to continue taking NATESTO? 
 Yes 
 No 
 Undecided  


 
 
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Part C: At Study Completion for Naïve Patients 
 
1. Patient Study Number (to be entered by Study Coordinator)  
_________________________ 
2. Age (years)  
 
 
 
 
 
_________________________ 
3. City, Province 
 
 
 
 
 
_________________________ 
4. Date 
 
 
 
 
 
 
_________________________ 
 
5. Are you aware that the testosterone from gels or solutions that are normally applied to the skin (i.e. shoulders, upper arms, etc.) can 
accidentally get onto and through the skin of women and children, causing undesirable side effects, such as early puberty or masculinization 
(hair growth, voice changes)? 
 Yes 
 No 
 
6. Is being on the lowest effective dose of testosterone important to you? 
 Yes 
 No 
 
7. Please indicate if you agree or disagree with the following statements.  (Check one box per line). 
General Statements 
Strongly 
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
Not 
applicable 
NATESTO restores my testosterone levels back to a normal range 
 
 
 
 
 
 
NATESTO relieves my symptoms 
 
 
 
 
 
 
NATESTO has no/few side effects 
 
 
 
 
 
 
NATESTO is easy to administer/use 
 
 
 
 
 
 
NATESTO is the lowest dose of testosterone that will provide symptom relief 
 
 
 
 
 
 
NATESTO cannot be transferred to women and/or children 
 
 
 
 
 
 
NATESTO is affordable 
 
 
 
 
 
 
 
 


 
 
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Use Statements 
Strongly 
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
Not 
applicable 
I can take NATESTO at home without visiting my doctor 
 
 
 
 
 
 
The time it takes to use  NATESTO is acceptable/convenient 
 
 
 
 
 
 
Symptom Statements 
Strongly 
Agree 
Agree 
Neutral 
Disagree 
Strongly 
Disagree 
Not 
applicable 
NATESTO increased my sex drive 
 
 
 
 
 
 
NATESTO helps in achieving and/or maintaining an erection 
 
 
 
 
 
 
NATESTO reduced my body fat 
 
 
 
 
 
 
NATESTO increased my muscle/strength 
 
 
 
 
 
 
NATESTO increased my energy level  
 
 
 
 
 
 
 
 
 
 
 
NATESTO increased my physical activity level/vitality 
 
 
 
 
 
 
NATESTO reduced my loss of facial, underarm and/or pubic hair 
 
 
 
 
 
 
NATESTO improved my general feeling of well-being  
 
 
 
 
 
 
NATESTO helped me feel less depressed 
 
 
 
 
 
 
NATESTO helped  me to feel less irritable 
 
 
 
 
 
 
NATESTO improved my concentration 
 
 
 
 
 
 
NATESTO improved my ability to fall asleep/stay asleep 
 
 
 
 
 
 
 
 
8. How much would you be willing to pay out-of-pocket for NATESTO if your health insurance does not cover the full amount or you do not 
have health insurance?  (Select one) 
 Up to $25 per month 
 Up to $50 per month 
 Up to $75 per month 
 Up to $100 per month 
 Up to $150 per month 
 I would not pay anything out-of-pocket for NATESTO 
 
 


 
 
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9. What do you like about NATESTO?  
 
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
________________________________________________________________________________________________________ 
 
10. What do you dislike about NATESTO? 
 
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________
________________________________________________________________________________________________________ 
 
11. Following this study, do you plan to continue taking NATESTO? 
 Yes 
 No 
 Undecided  
 
 
 
 

SAP_001.pdf: 
Protocol #: NAT-2016-01 
Confidential 
SAP 
Acerus Pharmaceutical Corporation 
 
 
i 
 
 
 
 
 
 
 
Statistical Analysis Plan for Natesto™ 
 
Protocol #: NAT-2016-01 
 
A 150-DAY, PROSPECTIVE, PHASE 4, OPEN-LABEL STUDY, EVALUATING 
PATIENT SATISFACTION AND SYMPTOM IMPROVEMENT WHEN 
TREATING MALE HYPOGONADISM WITH TESTOSTERONE NASAL GEL 
(Natesto™) (MY-T STUDY)  
 
 
Investigational Product: Testosterone nasal gel 4.5% w/w (Natesto™) 
 
 
 
 
 
 
 
 
Prepared by:  
Chris Sigouin 
 
 
 
Biostatistician 
 
 
 
CMX Research Inc. 
 
 
 
 
Version: 
 
Final 
Date of Creation: 
October 17, 2017 
Last Updated:  
November 28, 2017 
 




Protocol #: NAT-2016-01 
Confidential 
SAP 
Acerus Pharmaceutical Corporation 
 
 
iii 
 
TABLE OF CONTENTS 
Page No. 
1.0 
INTRODUCTION ...................................................................................................................................... 6 
2.0 
STUDY OBJECTIVES ............................................................................................................................... 6 
2.1 
Primary Objective ................................................................................................................................... 6 
2.2 
Secondary Objectives .............................................................................................................................. 6 
2.3 
Exploratory Objectives ............................................................................................................................ 6 
3.0 
STUDY OVERVIEW ................................................................................................................................. 6 
Schedule of Procedures ....................................................................................................................................... 7 
4.0 
SAMPLE SIZE ........................................................................................................................................... 8 
5.0 
ANALYSIS ENDPOINTS .......................................................................................................................... 8 
5.1 
Primary Efficacy Endpoints..................................................................................................................... 8 
5.2 
Secondary Efficacy Endpoints ................................................................................................................. 8 
5.3 
Safety Endpoints ..................................................................................................................................... 9 
5.4 
Exploratory Endpoints ............................................................................................................................ 9 
6.0 
ANALYSIS POPULATION AND ANALYSIS SUBSETS .......................................................................... 9 
6.1 
All Participants Population ................................................................................................................... 10 
6.2 
BID Intent-to-Treat (ITT) Population .................................................................................................... 10 
6.3 
TID Intent-to-Treat (ITT) Population .................................................................................................... 10 
6.4 
Intent-to-Treat (ITT) Population ........................................................................................................... 10 
6.5 
Safety Population .................................................................................................................................. 10 
6.6 
BID Per-Protocol (PP) Population ......................................................................................................... 10 
6.7 
TID Per-Protocol (PP) Population ......................................................................................................... 10 
6.8 
Per-Protocol (PP) Population ................................................................................................................. 11 
7.0 
DATA CONVENTIONS .......................................................................................................................... 11 
7.1 
Definitions ............................................................................................................................................ 11 
7.2 
Visit Windows ...................................................................................................................................... 12 
7.3 
Missing Data ........................................................................................................................................ 12 
7.4 
Early Terminations ............................................................................................................................... 13 
8.0 
ANALYSIS STRATEGY ......................................................................................................................... 13 
9.0 
EFFICACY ANALYSES .......................................................................................................................... 13 
9.1 
Primary Efficacy Analyses .................................................................................................................... 13 
9.2 
Secondary Efficacy Analyses ................................................................................................................. 14 
9.3 
Exploratory Analyses ............................................................................................................................ 16 
10.0 
SAFETY ANALYSES .............................................................................................................................. 17 
10.1 
Adverse Events ..................................................................................................................................... 17 
10.2 
Laboratory Data .................................................................................................................................... 17 
10.3 
Testosterone Data ................................................................................................................................. 18 
10.4 
Vital Signs ............................................................................................................................................ 18 
10.5 
Physical Examination ........................................................................................................................... 19 
11.0 
COMPARABILITY ANALYSES ............................................................................................................. 19 
11.1 
Demographic Characteristics ................................................................................................................ 19 
11.2 
Disease Characteristics ......................................................................................................................... 19 
11.3 
Medical/Surgical History....................................................................................................................... 19 
11.4 
Study Duration ...................................................................................................................................... 19 
11.5 
Concomitant Medications ..................................................................................................................... 19 
12.0 
RANDOMIZATION AND BLINDING .................................................................................................... 20 
13.0 
INTERIM ANALYSIS ............................................................................................................................. 20 
14.0 
ANALYSIS PROGRAMS and SOFTWARE ............................................................................................. 20 


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15.0 
REFERENCES ......................................................................................................................................... 20 


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1.0 
INTRODUCTION 
 
This document provides a detailed description of the statistical methods and procedures to be 
implemented during the analysis of Acerus Pharmaceutical Corporation protocol # NAT-2016-01.  
The proposed methods and approaches to the data analysis should be viewed as flexible if the data 
suggest and warrant deviations from this plan.  However, any deviations from this analysis plan 
must be substantiated by sound statistical rationale and documented in the final clinical study 
report. 
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
The primary objective of the study is to measure patient satisfaction with testosterone replacement 
therapy before (for non-naïve patients), during and after treatment with NatestoTM. 
 
2.2 
Secondary Objectives 
 
The secondary objectives of this study are to evaluate the following:  
1. Improvement in hypogonadism symptoms 
2. Patient treatment preference versus prior testosterone replacement therapy 
3. Frequency of daily dose of NatestoTM 
4. Safety monitoring 
 
2.3 
Exploratory Objectives 
 
Exploratory objectives will include analysis of the rate of change of the primary or secondary 
efficacy measures over the treatment period be that 90 days for patients on NatestoTM BID or 120 
days for patients on NatestoTM TID. 
 
3.0 
STUDY OVERVIEW 
 
This is a phase 4, multi-centre study consisting of two study periods and a post study follow-up. 
 
90-Day Treatment Period: With potential extension by 30 days for those patients requiring a dose 
increase, as determined by the treating physician.  Participants receiving 122.5mg of NatestoTM 
(5.5 mg of testosterone) per nostril twice daily may have an increased daily dose adjustment on 
Day 90, based on their hypogonadism symptoms. 
 
1-Day Study Completion Period: Patient will return to the site for examination, discussion of 
symptoms with physician and questionnaire completion.  Serum testosterone levels will be 
determined for all patients on Day 90 (BID dose) and on Day 120 for the TID patients. 
 


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Post Study Follow-Up: All study patients will be followed up at Day 150 after the Treatment 
Phase to determine if they have continued using NATESTO and why (or why not?). 
 
 
Schedule of Procedures 
Study Phase 
Treatment Period 
 
Treatment 
Start 
Efficacy Analysis 
Post Study 
Follow Up 
Early 
Withdrawal/ 
Termination 
 
 
 
 
Day 0 
 
 
 
 
Day 30 
+/- 3 days 
 
 
 
Day 60 
+/- 3 days 
End of Study: 
BID Patients 
 
Day 90 
+/- 3 days 
End of Study: 
TID Patients 
 
Day 120 
+/- 3 days 
 
 
 
Day 150 
+/- 3 days 
 
Visit 
1 
2 
3 
4a 
5b 
6 
 
Location/Type 
clinic 
telephone telephone 
clinic 
 
clinic 
 
telephone 
clinic 
Study Procedures: 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
Medical history 
x 
 
 
x 
x 
 
 
Demographics 
x 
 
 
 
 
 
 
Physical examination +  nasal 
exam 
x 
 
 
x 
x 
 
x 
Height and weight 
x 
 
 
x 
x 
 
x 
Vital signs (HR, BP, RR, and 
temperature) 
x 
 
 
x 
x 
 
x 
Serum total testosterone plus 
safety labs 
xc 
 
 
x 
xd 
 
x 
Participant training on NATESTO 
administration 
x 
 
 
 
 
 
 
Provide Study Drug Access Card 
for NATESTO  
x 
 
 
 
 
 
 
Provide Pharmacy Prescription  
x 
 
 
xg 
 
 
 
Potential study drug daily dose 
increase to TID 
 
 
 
x 
 
 
 
TSQM 
xe 
x 
x 
x 
x 
 
x 
qADAM 
xf 
x 
x 
x 
x 
 
x 
Patient Preference + Use 
x 
 
 
x 
x 
 
x 
Concomitant medications 
x 
x 
x 
x 
x 
 
x 
Assess adverse events 
x 
x 
x 
x 
x 
 
x 
Assess voluntary treatment 
continuation 
 
 
 
 
 
x 
 
 
a.  All patients are required to complete Visit 4  
b.  Only patients assigned to NATESTO TID are required to complete Visit 5 
c.  Naïve patients will require confirmation of hypogonadism by serum testosterone within the last 6 months 
d.  Only patients who continued on TID  
e.  TSQM to be completed by non-naïve patients only 
f.  qADAM to be completed by all patients 
g.  Patients who are assigned to NATESTO TID will be provided with a new Pharmacy Prescription increasing their dosage to TID 


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4.0 
SAMPLE SIZE 
 
A sample size of approximately 100 participants will be selected to provide a sufficient number of 
participants for the analysis. Since this is an observational study, no formal sample size calculation 
will be performed.  Interim analysis and sample size re-estimation may be performed after results 
are acquired from 50 and 75 patients.  
 
5.0 
ANALYSIS ENDPOINTS 
 
5.1 
Primary Efficacy Endpoints 
 
Primary efficacy is the self-reported patient satisfaction with treatment assessed by the Treatment 
Satisfaction Questionnaire for Medication (TSQM), a validated, 9-item instrument with domains 
for Effectiveness, Convenience and Global Satisfaction.   
 
The primary efficacy endpoints are: 
• change in satisfaction for each TSQM domain from Visit 1 (Day 0) to Visit 4 (Day 
90) for non-naïve BID patients  
• change in satisfaction for each TSQM domain from Visit 1 (Day 0) to Visit 5 (Day 
120) for non-naïve TID patients 
 
5.2 
Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints are: 
• change in satisfaction for each TSQM domain from Visit 2 (Day 30) to Visit 4 
(Day 90) for naïve BID patients 
• change in satisfaction for each TSQM domain from Visit 2 (Day 30) to Visit 5 
(Day 120) for naïve TID patients 
 
• change in total qADAM score from Visit 1 (Day 0) to Visit 4 (Day 90) for non-
naïve BID patients 
• change in total qADAM score from Visit 1 (Day 0) to Visit 5 (Day 120) for non-
naïve TID patients  
• change in total qADAM score from Visit 1 (Day 0) to Visit 4 (Day 90) for naïve 
BID patients 
• change in total qADAM score from Visit 1 (Day 0) to Visit 5 (Day 120) for naïve 
TID patients 
• change in total qADAM score from Visit 1 (Day 0) to Visit 5 (Day 120) for non-
naïve ALL patients 
• change in total qADAM score from Visit 1 (Day 0) to Visit 5 (Day 120) for naïve 
ALL patients 
• change in total qADAM score from Visit 1 (Day 0) to Visit 5 (Day 120) for non-
naïve and naïve ALL patients 


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• patient preference of therapy as measured by Part A of the Treatment Preference 
and Use Questionnaire at Visit 1 (Day 0) for the following groups of patients: 
o non-naïve and naive ALL 
o non-naïve ALL 
o naïve ALL 
o non-naïve BID 
o naïve BID 
o non-naïve TID 
o naïve TID 
• patient preference of therapy as measured by Part B of the Treatment Preference 
and Use Questionnaire for the following groups of non-naïve patients: 
o BID at Visit 4 (Day 90) 
o TID at Visit 4 (Day 90) 
o TID at Visit 5 (Day 120) 
• patient preference of therapy as measured by Part C of the Treatment Preference 
and Use Questionnaire for the following groups of naïve patients: 
o BID at Visit 4 (Day 90) 
o TID at Visit 4 (Day 90) 
o TID at Visit 5 (Day 120) 
• NatestoTM dosing frequency by hypogonadism treatment status (naïve/non-naïve) 
assigned at Visit 4 (Day 90) 
 
5.3 
Safety Endpoints 
 
Safety endpoints will include: 
• adverse events recorded during the study 
• clinical laboratory measurements at Visit 1 (Day 0), Visit 4 (Day 90) , Visit 5 (Day 
120) and Early Termination 
• vitals sign measurements at Visit 1 (Day 0), Visit 4 (Day 90), Visit 5 (Day 120) 
and Early Termination 
• physical examination at Visit 1 (Day 0), Visit 4 (Day 90), Visit 5 (Day 120), and 
Early Termination 
 
5.4 
Exploratory Endpoints 
 
Exploratory endpoints will include: 
• change in satisfaction for each TSQM domain from Visit 1 (Day 0) to Visit 5 (Day 
120) for non-naïve ALL patients  
• change in satisfaction for each TSQM domain from Visit 2 (Day 30) to Visit 5 
(Day 120) for naïve ALL patients 
 
6.0 
ANALYSIS POPULATION AND ANALYSIS SUBSETS 
 


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6.1 
All Participants Population 
 
The All Participants population includes all patients who signed the informed consent form and 
were entered into the MY-T study web-based application. Study enrollment and patient 
disposition will be reported using the All Participants population. 
 
6.2 
BID Intent-to-Treat (ITT) Population 
 
The BID ITT population includes all patients who received at least one dose of study drug, are 
part of the BID treatment group and have a valid post-dose efficacy measurement at Visit 2 (Day 
30) or Visit 3 (Day 60) or Visit 4 (Day 90).  Data will be analysed using the BID ITT population 
as per the Table Mock-Up (TMU) document. 
 
6.3 
TID Intent-to-Treat (ITT) Population 
 
The TID ITT population includes all patients who received at least one dose of study drug, are 
part of the TID treatment group and have a valid post-dose efficacy measurement at Visit 2 (Day 
30) or Visit 3 (Day 60) or Visit 4 (Day 90) or Visit 5 (Day 120).  Data will be analysed using the 
TID ITT population as per the Table Mock-Up (TMU) document. 
 
6.4 
Intent-to-Treat (ITT) Population 
 
The ITT population includes all patients who are included in either the BID ITT or TID ITT 
population.  Data will be analysed using the ITT population as per the Table Mock-Up (TMU) 
document. 
 
6.5 
Safety Population 
 
The Safety population includes all patients who received at least one dose of the study drug.  All 
safety data including adverse events, physical examination parameters, vital signs, total 
testosterone and laboratory data will be analysed using the Safety population. 
 
6.6 
BID Per-Protocol (PP) Population 
 
The BID PP population includes all BID ITT patients who completed the 90-day (Visit 4) 
Treatment Period without any major protocol deviations.  Data will be analysed using the BID PP 
population as per the Table Mock-Up (TMU) document. 
 
6.7 
TID Per-Protocol (PP) Population 
 
The TID PP population includes all TID ITT patients who completed the 120-day (Visit 5) 
Treatment Period without any major protocol deviations.  Data will be analysed using the TID PP 
population as per the Table Mock-Up (TMU) document. 
 


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6.8 
Per-Protocol (PP) Population 
 
The PP population includes all patients who are included in either the BID PP or TID PP 
population.  Data will be analysed using the PP population as per the Table Mock-Up (TMU) 
document. 
 
7.0 
DATA CONVENTIONS 
 
7.1 
Definitions 
 
Visit 1 (Day 0) is defined as the day in which the patient provides informed consent and starts the 
study.  All study days are determined relative to Visit 1 (Day 0).  
 
End of treatment is defined as the day on which the last dose of treatment is taken.  This date was 
not collected for this study. 
 
End of study is defined as the last day on which data were collected from the patient. Using the 
Early Termination Visit eCRF, it is the date of early termination.  Using the Visit 6 - Post Study 
Follow-Up (Day 150) eCRF, it is the post study follow-up date.  Otherwise, it is the date of last 
contact, if the patient was lost to follow-up, or the date of death, if the patient died.  
 
Baseline serum testosterone values will be defined as those values recorded on Visit 1 (Day 0).  
Naive patients were asked for 2 measurements (average used in analysis) and non-naive patients 
were asked for 1 measurement at Baseline (Visit 1/Day 0). 
 
Serum Testosterone will be reported in (nmol/L).  If value is reported in (ng/dL) then value will 
be multiplied by 0.0347 to convert to (nmol/L). 
 
Testosterone collected in (pmol/L) will be considered Free Testosterone and will not be used in 
any analyses. 
 
Hematocrit will be reported in (%).  Values will be multiplied by 1 and if the value is less than 1 
then the value will be multiplied by 100. 
 
Total Cholesterol will be reported in (mmol/L).  If value is reported in (mg/dL) then value will be 
divided by 38.67 to convert to (mmol/L). 
 
LDL will be reported in (mmol/L). If value is reported in (mg/dL) then value will be divided by 
38.67 to convert to (mmol/L). 
 
HDL will be reported in (mmol/L). If value is reported in (mg/dL) then value will be divided by 
38.67 to convert to (mmol/L). 
 


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Triglycerides will be reported in (mmol/L).  If value is reported in (mg/dL) then value will be 
divided by 88.57 to convert to (mmol/L). 
 
Hemoglobin will be reported in (g/L).  If value is reported in (g/dL) then value will be divided by 
0.1 to convert to (g/L). 
 
ALT and AST will be reported in (U/L). 
 
Study duration (days) will be defined as the (end of study date – date of informed consent + 1). 
 
The ALL treatment group will be defined as patients who were either naïve or non-naïve. 
 
The BID treatment group will be defined as patients who were either naïve or non-naïve and did 
not titrate to TID (Visit 5/Day 120). 
 
The TID treatment group will be defined as patients who were either naïve or non-naïve and did 
titrate up to TID (Visit 5/Day 120). 
 
7.2 
Visit Windows 
 
The visit window for all post baseline visits was a +3 day window relative to the expected nominal 
time point except for Early Termination visit. For example, Visit 2 is Day 30±3. For the purpose 
of the statistical analyses data entered at the nominal time points will be used (Visit 1/Day 0, Visit 
2/Day 30, Visit 3/Day 60, Visit 4/Day 90, Visit 5/Day 120, Visit 6/Day 150 and Early 
Termination). 
 
7.3 
Missing Data 
 
Dates with missing day will be imputed as the 15th.  Dates will both missing day and month will be 
imputed as July 1st.  Date of hypogonadism diagnosis will be imputed. 
 
Missing TSQM domain scores for both the BID and TID treatment groups will be imputed using 
LOCF (Last Observation Carried Forward).  For LOCF to apply there must be at least a Visit 2 
domain score available so that the patient had sufficient exposure to give a measurable change. 
The TSQM domain scores will be calculated based on the LOCF domain.  Summaries for paired 
change from Visit 1/Day 0 will require both TSQM domain scores at Visit 1/Day 0 and Visit 
2/Day 30 to be available to be included in output. Summaries for paired change from Visit 2/Day 
30 will require the TSQM domain scores at Visit 2/Day 30 to be available to be included in 
output. 
 
Missing qADAM questions for both the BID and TID treatment groups will be imputed using 
LOCF (Last Observation Carried Forward).  For LOCF to apply there must be at least a Visit 2 
question available so that the patient had sufficient exposure to give a measurable change.  The 
total qADAM score will be calculated based on the LOCF items. Summaries for paired change 


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from Visit 1/Day 0 will require both total qADAM scores at Visit 1/Day 0 and Visit 2/Day 30 to 
be available to be included in output. 
 
7.4 
Early Terminations 
 
Patients who withdraw from the study before Visit 6 (Day 150) are considered “early 
terminations.” 
 
8.0 
ANALYSIS STRATEGY 
 
A Table Mock-Up (TMU) document which will illustrate the details of presentation and analysis 
for data collected in this study will accompany this document.  A brief discussion of the 
presentation, planned inferences, and statistical methods follows below.  Data not presented in the 
TMU document will be provided in listings. 
 
Continuous variables will be summarized descriptively by number of observations, number of 
missing observations, mean, standard deviation, median, 1st quartile, 3rd quartile, minimum and 
maximum.  Categorical variables will be summarized descriptively as frequency counts and 
percentages. 
 
A number of p-values may be presented in the reported tables for exploratory purposes.  
Statistical testing will be performed at the two-sided 0.05 significance level unless otherwise 
specified in the sections that follow.  These p-values will not be adjusted for multiple 
comparisons. 
 
9.0 
EFFICACY ANALYSES 
 
9.1 
Primary Efficacy Analyses 
 
The primary efficacy analyses will be performed using the ITT and the respective PP populations.  
 
BID Treatment Group: 
TSQM domain scores at Visit1, Visit 2, Visit 3 and Visit 4 will be summarized and presented 
descriptively for non-naïve patients. There are three domains which include effectiveness (3 
items), convenience (3 items) and global satisfaction (3 items). 
 
TSQM domain change from baseline (Visit 1) scores at Visit 2, Visit 3 and Visit 4 (primary 
endpoint) will be summarized and presented descriptively for non-naïve patients using 2 different 
approaches, LOCF and no LOCF.  Change from baseline scores will be analysed using a two-
sided paired t-test or a non-parametric equivalent if warranted by the data. 
 
TID Treatment Group: 


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TSQM domain scores at Visit 1, Visit 2, Visit 3, Visit 4 and Visit 5 will be summarized and 
presented descriptively for non-naïve patients. There are three domains which include 
effectiveness (3 items), convenience (3 items) and global satisfaction (3 items). 
 
TSQM domain change from baseline (Visit 1) scores at Visit 2, Visit 3, Visit 4 and Visit 5 
(primary endpoint) will be summarized and presented descriptively for non-naïve patients using 2 
different approaches, LOCF and no LOCF.  Change from baseline scores will be analysed using a 
two-sided paired t-test or a non-parametric equivalent if warranted by the data. 
 
9.2 
Secondary Efficacy Analyses 
 
The following secondary efficacy analyses will be performed using the ITT and the respective PP 
populations where indicated. 
 
BID Treatment Group: 
TSQM domain scores at Visit 2, Visit 3 and Visit 4 will be summarized and presented 
descriptively for naïve patients. There are three domains which include effectiveness (3 items), 
convenience (3 items) and global satisfaction (3 items). (ITT/PP) 
 
TSQM domain change from baseline (Visit 2) scores at Visit 3 and Visit 4 (secondary endpoint) 
will be summarized and presented descriptively for naïve patients using 2 different approaches, 
LOCF and no LOCF.  Change from baseline scores will be analysed using a two-sided paired t-
test or a non-parametric equivalent if warranted by the data. (ITT/PP) 
 
Total qADAM scores at Visit 1, Visit 2, Visit 3 and Visit 4 will be summarized and presented 
descriptively for non-naïve patients. (ITT/PP) 
 
Total qADAM change from baseline (Visit 1) scores at Visit 2, Visit 3 and Visit 4 will be 
summarized and presented descriptively for non-naïve patients using 2 different approaches, 
LOCF and no LOCF.  Change from baseline scores will be analysed using a two-sided paired t-
test or a non-parametric equivalent if warranted by the data. (ITT/PP) 
 
Total qADAM scores at Visit 1, Visit 2, Visit 3 and Visit 4 will be summarized and presented 
descriptively for naïve patients. (ITT/PP) 
 
Total qADAM change from baseline (Visit 1) scores at Visit 2, Visit 3 and Visit 4 will be 
summarized and presented descriptively for naïve patients using 2 different approaches, LOCF 
and no LOCF.  Change from baseline scores will be analysed using a two-sided paired t-test or a 
non-parametric equivalent if warranted by the data. (ITT/PP) 
 
Part A questions 5, 6, 7, 8, 9, 10 and 11 of the Patient Preference and Use Questionnaire at Visit 
1 will be summarized and presented descriptively/categorically for non-naïve and naïve patients. 
(ITT) 
 


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TID Treatment Group: 
TSQM domain scores at Visit 2, Visit 3, Visit 4 and Visit 5 will be summarized and presented 
descriptively for naïve patients. There are three domains which include effectiveness (3 items), 
convenience (3 items) and global satisfaction (3 items). (ITT/PP) 
 
TSQM domain change from baseline (Visit 2) scores at Visit 3, Visit 4 and Visit 5 (secondary 
endpoint) will be summarized and presented descriptively for naïve patients using 2 different 
approaches, LOCF and no LOCF.  Change from baseline scores will be analysed using a two-
sided paired t-test or a non-parametric equivalent if warranted by the data. (ITT/PP) 
 
Total qADAM scores at Visit 1, Visit 2, Visit 3, Visit 4 and Visit 5 will be summarized and 
presented descriptively for non-naïve patients. (ITT/PP) 
 
Total qADAM change from baseline (Visit 1) scores at Visit 2, Visit 3, Visit 4 and Visit 5 will be 
summarized and presented descriptively for non-naïve patients using 2 different approaches, 
LOCF and no LOCF.  Change from baseline scores will be analysed using a two-sided paired t-
test or a non-parametric equivalent if warranted by the data. (ITT/PP) 
 
Total qADAM scores at Visit 1, Visit 2, Visit 3, Visit 4 and Visit 5 will be summarized and 
presented descriptively for naïve patients. (ITT/PP) 
 
Total qADAM change from baseline (Visit 1) scores at Visit 2, Visit 3, Visit 4 and Visit 5 will be 
summarized and presented descriptively for naïve patients using 2 different approaches, LOCF 
and no LOCF.  Change from baseline scores will be analysed using a two-sided paired t-test or a 
non-parametric equivalent if warranted by the data. (ITT/PP) 
 
Part A questions 5, 6, 7, 8, 9, 10 and 11 of the Patient Preference and Use Questionnaire at Visit 
1 will be summarized and presented descriptively/categorically for non-naïve and naïve patients. 
(ITT) 
 
ALL Treatment Group: 
Total qADAM scores at Visit 1, Visit 2, Visit 3, Visit 4 and Visit 5 will be summarized and 
presented descriptively for non-naïve patients. (ITT/PP) 
 
Total qADAM change from baseline (Visit 1) scores at Visit 2, Visit 3, Visit 4 and Visit 5 will be 
summarized and presented descriptively for non-naïve patients using 2 different approaches, 
LOCF and no LOCF.  Change from baseline scores will be analysed using a two-sided paired t-
test or a non-parametric equivalent if warranted by the data. (ITT/PP) 
 
Total qADAM scores at Visit 1, Visit 2, Visit 3, Visit 4 and Visit 5 will be summarized and 
presented descriptively for naïve patients. (ITT/PP) 
 
Total qADAM change from baseline (Visit 1) scores at Visit 2, Visit 3, Visit 4 and Visit 5 will be 
summarized and presented descriptively for naïve patients using 2 different approaches, LOCF 


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and no LOCF.  Change from baseline scores will be analysed using a two-sided paired t-test or a 
non-parametric equivalent if warranted by the data. (ITT/PP) 
 
Total qADAM scores at Visit 1, Visit 2, Visit 3, Visit 4 and Visit 5 will be summarized and 
presented descriptively for non-naïve and naïve patients combined. (ITT/PP) 
 
Total qADAM change from baseline (Visit 1) scores at Visit 2, Visit 3, Visit 4 and Visit 5 will be 
summarized and presented descriptively for non-naïve and naïve patients combined using 2 
different approaches, LOCF and no LOCF.  Change from baseline scores will be analysed using a 
two-sided paired t-test or a non-parametric equivalent if warranted by the data. (ITT/PP) 
 
Part A questions 5, 6, 7, 8, 9, 10 and 11 of the Patient Preference and Use Questionnaire at Visit 
1 will be summarized and presented descriptively/categorically for non-naïve, naïve, and non-
naïve and naïve patients combined. (ITT) 
 
Various Treatment Groups: 
Part B questions 5, 6, 7, 8, 9 and 12 of the Patient Preference and Use Questionnaire will be 
summarized and presented descriptively/categorically for non-naïve patients for the following 
groups and time points: 
• BID at Visit 4 (ITT) 
• TID at Visit 4 (ITT) 
• TID at Visit 5 (ITT) 
 
Part B questions 5, 6, 7, 8 and 11 of the Patient Preference and Use Questionnaire will be 
summarized and presented descriptively/categorically for naïve patients for the following groups 
and time points: 
• BID at Visit 4 (ITT) 
• TID at Visit 4 (ITT) 
• TID at Visit 5 (ITT) 
 
NatestoTM dosing frequency (BID/TID) by hypogonadism treatment status (naïve/non-naïve) 
assigned at Visit 4 will be summarized and presented categorically for non-naïve and naïve 
patients combined. (ITT/PP) 
 
9.3 
Exploratory Analyses 
 
ALL Treatment Group: 
TSQM domain scores at Visit 1, Visit 2, Visit 3, Visit 4 and Visit 5 will be summarized and 
presented descriptively for non-naïve patients. There are three domains which include 
effectiveness (3 items), convenience (3 items) and global satisfaction (3 items). 
 
TSQM domain change from baseline (Visit 1) scores at Visit 2, Visit 3, Visit 4 and Visit 5 will be 
summarized and presented descriptively for non-naïve patients using 2 different approaches, 
LOCF and no LOCF.  Change from baseline scores will be analysed using a two-sided paired t-
test or a non-parametric equivalent if warranted by the data. 


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TSQM domain scores at Visit 2, Visit 3, Visit 4 and Visit 5 will be summarized and presented 
descriptively for naïve patients. There are three domains which include effectiveness (3 items), 
convenience (3 items) and global satisfaction (3 items). 
 
TSQM domain change from baseline (Visit 2) scores at Visit 3, Visit 4 and Visit 5 will be 
summarized and presented descriptively for naïve patients using 2 different approaches, LOCF 
and no LOCF.  Change from baseline scores will be analysed using a two-sided paired t-test or a 
non-parametric equivalent if warranted by the data. 
 
10.0 
SAFETY ANALYSES 
 
The following safety analyses will be performed using the Safety population. 
 
10.1 
Adverse Events 
 
Adverse event data will be tabulated separately for each treatment group (ALL, BID, TID) by 
system organ class and preferred term. Adverse events will be summarized by presenting counts 
and percentage of patients (each patient contributes a single count to a category) and the total 
number of events in each system organ class and in each system organ class/preferred term. 
 
In addition, adverse event data with a possible drug relationship (possible, probable, definitely 
related) will be tabulated separately for each treatment group (ALL, BID, TID) by system organ 
class and preferred term. Adverse events will be summarized in a similar manner as above. 
 
As well, adverse event data will be tabulated separately for each treatment group (ALL, BID, 
TID) by system organ class, preferred term and severity (mild, moderate, severe). Adverse events 
will be summarized by presenting counts and percentage of patients (each patient contributes a 
single count to a category) and the total number of events in each system organ class by severity 
and in each system organ class/preferred term by severity. 
 
The Medical Dictionary for Regulatory Activities (MedDRA™ version 20.1) will be utilized for 
the coding of adverse events.  
 
All adverse events that occurred on or after the date of informed consent up to 30 days after the 
end of study date will be summarized. 
 
Serious adverse events will not be tabulated due to the expected small number of events. 
Narratives will be provided for serious adverse events. 
 
10.2 
Laboratory Data 
 
Laboratory data (Hematocrit (%), Total Cholesterol (mmol/L),  LDL (mmol/L),  HDL (mmol/L), 
Triglycerides (mmol/L), Hemoglobin (g/L), ALT (U/L), AST (U/L)) at Visit 1, Visit 4, Visit 5 


Protocol #: NAT-2016-01 
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Acerus Pharmaceutical Corporation 
 
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and Early Terminations will be summarized and presented descriptively for the ALL and TID 
treatment groups.  
 
Laboratory data change from baseline (Visit 1) results at Visit 4, Visit 5 and Early Terminations 
will be summarized and presented descriptively for the ALL and TID treatment groups.  Change 
from baseline results will be analysed using a two-sided paired t-test or a non-parametric 
equivalent if warranted by the data. 
 
Laboratory data (Hematocrit (%), Total Cholesterol (mmol/L),  LDL (mmol/L),  HDL (mmol/L), 
Triglycerides (mmol/L), Hemoglobin (g/L), ALT (U/L), AST (U/L)) at Visit 1, Visit 4 and Early 
Terminations will be summarized and presented descriptively for the BID treatment group.  
 
Laboratory data change from baseline (Visit 1) results at Visit 4 and Early Terminations will be 
summarized and presented descriptively for the BID treatment group.  Change from baseline 
results will be analysed using a two-sided paired t-test or a non-parametric equivalent if warranted 
by the data. 
 
10.3 
Testosterone Data 
 
Testosterone data (nmol/L) at Visit 1, Visit 4, Visit 5 and Early Terminations will be summarized 
and presented descriptively for the non-naïve TID, naïve TID, non-naïve ALL, naïve ALL and the 
non-naïve and naïve combined ALL treatment groups.  
 
Testosterone data change from baseline (Visit 1) results at Visit 4, Visit 5 and Early Terminations 
will be summarized and presented descriptively for the non-naïve TID, naïve TID, non-naïve 
ALL, naïve ALL and the non-naïve and naïve combined ALL treatment groups.  Change from 
baseline results will be analysed using a two-sided paired t-test or a non-parametric equivalent if 
warranted by the data. 
 
Testosterone data (nmol/L) at Visit 1, Visit 4, Visit 5 and Early Terminations will be summarized 
and presented descriptively for the non-naïve BID and naïve BID treatment groups.  
 
Testosterone data change from baseline (Visit 1) results at Visit 4, Visit 5 and Early Terminations 
will be summarized and presented descriptively for the non-naïve BID and naïve BID treatment 
groups.  Change from baseline results will be analysed using a two-sided paired t-test or a non-
parametric equivalent if warranted by the data. 
 
10.4 
Vital Signs 
 
Vital signs (Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Heart Rate 
(beats/minute), Oral/Tympanic Temperature (Celcuis), BMI (kg/m*m)) at Visit 1, Visit 4 and 
Early Terminations will be summarized and presented descriptively for the BID treatment group.  
 
Vital signs (Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Heart Rate 
(beats/minute), Oral/Tympanic Temperature (Celcuis), BMI (kg/m*m)) at Visit 1, Visit 4, Visit 5 


Protocol #: NAT-2016-01 
Confidential 
SAP 
Acerus Pharmaceutical Corporation 
 
18 
 
and Early Terminations will be summarized and presented descriptively for the ALL and TID 
treatment groups.  
 
10.5 
Physical Examination 
 
Physical examination (General Appearance, Skin, Nose, Head/Neck, Heart, Lungs, Abdomen, 
Neuromuscular, Extremities, Other) at Visit 1, Visit 4, Visit 5 and Early Terminations will be 
summarized and presented categorically for the ALL treatment group.  
 
11.0 
COMPARABILITY ANALYSES 
 
11.1 
Demographic Characteristics 
 
Quantitative and/or categorical summaries will be presented for age, height, weight, bmi, race, 
patient smoke and patient drink alcohol by overall, naïve and non-naïve patients. 
 
11.2 
Disease Characteristics 
 
Quantitative and/or categorical summaries will be presented for hypogonadal treatment status, 
baseline testosterone, and age of hypogonadism diagnosis by overall, naïve and non-naïve 
patients. 
 
11.3 
Medical/Surgical History 
 
Categorical summaries (% yes) will be presented for each body system by overall, naïve and non-
naïve patients. 
 
11.4 
Study Duration 
 
Quantitative summaries will be presented for study duration (days) by overall, naïve and non-
naïve patients. 
 
11.5 
Concomitant Medications 
 
Concomitant medications will be recorded at Day 0 (Visit 1) and reviewed at each subsequent 
visit until the end of study.  All medications taken 30 days prior to Day 0 (Visit 1) and during the 
study period will be tabulated.  Numbers and percentages of overall, naïve and non-naïve patients 
will be presented for concomitant medication data levels 3 and 5. Medication will be coded using 
the Anatomical-Therapeutic-Chemical (ATC) classification text from the WHO Drug Dictionary 
version January 2017.   
 


Protocol #: NAT-2016-01 
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Acerus Pharmaceutical Corporation 
 
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12.0 
RANDOMIZATION AND BLINDING 
 
This was a phase 4 open-label study. Randomization and blinding was not performed. 
 
13.0 
INTERIM ANALYSIS 
 
As stated in the protocol an interim analysis and sample size re-estimation may be performed after 
results are acquired from 50 and 75 patients. 
 
14.0 
ANALYSIS PROGRAMS and SOFTWARE 
 
SAS Version 9.2 or higher will be utilized for all analyses, data listings and figures.   
 
The biostatistician will specify all summary programs for the study in a Table Mock-Up (TMU) 
document with Sponsor sign-off.  The biostatistician will implement these specifications and then 
validate the output of each summary program.  The same biostatistician will create a separate 
validation program for each summary output and the output from the summary program and the 
validation program will be compared.  
 
15.0 
REFERENCES 
 
Not applicable.